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The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the
Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research
(CNRS) on its electronic publishing platform I-Revues.
Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open
access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.
It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more
traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology, and
educational items in the various related topics for students in Medicine and in Sciences.
Editorial correspondance
Jean-Loup Huret Genetics, Department of Medical Information,
University Hospital
F-86021 Poitiers, France
tel +33 5 49 44 45 46 or +33 5 49 45 47 67
[email protected] or [email protected]
Staff Mohammad Ahmad, Mélanie Arsaban, Houa Delabrousse, Marie-Christine Jacquemot-Perbal, Maureen Labarussias,
Vanessa Le Berre, Anne Malo, Catherine Morel-Pair, Laurent Rassinoux, Sylvie Yau Chun Wan - Senon, Alain
Zasadzinski.
Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy
Institute – Villejuif – France).
The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 12 times a year
by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French
National Center for Scientific Research (INIST-CNRS) since 2008.
The Atlas is hosted by INIST-CNRS (http://www.inist.fr)
http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Editor
Jean-Loup Huret
(Poitiers, France)
Editorial Board
Sreeparna Banerjee (Ankara, Turkey) Solid Tumours Section
Alessandro Beghini (Milan, Italy) Genes Section
Anne von Bergh (Rotterdam, The Netherlands) Genes / Leukaemia Sections
Judith Bovée (Leiden, The Netherlands) Solid Tumours Section
Vasantha Brito-Babapulle (London, UK) Leukaemia Section
Charles Buys (Groningen, The Netherlands) Deep Insights Section
Anne Marie Capodano (Marseille, France) Solid Tumours Section
Fei Chen (Morgantown, West Virginia) Genes / Deep Insights Sections
Antonio Cuneo (Ferrara, Italy) Leukaemia Section
Paola Dal Cin (Boston, Massachussetts) Genes / Solid Tumours Section
Louis Dallaire (Montreal, Canada) Education Section
Brigitte Debuire (Villejuif, France) Deep Insights Section
François Desangles (Paris, France) Leukaemia / Solid Tumours Sections
Enric Domingo-Villanueva (London, UK) Solid Tumours Section
Ayse Erson (Ankara, Turkey) Solid Tumours Section
Richard Gatti (Los Angeles, California) Cancer-Prone Diseases / Deep Insights Sections
Ad Geurts van Kessel (Nijmegen, The Netherlands) Cancer-Prone Diseases Section
Oskar Haas (Vienna, Austria) Genes / Leukaemia Sections
Anne Hagemeijer (Leuven, Belgium) Deep Insights Section
Nyla Heerema (Colombus, Ohio) Leukaemia Section
Jim Heighway (Liverpool, UK) Genes / Deep Insights Sections
Sakari Knuutila (Helsinki, Finland) Deep Insights Section
Lidia Larizza (Milano, Italy) Solid Tumours Section
Lisa Lee-Jones (Newcastle, UK) Solid Tumours Section
Edmond Ma (Hong Kong, China) Leukaemia Section
Roderick McLeod (Braunschweig, Germany) Deep Insights / Education Sections
Cristina Mecucci (Perugia, Italy) Genes / Leukaemia Sections
Yasmin Mehraein (Homburg, Germany) Cancer-Prone Diseases Section
Fredrik Mertens (Lund, Sweden) Solid Tumours Section
Konstantin Miller (Hannover, Germany) Education Section
Felix Mitelman (Lund, Sweden) Deep Insights Section
Hossain Mossafa (Cergy Pontoise, France) Leukaemia Section
Stefan Nagel (Braunschweig, Germany) Deep Insights / Education Sections
Florence Pedeutour (Nice, France) Genes / Solid Tumours Sections
Elizabeth Petty (Ann Harbor, Michigan) Deep Insights Section
Susana Raimondi (Memphis, Tennesse) Genes / Leukaemia Section
Mariano Rocchi (Bari, Italy) Genes Section
Alain Sarasin (Villejuif, France) Cancer-Prone Diseases Section
Albert Schinzel (Schwerzenbach, Switzerland) Education Section
Clelia Storlazzi (Bari, Italy) Genes Section
Sabine Strehl (Vienna, Austria) Genes / Leukaemia Sections
Nancy Uhrhammer (Clermont Ferrand, France) Genes / Cancer-Prone Diseases Sections
Dan Van Dyke (Rochester, Minnesota) Education Section
Roberta Vanni (Montserrato, Italy) Solid Tumours Section
Franck Viguié (Paris, France) Leukaemia Section
José Luis Vizmanos (Pamplona, Spain) Leukaemia Section
Thomas Wan (Hong Kong, China) Genes / Leukaemia Sections
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Volume 14, Number 3, March 2010
Table of contents
Gene Section
MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian)) 235 Celio Pouponnot, Alain Eychène
MAP3K7 (mitogen-activated protein kinase kinase kinase 7) 238 Hui Hui Tang, Kam C Yeung
MCPH1 (microcephalin 1) 243 Yulong Liang, Shiaw-Yih Lin, Kaiyi Li
NKX3-1 (NK3 homeobox 1) 246 Liang-Nian Song, Edward P Gelmann
PLXNB1 (plexin B1) 249 José Javier Gómez-Román, Montserrat Nicolas Martínez,
Servando Lazuén Fernández, José Fernando Val-Bernal
RUVBL1 (RuvB-like 1 (E. coli)) 254 Valérie Haurie, Aude Grigoletto, Jean Rosenbaum
RUVBL2 (RuvB-like 2 (E. coli)) 257 Aude Grigoletto, Valérie Haurie, Jean Rosenbaum
SH3GL2 (SH3-domain GRB2-like 2) 260 Chinmay Kr Panda, Amlan Ghosh, Guru Prasad Maiti
TOPORS (topoisomerase I binding, arginine/serine-rich) 263 Jafar Sharif, Asami Tsuboi, Haruhiko Koseki
TRPV6 (transient receptor potential cation channel, subfamily V, member 6) 267 Yoshiro Suzuki, Matthias A Hediger
ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) 270 Shian-Ying Sung
CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1) 275 Maria Norlin
EPHA3 (EPH receptor A3) 279 Brett Stringer, Bryan Day, Jennifer McCarron, Martin Lackmann, Andrew Boyd
JAZF1 (JAZF zinc finger 1) 286 Hui Li, Jeffrey Sklar
LPAR1 (lysophosphatidic acid receptor 1) 289 Mandi M Murph, Harish Radhakrishna
PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) 293 Montserrat Sanchez-Cespedes
SFRP4 (Secreted Frizzled-Related Protein 4) 296 Kendra S Carmon, David S Loose
SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)) 301 Stephen Hiscox
t(11;14)(q13;q32) in multiple myeloma Huret JL, Laï JL
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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TACC3 (transforming, acidic coiled-coil containing protein 3) 305 Melissa R Eslinger, Brenda Lauffart, Ivan H Still
TP53INP1 (tumor protein p53 inducible nuclear protein 1) 311 Mylène Seux, Alice Carrier, Juan Iovanna, Nelson Dusetti
Leukaemia Section
del(5q) in myeloid neoplasms 314 Kazunori Kanehira, Rhett P Ketterling, Daniel L Van Dyke
t(11;11)(q13;q23) 317 Jean-Loup Huret
t(11;19)(q23;p13.3) MLL/ACER1 319 Jean-Loup Huret
t(2;5)(p21;q33) 320 Jean-Loup Huret
Solid Tumour Section
Head and Neck: Ear: Endolymphatic Sac Tumor (ELST) 321 Rodney C Diaz
Lymphangioleiomyoma 327 Connie G Glasgow, Angelo M Taveira-DaSilva, Joel Moss
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 235
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian)) Celio Pouponnot, Alain Eychène
Institut Curie, CNRS UMR 146, F-91405 Orsay, France (CP, AE)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/MAFAID41235ch8q24.html DOI: 10.4267/2042/44698
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: RIPE3b1; KLRG1; Maf-A,: hMafA; L-
Maf
HGNC (Hugo): MAFA
Location: 8q24.3
Local order: C8orf51, RHPN1, MAFA, ZC3H3,
GSDMD
DNA/RNA
Note
The MAFA open reading frame is encoded by a unique
exon. The entire genomic organization and the putative
existence of non-coding exons remain unknown.
Transcription
MAFA displays a restricted expression pattern. It is
notably expressed in pancreas (in beta-cells) and lens.
Pseudogene
Unknown.
Protein
Note
Maf oncoproteins are b-ZIP transcription factors that
belong to the AP-1 super-family, which notably
includes JUN and FOS. The Maf family contains seven
members, which can be subdivided into two groups; the
large and small Maf proteins. While the small Maf
proteins, MAFF, MAFG and MAFK, are essentially
composed of a b-Zip domain, the large Maf proteins,
MAFA/L-MAF, MAFB, MAF/c-MAF and NRL
contain an additional amino-terminal transactivation
domain. MAFA was initially cloned in quail and
chicken species and named MAFA and L-MAF,
respectively. More recently, mammalian MAFA was
cloned and identi-fied as an essential component of the
RIPE3b1 complex, which binds the insulin promoter.
Schematic representation of the MAFA protein structure. Critical residues involved in post-translational modifications are indicated by the color code. The kinases responsible for S14 and S65 phosphorylation in MAFA remain to be identified. GSK-3 phosphorylates the transactivation domain of MAFA, thereby inducing its ubiquitination and proteasome-dependent degradation. This is linked to an increase in MAFA transactivation. These phosphorylations are required for MAFA transforming activity. In contrast, sumoylation of MAFA transactivation domain decreases its transactivation activity.
MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian)) Pouponnot C, Eychène A
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 236
Description
MAFA, like all large Maf proteins, contains an amino-
terminal transactivation domain and a carboxy-terminal
b-ZIP DNA binding domain. Large Maf proteins
stimulate transcription of their target genes through
their binding to two types of palindromic sequences
called TRE- or CRE- type MARE (Maf Responsive
Element) (TGCTGAC(G) TCAGCA). The leucine
zipper domain allows the formation of homo- or hetero-
dimers, an absolute pre-requisite for DNA binding. As
homodimers, these proteins recognize palindromic
sequences, with the basic domain contacting DNA
directly. Among the AP-1 family, the Maf proteins are
defined by the presence of an additional homolo-gous
domain, called the Extended Homology Region (EHR)
or ancillary domain, which also contacts DNA.
Consequently, they recognize a longer palindromic
sequence than other AP-1 family members. The MARE
sequence is composed of a TRE or CRE core contacted
by the basic domain and a TGC flanking sequence,
which is recognized by the EHR domain. While the
TGC motif is crucial for Maf binding, the TRE/CRE
core can be more degenerate. MAFA transactivation
activity and stability is regulated by post-trans-lational
modifications (phosphorylation, ubiquityla-tion and
sumoylation) mostly occuring on the transactivation
domain. GSK-3 was identified as the major protein
kinase regulating MAFA activity and oncogenic
properties.
Expression
Endogenous MAFA protein is detected and phos-
phorrylated in pancreatic beta cells.
Localisation
Nucleus.
Function
During development, Maf proteins are involved early in
specification and later in terminal differen-tiation.
MAFA is involved in the regulation of insulin gene
expression in pancreatic beta cells. Accordingly,
MAFA ablation in mice leads to diabetes.
Besides their roles during development, large Maf
proteins, MAFA, MAFB, and MAF/c-MAF are also
involved in oncogenesis.
Homology
MAFB and MAF/c-MAF are the closest MAFA
homologs. The MAFA entire protein sequence shares
52%, 48% and 40% identity with those of MAFB,
MAF/c-MAF and NRL, respectively. MAFA DNA
binding domain (EHR + b-ZIP) shares 82%, 83%, 64%
and 55-60% identity with those of MAFB, MAF/c-
MAF, NRL and small MAFs, respectively. MAFA and
JUN share 30% sequence identity in their b-ZIP
domain (20% identity in their entire sequence).
Implicated in
Multiple myeloma
Hybrid/Mutated gene
Two cases reported translocations of MAFA to the
immunoglobulin heavy-chain (IgH) locus, juxta-posing
the MAFA gene with the strong enhancers of the IgH
locus (meeting report, accurate description lacking).
Oncogenesis
Large Maf proteins, MAFA, MAFB, and MAF/c-MAF
are bona fide oncogenes as demonstrated in tissue
culture, animal models and in human cancers. MAFA
displays the strongest transforming activity, in vitro. In
human, MAF/c-MAF, MAFB and MAFA genes are
translocated to the immunoglo-bulin heavy chain (IgH)
locus in 8-10% of multiple myelomas. MAFA
translocations are present in less than 1% of multiple
myelomas. MAF/C-MAF over-expression plays a
causative role in multiple myeloma by promoting
proliferation and patholo-gical interactions with bone
marrow stroma.
The transforming activity of Maf proteins is context
dependent and they can occasionally display tumor
suppressor-like activity in specific cellular settings.
Their transforming activity relies on overexpression
and does not require an activating mutation (no
activating mutation has been identified to be associated
with human cancers). It is regulated by post-
translational modifications, notably phospho-rylation.
References Benkhelifa S, Provot S, Lecoq O, Pouponnot C, Calothy G, Felder-Schmittbuhl MP. mafA, a novel member of the maf proto-oncogene family, displays developmental regulation and mitogenic capacity in avian neuroretina cells. Oncogene. 1998 Jul 16;17(2):247-54
Ogino H, Yasuda K. Induction of lens differentiation by activation of a bZIP transcription factor, L-Maf. Science. 1998 Apr 3;280(5360):115-8
Benkhelifa S, Provot S, Nabais E, Eychène A, Calothy G, Felder-Schmittbuhl MP. Phosphorylation of MafA is essential for its transcriptional and biological properties. Mol Cell Biol. 2001 Jul;21(14):4441-52
Kataoka K, Han SI, Shioda S, Hirai M, Nishizawa M, Handa H. MafA is a glucose-regulated and pancreatic beta-cell-specific transcriptional activator for the insulin gene. J Biol Chem. 2002 Dec 20;277(51):49903-10
Olbrot M, Rud J, Moss LG, Sharma A. Identification of beta-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA. Proc Natl Acad Sci U S A. 2002 May 14;99(10):6737-42
Matsuoka TA, Zhao L, Artner I, Jarrett HW, Friedman D, Means A, Stein R. Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells. Mol Cell Biol. 2003 Sep;23(17):6049-62
Nishizawa M, Kataoka K, Vogt PK. MafA has strong cell transforming ability but is a weak transactivator. Oncogene. 2003 Sep 11;22(39):7882-90
MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian)) Pouponnot C, Eychène A
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 237
Hanamura I, Iida S, Ueda R, Kuehl M, Cullraro C, Bergsagel L, Sawyer J, Barlogie B, Shaughnessy Jr J.. Identification of three novel chromosomal translocation partners involving the immunoglobulin loci in newly diagnosed myeloma and human myeloma cell lines. Blood (ASH Annual Meeting Abstracts) 2005; 106:1552.
Sii-Felice K, Pouponnot C, Gillet S, Lecoin L, Girault JA, Eychène A, Felder-Schmittbuhl MP. MafA transcription factor is phosphorylated by p38 MAP kinase. FEBS Lett. 2005 Jul 4;579(17):3547-54
Zhang C, Moriguchi T, Kajihara M, Esaki R, Harada A, Shimohata H, Oishi H, Hamada M, Morito N, Hasegawa K, Kudo T, Engel JD, Yamamoto M, Takahashi S. MafA is a key regulator of glucose-stimulated insulin secretion. Mol Cell Biol. 2005 Jun;25(12):4969-76
Pouponnot C, Sii-Felice K, Hmitou I, Rocques N, Lecoin L, Druillennec S, Felder-Schmittbuhl MP, Eychène A. Cell context reveals a dual role for Maf in oncogenesis. Oncogene. 2006 Mar 2;25(9):1299-310
Chng WJ, Glebov O, Bergsagel PL, Kuehl WM. Genetic events in the pathogenesis of multiple myeloma. Best Pract Res Clin Haematol. 2007 Dec;20(4):571-96
Han SI, Aramata S, Yasuda K, Kataoka K. MafA stability in pancreatic beta cells is regulated by glucose and is dependent on its constitutive phosphorylation at multiple sites by glycogen synthase kinase 3. Mol Cell Biol. 2007 Oct;27(19):6593-605
Rocques N, Abou Zeid N, Sii-Felice K, Lecoin L, Felder-Schmittbuhl MP, Eychène A, Pouponnot C. GSK-3-mediated phosphorylation enhances Maf-transforming activity. Mol Cell. 2007 Nov 30;28(4):584-97
Eychène A, Rocques N, Pouponnot C. A new MAFia in cancer. Nat Rev Cancer. 2008 Sep;8(9):683-93
Shao C, Cobb MH. Sumoylation regulates the transcriptional activity of MafA in pancreatic beta cells. J Biol Chem. 2009 Jan 30;284(5):3117-24
This article should be referenced as such:
Pouponnot C, Eychène A. MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):235-237.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 238
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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MAP3K7 (mitogen-activated protein kinase kinase kinase 7) Hui Hui Tang, Kam C Yeung
Department of Cancer Biology and Biochemistry, College of Medicine, Univeristy of Toledo, Health Science
Campus, 3035 Arlington Ave., Toledo, OH 43614, USA (HHT, KCY)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/MAP3K7ID454ch6q15.html DOI: 10.4267/2042/44699
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: TAK1; TGF1a
HGNC (Hugo): MAP3K7
Location: 6q15
DNA/RNA
Description
MAP3K7/TAK1 gene spans 71 kb of DNA and
contains 17 exons and 16 introns. Exon 1 contains the
5' UTR of the mRNA and encodes 40 amino acid of N-
terminal of the protein. Exons 2 to 8 encode the kinase
domain. Exon 17 encodes the carboxyl end of the
TAK1 protein and contains the 3'UTR. Exon 12 and
exon 16 are alternative exons.
The promoter is located between 799 bp and 1215 bp
upsteam of the exon 1. The promoter has the character
of housekeeping genes: the absence of TATA box, the
presence of CpG island and SP1 binding sites.
Transcription
Four alternatively spliced transcripts encoding 4
distinct isoforms because of the presence or absence of
alternative exons 12 or/and 16 are detected.
Variant A: It lacks an in-frame coding segment, exon
12.
Variant B: This variant contains both alternative exons
12 and 16 and encodes the longest isoform.
Variant C: Variant C lacks the exon 16 resulting in a
frame shift in exon 17. The resulting isoform C has a
distinct and shorter C terminus when compared with
variants A and B.
Variant D: Variant D lacks both exons 12 and 16.
The regulation of the TAK1 mRNA alternative splicing
is tissue specific. The different variants of TAK1 may
have specialized functions.
A: The 17 exons are shown as black vertical bars. The exon numbers are shown on top of each exon. The CpG island is shown as a white box. The positions of exons in the cDNA are 1-282, 283-393, 394-459, 460-505, 506-644, 645-768, 770-898, 899-1029, 1030-1111, 1112-1242, 1243-1372, 1373-1453, 1454-1518, 1519-1624, 1625-1686, 1687-1802, and 1803-2850. The sizes (in base pairs) of intron 1 to 16 are 14956, 3073, 6891, 1407, 3451, 2913, 1278, 1499, 2290, 659, 2625, 8150, 12553, 4358, 695, and 1765, respectively.
MAP3K7 (mitogen-activated protein kinase kinase kinase 7) Tang HH, Yeung KC
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 239
B: MAP3K7 transcripts.
Pseudogene
No pseudogene of MAP3K7/TAK1 was reported in
human.
Protein
Note
MAP3K7/TAK1 isoform B contains 606 amino acids
(aa) and has a predicted molecular weight of 67 kDa,
isoform D contains 491 aa and has a predicted
molecular weight of 53.7 kDa, isoform C contains 518
aa and has a predicted molecular weight of 56.7 kDa,
and isoform A contains 579 aa and has a predicted
molecular weight of 64 kDa.
Description
MAP3K7/TAK1 was first identified by screening a
mouse cDNA library for clones that could act as
MAPKKKs. The mouse TAK1 cDNA encodes a 579-
amino acid protein. The mouse TAK1 protein contains
a 300-residue COOH-terminal domain and a putative
NH2-terminal protein kinase catalytic domain.
The kinase domain has approximately 30% identity to
the catalytic domains of Raf-1 and MEKK1. Kondo et
al. (1998) cloned human TAK1 from lung cDNA
library by screening with mouse TAK1 sequence.
Human TAK1 gene encodes a 579-amino-acid protein.
The hTAK1 gene has 91.8% identity with the mTAK1
gene at the nucleotide level and has 99.3% to that at the
amino acid level. Human TAK1 mRNA with a size of
3.0 kb was observed to express in all the tissues
examined by Northern blotting. Kondo et al. (1998)
found 2 isoforms of TAK1. Isoform 2 had an insertion
of 27 amino acids between amino acids 403 and 404 of
isoform 1 which corresponded to the mTAK1 sequence
previously identified by Yamaguchi et al. (1995). The
two isoforms were expressed at different ratios.
Isoform 1 (Variant A) was predominantly expressed in
brain, heart and spleen while the isoform 2 (Variant B)
was preferentially in the kidney.
Independently, Sakurai et al. (1998) cloned hTAK1 as
well as two alternatively spliced isoforms. Human
TAK1a (Variant A) has 99.3% identity to murine
TAK1. TAK1b (Variant B) had an insertion of 27
amino acids and TAK1c had a deletion of 39 amino
acids in the carboxyl-terminal region. The catalytic
domains of these three isoforms were 100% identical to
that of murine TAK1. The mRNA for TAK1a and
TAK1b were expressed in Hela, Jurkat and THP1 cells
and TAK1a mRNA expessed predominantly in these
cell lines. TAK1c mRNA (Variant C) was expressed
only in Hela cells. Northern blot analysis revealed the
expression of TAK1 mRNA in all the human tissues
examined with the size of 3.2 and 5.7 kb. Dempsey et
al. (2000) identified a fourth splice variant of TAK1
called TAK1d (Variant D). TAK1d lacked the two
alternative exons and encoded a 491 amino acid
protein. TAK1a and b were the most abundant forms in
most tissues examined. The carboxyl-end variant
TAK1 proteins were unlikely to interfere with the
catalytic activity of TAK1 or its interaction with TAB1
since both of which involve the N terminus, but may
affect its interaction with TAB2 which associates with
the carboxyl-ends of the TAK1 proteins.
Expression
TAK1 was ubiquitously expressed in all tissues.
TAK1a (variant A) was the most abundant form in
heart, liver, skeletal muscle, ovary, spleen and
peripheral blood mononuclear cells; TAK1b (Variant
B) was more abundant in brain, kidney, prostate and
small intestine; TAK1c (Variant C) is ubiquitously
expressed and predominantly in prostate; and TAK1d
(Variant D) existed in most tested tissues as a minor
variant.
Localisation
TAK1 is mostly localized in cytoplasm.
Function
TAK1 is a member of the serine/threonine protein
MAP3K7 (mitogen-activated protein kinase kinase kinase 7) Tang HH, Yeung KC
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 240
kinase family. It can be activated by transforming
growth factor-beta (TGF-b) and TAK1 deletion mutant
missing the N-terminal 22 amino acid is constitutively
active. In response to TGF-b, TAK1 can phosphorylate
and activate MAP kinase kinases MKK3, MKK4 and
MKK6. TAK1 can activate NF-kB in the presence of
TAB1. TAK1 is also involved in pro-inflammatory
cytokines signaling by activa-ting two kinase pathways.
One is a MAPK cascade that leads to the activation of
JNK and the other is IkB kinase cascade that causes the
activation of NF-kB. It was shown that TRAF6 is a
signal mediator that activates IKK and JNK in response
to pro-inflammatory cytokine interleukin 1. The
activation of IKK by TRAF6 requires two intermediary
factors, TRAF6-regulated IKK activator 1 (TRIKA1)
and TRIKA2. TRIKA1 is an ubiquitin-conjugating
enzyme complex consisted of Ubc13 and Uev1A.
TRIKA1, together with TRAF6, catalyze the formation
of a Lys63-linked polyubi-quitin chain that mediates
IKK activation. TRIKA2 is composed of TAK1, TAB1
and TAB2. The activation of TAK1 kinase complex is
dependent on its polyubiquitination by the TRAF6-Ubc
complex and phosphorylation of several residues within
the kinase activation loop by yet-to-be identified
kinases. The ubiquitinated TAK1 can phosphorylate
IKKbeta specifically at S177 and S181. Mutation
analysis revealed that a point mutation in the ATP-
binding domain of TAK1 (K63W), which abolished its
kinase activity, was unable to activate IKK. TAK1 was
activated by auto-phosphorylation on Ser192 and dual
phosphorylation of Thr-178 and Thr-184 residues
within the activation loop. Mutation of a conserved
serine residue (Ser192) in the activation loop between
kinase domain VII and VIII abrogated the
phosphorylation and activation of TAK1. TAK1 is
linked to TRAFs by two adaptor proteins TAB2 and
TAB3. The interaction of TAB2/TAB3 with TAK1 is
essential for the activation of signaling pathway
mediated by IL-1.
It was shown that protein phosphatase 2Cepsilon
(PP2Cepsilon) inhibited the IL-1 and TAK1 induced
activation of MKK4-JNK or MKK3-p38 signaling
pathway. PP2Cepsilon inactivated TAK1 by
associating with and dephosphorylating TAK1. A type-
2A phosphatase, protein phosphatase 6 (PP6), was also
identified as a TAK1-binding protein. PP6 repressed
TAK1 activity by dephos-phorylating Thr187.
Homology
Human TAK1-like (TAKL) gene encoded a 242 amino
acid protein which shared a homology with human
TAK1. The amino acid sequences of TAK1 were
highly conserved between human and mouse.
Mutations
Note
No mutation of human MAP3K7 was reported.
Implicated in
Breast cancer
Note
TGF-b1 signaling is involved in tumor angiogenesis
and metastasis by regulating matrix proteosis. MMP-9
is an important component of these TGF-b1 responses.
TAK1 is important for TGF-b1 regulation of MMP9
and metastatic potential of breast cancer cell line
MDA-MB231. Suppression of TAK1 reduces the
expression of MMP9 and tumor cell invasion. TAK1
and NFkB are required for the human MCF10A-CA1a
breast cancer cells to undergo invasion in response to
TGF-b. A novel TAB1:TAK1: IKKb: NFkB signaling
axis forms aberrantly in breast cancer cells and enables
oncogenic signaling by TGF-b.
Lung cancer
Note
Mutation analysis: Study on 39 lung cancer specimens
and 16 lung cancer cell lines indicated that hTAK1 was
not a frequent target for genetic alternations in lung
cancer.
TAK1 variant D activated by siRNAs of specific
sequences leads to down stream activation of p38
MAPK and JNK but not NFkB pathway. In human lung
cancer cell line NCI-H460 the activation of these
pathway cause cell cycle arrest and apoptosis. It
suggests that TAK1 D may be a new and promising
therapeutic target for the treatment of non-small cell
lung cancer. Telomeres are essential elements at the
ends of chromosomes that contribute to chromosomal
stability. The length of the telomere is maintained by
the telomerase holoenzyme, which contains the reverse
trans-criptase hTERT as a major enzymatic subunit.
The activity of telomerase is absent in most normal
human cells because of the downregulation of the
hTERT transcript resulting in the shortening of
telomeres after each replicative cycle. However, in
immortalized cells and cancer cells, the telomere
lengths are maintained through an increase in hTERT
expression. TAK1 can repress the transcription of
hTERT in A549 human lung adenocarcinoma cell line
and this repression is caused by recruitment of HDAC
to the hTERT promoter.
Cervical carcinoma
Note
Tumor necrosis factor (TNF)-related apoptosis-
inducing ligand (TRAIL), a member of TNFa ligand
family, induces apoptosis in a variety of tumor cells.
TRAIL induced the delayed phospho-rylation of TAK1
in human cervical carcinoma HeLa cells. TRAIL
induced apoptosis was enhanced by downregulation of
TAK1.
MAP3K7 (mitogen-activated protein kinase kinase kinase 7) Tang HH, Yeung KC
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 241
Head and neck squamous cell carcinoma
Note
NFkB was constitutively activated in head and neck
squamous cell carcinoma (HNSCC). Constitutive
activation of NFkB in HNSCC was caused by
constitutive activation of IKK. Constitutive activa-tion
of NFkB is mediated through the TRADD-TRAF2-
RIP-TAK1-IKK pathway.
Arthritis
Note
Exercise/joint mobility has therapeutic potency for
inflammatory joint diseases such as rheumatoid and
osteoarthritis. The biomechanical signals at
physiological magnitudes are potent inhibitors of
inflammation induced by NFkB activation in
fibrochondrocytes. The biomechanical signals exert
anti-inflammatory effects by inhibiting phosphory-
lation of TAK1.
JNK is essential for metalloproteinase (MMP) gene
expression and joint destruction in inflammatory
arthritis. TAK1 is an upstream kinase of JNK. TAK1
play an important role for the IL1b induced JNK
activation and the JNK induced gene expression in
fibroblast-like synoviocytes (FLSs). It suggests that
TAK1 is a potential therapeutic target to modulate
synoviocyte activation in rheumatoid arthritis (RA).
Inflammation
Note
Pro-inflammatory molecules lipopolysaccharide and
Interleukin 1 trigger the activation of TAK1, which in
turn activates multiple kinase JNK, p38, IKK and
PKB/Akt which are important components of kinase
cascades involved in inflammation. Thus TAK1 plays
an important role in inflammation.
Human airway epithelial cells
Note
Act1/TRAF6/TAK1-mediated NF-kB activation
stimulated by IL-17A regulates gene induction in
human airway epithelial cells. Dominant negative
TAK1 reduces IL-17A induced gene expression.
References Hirose T, Fujimoto W, Tamaai T, Kim KH, Matsuura H, Jetten AM. TAK1: molecular cloning and characterization of a new member of the nuclear receptor superfamily. Mol Endocrinol. 1994 Dec;8(12):1667-80
Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, et al. Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science. 1995 Dec 22;270(5244):2008-11
Kondo M, Osada H, Uchida K, Yanagisawa K, Masuda A, Takagi K, Takahashi T, Takahashi T. Molecular cloning of human TAK1 and its mutational analysis in human lung cancer. Int J Cancer. 1998 Feb 9;75(4):559-63
Sakurai H, Shigemori N, Hasegawa K, Sugita T. TGF-beta-activated kinase 1 stimulates NF-kappa B activation by an NF-kappa B-inducing kinase-independent mechanism. Biochem Biophys Res Commun. 1998 Feb 13;243(2):545-9
Dempsey CE, Sakurai H, Sugita T, Guesdon F. Alternative splicing and gene structure of the transforming growth factor beta-activated kinase 1. Biochim Biophys Acta. 2000 Dec 15;1517(1):46-52
Kishimoto K, Matsumoto K, Ninomiya-Tsuji J. TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop. J Biol Chem. 2000 Mar 10;275(10):7359-64
Lee J, Mira-Arbibe L, Ulevitch RJ. TAK1 regulates multiple protein kinase cascades activated by bacterial lipopolysaccharide. J Leukoc Biol. 2000 Dec;68(6):909-15
Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature. 2001 Jul 19;412(6844):346-51
Li MG, Katsura K, Nomiyama H, Komaki K, Ninomiya-Tsuji J, Matsumoto K, Kobayashi T, Tamura S. Regulation of the interleukin-1-induced signaling pathways by a novel member of the protein phosphatase 2C family (PP2Cepsilon). J Biol Chem. 2003 Apr 4;278(14):12013-21
Takaesu G, Surabhi RM, Park KJ, Ninomiya-Tsuji J, Matsumoto K, Gaynor RB. TAK1 is critical for IkappaB kinase-mediated activation of the NF-kappaB pathway. J Mol Biol. 2003 Feb 7;326(1):105-15
Li J, Ji C, Yang Q, Chen J, Gu S, Ying K, Xie Y, Mao Y. Cloning and characterization of a novel human TGF-beta activated kinase-like gene. Biochem Genet. 2004 Apr;42(3-4):129-37
Kishida S, Sanjo H, Akira S, Matsumoto K, Ninomiya-Tsuji J. TAK1-binding protein 2 facilitates ubiquitination of TRAF6 and assembly of TRAF6 with IKK in the IL-1 signaling pathway. Genes Cells. 2005 May;10(5):447-54
Choo MK, Kawasaki N, Singhirunnusorn P, Koizumi K, Sato S, Akira S, Saiki I, Sakurai H. Blockade of transforming growth factor-beta-activated kinase 1 activity enhances TRAIL-induced apoptosis through activation of a caspase cascade. Mol Cancer Ther. 2006 Dec;5(12):2970-6
Kajino T, Ren H, Iemura S, Natsume T, Stefansson B, Brautigan DL, Matsumoto K, Ninomiya-Tsuji J. Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway. J Biol Chem. 2006 Dec 29;281(52):39891-6
Besse A, Lamothe B, Campos AD, Webster WK, Maddineni U, Lin SC, Wu H, Darnay BG. TAK1-dependent signaling requires functional interaction with TAB2/TAB3. J Biol Chem. 2007 Feb 9;282(6):3918-28
Hammaker DR, Boyle DL, Inoue T, Firestein GS. Regulation of the JNK pathway by TGF-beta activated kinase 1 in rheumatoid arthritis synoviocytes. Arthritis Res Ther. 2007;9(3):R57
Jackson-Bernitsas DG, Ichikawa H, Takada Y, Myers JN, Lin XL, Darnay BG, Chaturvedi MM, Aggarwal BB. Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-kappaB activation and proliferation in human head and neck squamous cell carcinoma. Oncogene. 2007 Mar 1;26(10):1385-97
Madhavan S, Anghelina M, Sjostrom D, Dossumbekova A, Guttridge DC, Agarwal S. Biomechanical signals suppress TAK1 activation to inhibit NF-kappaB transcriptional activation in fibrochondrocytes. J Immunol. 2007 Nov 1;179(9):6246-54
MAP3K7 (mitogen-activated protein kinase kinase kinase 7) Tang HH, Yeung KC
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 242
Maura M, Katakura Y, Miura T, Fujiki T, Shiraishi H, Shirahata S.. Molecular Mechanism of TAK1-Induced Repression of hTERT Transcription. Cell Technology for Cell Products, R. Smith (ed.), 91-93. 2007 Springer.
Honorato B, Alcalde J, Martinez-Monge R, Zabalegui N, Garcia-Foncillas J. TAK1 mRNA expression in the tumor tissue of locally advanced head and neck Cancer Patients. Gene Regulation and Systems Biology. 2008;2: 63-70.
Kodym R, Kodym E, Story MD. Sequence-specific activation of TAK1-D by short double-stranded RNAs induces apoptosis in NCI-H460 cells. RNA. 2008 Mar;14(3):535-42
Neil JR, Schiemann WP. Altered TAB1:I kappaB kinase interaction promotes transforming growth factor beta-mediated nuclear factor-kappaB activation during breast cancer progression. Cancer Res. 2008 Mar 1;68(5):1462-70
Safina A, Ren MQ, Vandette E, Bakin AV. TAK1 is required for TGF-beta 1-mediated regulation of matrix metalloproteinase-9 and metastasis. Oncogene. 2008 Feb 21;27(9):1198-207
Yu Y, Ge N, Xie M, Sun W, Burlingame S, Pass AK, et al. Phosphorylation of Thr-178 and Thr-184 in the TAK1 T-loop is required for interleukin (IL)-1-mediated optimal NFkappaB and AP-1 activation as well as IL-6 gene expression. J Biol Chem. 2008 Sep 5;283(36):24497-505
This article should be referenced as such:
Tang HH, Yeung KC. MAP3K7 (mitogen-activated protein kinase kinase kinase 7). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):238-242.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 243
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
MCPH1 (microcephalin 1) Yulong Liang, Shiaw-Yih Lin, Kaiyi Li
Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA (YL, KL); Department of
Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77054, USA
(SYL)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/MCPH1ID44370ch8p23.html DOI: 10.4267/2042/44700
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: BRIT1; MCT
HGNC (Hugo): MCPH1
Location: 8p23.1
Local order: According to NCBI Map Viewer, genes
flanking MCPH1 in telomere to centromere direction
on 8p23.1 are: ANGPT2 (angiopoietin 2); MCPH1
(also BRIT1); AGPAT5 (1-acylglycerol-3-phosphate
O-acyltransferase 5 (lysophosphatidic acid
acyltransferase, epsilon)); XKR5 (XK, Kell blood
group complex subunit-related family, member 5);
DEFB1 (defensin, beta 1); DEFA6 (defensin, alpha 6,
Paneth cell-specific).
Note
MCPH1 is one of DNA damage response proteins that
interact with other DNA damage and repair proteins
and signal transducers, form a DNA damage response
protein complex which can be seen through
immunofluorescent microscopy, and participate into
DNA repair, cell cycle checkpoint control, and
eventually maintain genomic integrity. The aberrant
expression of MCPH1 is observed in ovarian cancer
and breast cancer tissues and cell lines. Thus,
functional impairment of MCPH1 may significantly
contribute to tumour susceptibility
and/or tumour development. In addition, indivi-duals
who harbor a germline mutation of MCPH1 gene may
be highly susceptible to an autosomal recessive
neurological disorder, called primary microcephaly.
DNA/RNA
Description
According to Entrez-Gene, MCPH1 gene maps to
NC_000008.9 in the region between 6251529 and
6493434 on the plus strand and spans across 241.9 kilo
bases. According to GenBank, MCPH1 has 14 exons,
the sizes being 90, 92, 119, 88, 115, 144, 90, 1155, 110,
38, 163, 78, 238, and 5512 bp.
Transcription
8032 bp mRNA (NM_024596.2), 2508 bp open reading
frame.
Protein
Note
MCPH1 has three BRCA1 carboxyl-terminal (BRCT)
domains, so it is regarded as a protein family member
involved in DNA damage repair and checkpoint
control.
The protein of MCPH1 contains three BRCT domains, the nuclear localization signal motif and the large middle IMPDH domain. (AA, amino acids).
MCPH1 (microcephalin 1) Liang Y, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 244
Description
MCPH1 protein contains 835 amino acids with about
110 kDa of the molecular weight. According to
MotifScan prediction, MCPH1 has three BRCT
domains, one nuclear localization signal motif and the
large central IMPDH domain as depicted in the
diagram above. The BRCT domains of MCPH1, one in
N-terminus (N-BRCT), the other two tandemly
arranged in C-terminus (C-BRCTs), specifically bind to
the phosphorylated proteins commonly involved in
DNA damage response pathways. The N-BRCT is
required for centrosomal localization in irradiated cells,
and also essential to rescue the premature chromosome
condensation in MCPH1-deficient cells. C-BRCTs
direct self-oligo-merization of MCPH1, and are
necessary for ionizing radiation-induced foci formation.
The function of IMPDH domain predicted by
MotifScan is not clear yet. However, the region
(residues 376-485) in the central IMPDH domain (or
middle domain), binding with Condension II,
participates in homologous recombination.
Expression
MCPH1 is ubiquitously expressed in human with the
higher levels observed in the brain, testes, pancreas and
liver. It is a putative tumor suppressor and the aberrant
expression of MCPH1 is correlated with ovarian and
breast cancer. This reduced expression of MCPH1 may
have been caused by gene deletion detected by high-
density array comparative genomic hybridization
(CGH).
Localisation
Mainly localized in nucleus.
Function
MCPH1 function in DNA damage response: MCPH1
can modulate activities of two distinct DNA damage
repair networks, the ATM (ataxia telangiectaisia
mutated) pathway and the ATR (ATM and Rad3-
related) pathway. Upon exposure to DNA damaging
reagents, MCPH1 co-localizes with numerous proteins
associated with these two signaling pathways including
gamma-H2AX, MDC1, 53BP1, NBS1, p-ATM, ATR,
p-RAD17 and p-RPA34. In the absence of MCPH1, all
of these proteins with the exception of gamma-H2AX,
fail to localize to sites of DNA damage. The depletion
of MCPH1 inhibits the recruitment of phosphorylated
ATM to double-stranded DNA break ends, and
subsequently impair t phosphory-lation of multiple
down-stream members of the ATM pathway. MCPH1
deficiency also abolishes the UV-induced
phosphorylation of RPA34 and reduces the levels of
phosphorylated RAD17, suggesting the roles of
MCPH1 in the ATR path-way. Rad51, a homolog of
the bacterial RecA, is a central executioner in
homologous recombination (HR), catalyzing the
invasion of the single stranded DNA in a homologous
duplex and facilitating the homology search during the
establishment of joint molecules. Lack of MCPH1 can
alleviate localization of RAD51 onto the DNA break
sites. So MCPH1 is strongly implicated in HR.
Role of BRIT1 in cell cycle control: MCPH1 has been
demonstrated to regulate the expression of BRCA1 and
Chk1 and required for activation of intra-S and G2/M
cell cycle checkpoint after cellular exposure to ionizing
radiation. In the absence of MCPH1, BRCA1 and
ChK1 expression is significantly reduced and NBS1
fails to be phosphorylated, leading to loss of intra-S and
G2/M checkpoint control. Cells derived from a micro-
cephaly patient (MCPH1 defective) maintain a
persistent level of CDC25A and reduced level of Cdk1-
cyclin B complex, both of which attributes to entry of
mitosis. So besides expression control of ChK1 and
BRCA1, MCPH1 prevents premature entry into mitosis
in an ATR-dependent and ATR-independent manner.
Homology
According to NCBI-HomoloGene:
Chimpanzee (Pan troglodytes): MCPH1
(NP_001009010.1, 835 aa)
Dog (Canis familiaris): MCPH1 (NP_001003366.1,
850 aa)
Rat (Rattus norvegicus): MCPH1 (XP_225006.4, 986
aa)
Mouse (Mus musculus): MCPH1 (NP_775281.2, 822
aa)
Zebrafish (Danio rerio): zgc:136403 (NP_001035453.1,
422 aa)
Drosophila (Drosophila melanogaster): CG30038
(NP_725086.2, 219 aa)
Mutations
Note
Three point mutations in the autosomal recessive
mental retardation patients have been described for
MCPH1 so far. Two mutations (S25X and 427insA)
lead to premature stop condon, and one (T27R) leads to
missense mutation in the N-terminal BRCT domain. A
non-synonymous SNP (V761A in BRCA1 C-terminus
(BRCT) domain) of MCPH1 is significantly associated
with cranial volume in Chinese males. In addition, a
deletion of approximately 150-200 kb, encompassing
the promoter and the first six exons of the MCPH1
gene, was revealed by Array-based homozygosity
mapping and high-resolution microarray-based
comparative genomic hybridization (array CGH).
However, the patients with this deletion just showed
borderline of mild microcephaly.
Implicated in
Ovarian cancers
Note
Aberrations of MCPH1 have been identified in various
human cancers.
MCPH1 (microcephalin 1) Liang Y, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 245
Disease
MCPH1 DNA copy number was substatially decreased
in 40% of advanced epithelial ovarian cancer, and its
mRNA levels were also dramatically decreased in 63%
of ovarian cancer.
Breast cancers
Disease
MCPH1 mRNA and protein levels was aberrantly
reduced in several breast cancer cell lines.
Prognosis
Additionally, reduced MCPH1 expression correla-ted
with the duration of the relapse-free intervals and with
the occurrence of metastasis in breast cancers. BRIT1
deficiency may contribute to development and
aggressive nature of breast tumors.
Primary microcephaly
Disease
Primary microcephaly is an autosomal recessive
disorder, in which there is a marked reduction in brain
size. One form of primary microcephaly, MCPH, is
caused by mutation in the gene encoding microcephalin
1 (that is, MCPH1). In these patients, the MCPH1-
deficient cells show cellular phenotype of premature
chromosome condensation in the early G2 phase of the
cell cycle, which, therefore, appears to be a useful
diagnostic marker for these individuals. As mentioned
above, several mutations of MCPH1 have been
observed in these patients, including S25X, 427insA,
T27R, V761A and 5'-deletion of a large portion
encompassing the promoter region and first six exons,
especially the later two showing strong correlation with
micro-cephaly.
PCC syndrome
Disease
Premature chromosome condensation (PCC) syndrome
is characterized by premature chromosome
condensation in the early G2 phase. This disorder is
similar to microcephalin 1, and can also be caused by
MCPH1 mutations.
References Jackson AP, McHale DP, Campbell DA, Jafri H, Rashid Y, Mannan J, Karbani G, Corry P, Levene MI, Mueller RF, Markham AF, Lench NJ, Woods CG. Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter. Am J Hum Genet. 1998 Aug;63(2):541-6
Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM, Roberts E, Hampshire DJ, Crow YJ, Mighell AJ, Karbani G, Jafri H, Rashid Y, Mueller RF, Markham AF, Woods CG. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet. 2002 Jul;71(1):136-42
Trimborn M, Bell SM, Felix C, Rashid Y, Jafri H, Griffiths PD, Neumann LM, Krebs A, Reis A, Sperling K, Neitzel H, Jackson AP. Mutations in microcephalin cause aberrant regulation of chromosome condensation. Am J Hum Genet. 2004 Aug;75(2):261-6
Xu X, Lee J, Stern DF. Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1. J Biol Chem. 2004 Aug 13;279(33):34091-4
Lin SY, Rai R, Li K, Xu ZX, Elledge SJ. BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1-Chk1 pathway, implicating checkpoint dysfunction in microcephaly. Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15105-9
Trimborn M, Richter R, Sternberg N, Gavvovidis I, Schindler D, Jackson AP, Prott EC, Sperling K, Gillessen-Kaesbach G, Neitzel H. The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype. Hum Mutat. 2005 Nov;26(5):496
Alderton GK, Galbiati L, Griffith E, Surinya KH, Neitzel H, Jackson AP, Jeggo PA, O'Driscoll M. Regulation of mitotic entry by microcephalin and its overlap with ATR signalling. Nat Cell Biol. 2006 Jul;8(7):725-33
Chaplet M, Rai R, Jackson-Bernitsas D, Li K, Lin SY. BRIT1/MCPH1: a guardian of genome and an enemy of tumors. Cell Cycle. 2006 Nov;5(22):2579-83
Garshasbi M, Motazacker MM, Kahrizi K, Behjati F, Abedini SS, Nieh SE, Firouzabadi SG, Becker C, Rüschendorf F, Nürnberg P, Tzschach A, Vazifehmand R, Erdogan F, Ullmann R, Lenzner S, Kuss AW, Ropers HH, Najmabadi H. SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly. Hum Genet. 2006 Feb;118(6):708-15
Rai R, Dai H, Multani AS, Li K, Chin K, Gray J, Lahad JP, Liang J, Mills GB, Meric-Bernstam F, Lin SY. BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer. Cancer Cell. 2006 Aug;10(2):145-57
Wood JL, Singh N, Mer G, Chen J. MCPH1 functions in an H2AX-dependent but MDC1-independent pathway in response to DNA damage. J Biol Chem. 2007 Nov 30;282(48):35416-23
Jeffers LJ, Coull BJ, Stack SJ, Morrison CG. Distinct BRCT domains in Mcph1/Brit1 mediate ionizing radiation-induced focus formation and centrosomal localization. Oncogene. 2008 Jan 3;27(1):139-44
Wang JK, Li Y, Su B. A common SNP of MCPH1 is associated with cranial volume variation in Chinese population. Hum Mol Genet. 2008 May 1;17(9):1329-35
Wood JL, Liang Y, Li K, Chen J. Microcephalin/MCPH1 associates with the Condensin II complex to function in homologous recombination repair. J Biol Chem. 2008 Oct 24;283(43):29586-92
Yang SZ, Lin FT, Lin WC. MCPH1/BRIT1 cooperates with E2F1 in the activation of checkpoint, DNA repair and apoptosis. EMBO Rep. 2008 Sep;9(9):907-15
This article should be referenced as such:
Liang Y, Lin SY, Li K. MCPH1 (microcephalin 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):243-245.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 246
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
NKX3-1 (NK3 homeobox 1) Liang-Nian Song, Edward P Gelmann
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA (LNS,
EPG)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/NKX31ID41541ch8p21.html DOI: 10.4267/2042/44701
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: NKX3 BAPX2; NKX3A; NKX3.1
HGNC (Hugo): NKX3-1
Location: 8p21.2
Local order: Gene orientation: telomere-3' NKX3.1 5'-
centromere.
DNA/RNA
Description
The gene has two exons and one intron.
Transcription
Transcription takes place in a centromere --> telomere
orientation. The length of the processed mRNA is
about 3200 bp.
Pseudogene
Not known.
Protein
Description
234 amino acids; 35-38 kDa, contains one N-
terminal domain (residues 1-123), one homeo-domain
(residues 124-183), and one C-terminal domain
(residues 184-234).
Expression
Expression is restricted to the adult murine prostate and
bulbourethral gland. During early murine
embryogenesis NKX3-1 expression has also been
detected in developing somites and testes. In the adult
human expression is seen in prostate epithelium, testis,
ureter, and pulmonary bronchial mucous glands.
Localisation
Nuclear.
Function
Binds to DNA to suppress transcription. Interacts with
transcription factors, e.g. serum response factor, to
enhance transcriptional activation. Binds to and
potentiates topoisomerase I DNA resolving activity.
Acts as prostate tumor suppressor.
Homology
Homeodomain protein with membership of the NKX
family.
The gene for NKX3-1 comprises two exons of 334 and 2947 bp, respectively. The length of the intron is 964 bp. Positions of start and stop codons are indicated.
NKX3-1 contains two exons encoding a 234-amino acid protein including a homeodomain (grey).
NKX3-1 (NK3 homeobox 1) Song LN, Gelmann EP
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 247
Mutations
Germinal
Twenty-one germ-line variants have been identified in
159 probands of hereditary prostate cancer families.
These variants were linked to prostate cancer risk in
hereditary prostate cancer families. For example, the
C154T (11% of the population) polymorphism
mutation is associated with prostatic enlargement and
prostate cancer risk. A T164A mutations in one family
cosegregates with prostate cancer in three affected
brothers. For a more complete list of identified
mutations, please visit
http://cancerres.aacrjournals.org/cgi/content/full/66/1/6
9.
Somatic
None.
Implicated in
Prostate Cancer
Disease
Prostate cancer is the most commonly diagnosed cancer
in American men and the second leading cause of
cancer-related deaths. Prostate cancer predominantly
occurs in the peripheral zone of the human prostate,
with roughly 5 to 10% of cases found in the central
zone. Disease development involves the temporal and
spatial loss of the basal epithelial compartment
accompanied by increased proliferation and
dedifferentiation of the luminal (secretory) epithelial
cells. Prostate cancer is a slow developing disease that
is typically found in men greater than 60 years of age
and incidence increases with increasing age.
Prognosis
PSA test combined with digital-rectal exams are used
to screen for the presence of disease. If the digital-
rectal exams are positive, additional tests including
needle core biopsies are taken to assess disease stage
and grade. Patients with localized, prostate-restricted
disease are theoretically curable with complete removal
of the prostate (radical prostatectomy). Patients with
extra-prostatic disease are treated with hormone
(androgen ablation) therapy, radiation, and/or
antiandrogens; however, no curative treatments are
available for nonorgan confined metastatic disease.
Cytogenetics
Various forms of aneuploidy.
Oncogenesis
Nkx3.1 plays an essential role in normal murine
prostate development. Loss of function of Nkx3.1 leads
to defects in prostatic protein secretions and in ductal
morphogenesis. Loss-of-function of Nkx3.1 also
contributes to prostate carcinogenesis. For example,
Nkx3.1 mutant mice develop prostatic dysplasia.
Nkx3.1 loss potentiates prostate carcinogenesis in a
Pten+/-
background. Further-rmore, by a variety of
mechanisms NKX3.1 expression is reduced in
noninvasive and early stage human prostate cancer,
suggesting that its decreased expression is one of the
earliest steps in the majority of human prostate cancers.
References He WW, Sciavolino PJ, Wing J, Augustus M, Hudson P, Meissner PS, Curtis RT, Shell BK, Bostwick DG, Tindall DJ, Gelmann EP, Abate-Shen C, Carter KC. A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer. Genomics. 1997 Jul 1;43(1):69-77
Sciavolino PJ, Abrams EW, Yang L, Austenberg LP, Shen MM, Abate-Shen C. Tissue-specific expression of murine Nkx3.1 in the male urogenital system. Dev Dyn. 1997 May;209(1):127-38
Voeller HJ, Augustus M, Madike V, Bova GS, Carter KC, Gelmann EP. Coding region of NKX3.1, a prostate-specific homeobox gene on 8p21, is not mutated in human prostate cancers. Cancer Res. 1997 Oct 15;57(20):4455-9
Prescott JL, Blok L, Tindall DJ. Isolation and androgen regulation of the human homeobox cDNA, NKX3.1. Prostate. 1998 Apr 1;35(1):71-80
Bhatia-Gaur R, Donjacour AA, Sciavolino PJ, Kim M, Desai N, Young P, Norton CR, Gridley T, Cardiff RD, Cunha GR, Abate-Shen C, Shen MM. Roles for Nkx3.1 in prostate development and cancer. Genes Dev. 1999 Apr 15;13(8):966-77
Tanaka M, Lyons GE, Izumo S. Expression of the Nkx3.1 homobox gene during pre and postnatal development. Mech Dev. 1999 Jul;85(1-2):179-82
Bowen C, Bubendorf L, Voeller HJ, Slack R, Willi N, Sauter G, Gasser TC, Koivisto P, Lack EE, Kononen J, Kallioniemi OP, Gelmann EP. Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression. Cancer Res. 2000 Nov 1;60(21):6111-5
Korkmaz KS, Korkmaz CG, Ragnhildstveit E, Kizildag S, Pretlow TG, Saatcioglu F. Full-length cDNA sequence and genomic organization of human NKX3A - alternative forms and regulation by both androgens and estrogens. Gene. 2000 Dec 30;260(1-2):25-36
Schneider A, Brand T, Zweigerdt R, Arnold H. Targeted disruption of the Nkx3.1 gene in mice results in morphogenetic defects of minor salivary glands: parallels to glandular duct morphogenesis in prostate. Mech Dev. 2000 Jul;95(1-2):163-74
Steadman DJ, Giuffrida D, Gelmann EP. DNA-binding sequence of the human prostate-specific homeodomain protein NKX3.1. Nucleic Acids Res. 2000 Jun 15;28(12):2389-95
Tanaka M, Komuro I, Inagaki H, Jenkins NA, Copeland NG, Izumo S. Nkx3.1, a murine homolog of Ddrosophila bagpipe, regulates epithelial ductal branching and proliferation of the prostate and palatine glands. Dev Dyn. 2000 Oct;219(2):248-60
Xu LL, Srikantan V, Sesterhenn IA, Augustus M, Dean R, Moul JW, Carter KC, Srivastava S. Expression profile of an androgen regulated prostate specific homeobox gene NKX3.1 in primary prostate cancer. J Urol. 2000 Mar;163(3):972-9
Ornstein DK, Cinquanta M, Weiler S, Duray PH, Emmert-Buck MR, Vocke CD, Linehan WM, Ferretti JA. Expression studies and mutational analysis of the androgen regulated homeobox gene NKX3.1 in benign and malignant prostate epithelium. J Urol. 2001 Apr;165(4):1329-34
NKX3-1 (NK3 homeobox 1) Song LN, Gelmann EP
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 248
Abdulkadir SA, Magee JA, Peters TJ, Kaleem Z, Naughton CK, Humphrey PA, Milbrandt J. Conditional loss of Nkx3.1 in adult mice induces prostatic intraepithelial neoplasia. Mol Cell Biol. 2002 Mar;22(5):1495-503
Gelmann EP, Steadman DJ, Ma J, Ahronovitz N, Voeller HJ, Swope S, Abbaszadegan M, Brown KM, Strand K, Hayes RB, Stampfer MJ. Occurrence of NKX3.1 C154T polymorphism in men with and without prostate cancer and studies of its effect on protein function. Cancer Res. 2002 May 1;62(9):2654-9
Kim MJ, Cardiff RD, Desai N, Banach-Petrosky WA, Parsons R, Shen MM, Abate-Shen C. Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis. Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2884-9
Abate-Shen C, Banach-Petrosky WA, Sun X, Economides KD, Desai N, Gregg JP, Borowsky AD, Cardiff RD, Shen MM. Nkx3.1; Pten mutant mice develop invasive prostate adenocarcinoma and lymph node metastases. Cancer Res. 2003 Jul 15;63(14):3886-90
Gelmann EP, Bowen C, Bubendorf L. Expression of NKX3.1 in normal and malignant tissues. Prostate. 2003 May 1;55(2):111-7
Magee JA, Abdulkadir SA, Milbrandt J. Haploinsufficiency at the Nkx3.1 locus. A paradigm for stochastic, dosage-sensitive gene regulation during tumor initiation. Cancer Cell. 2003 Mar;3(3):273-83
Shen MM, Abate-Shen C. Roles of the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis. Dev Dyn. 2003 Dec;228(4):767-78
Korkmaz CG, Korkmaz KS, Manola J, Xi Z, Risberg B, Danielsen H, Kung J, Sellers WR, Loda M, Saatcioglu F. Analysis of androgen regulated homeobox gene NKX3.1 during prostate carcinogenesis. J Urol. 2004 Sep;172(3):1134-9
Asatiani E, Huang WX, Wang A, Rodriguez Ortner E, Cavalli LR, Haddad BR, Gelmann EP. Deletion, methylation, and expression of the NKX3.1 suppressor gene in primary human prostate cancer. Cancer Res. 2005 Feb 15;65(4):1164-73
Bethel CR, Faith D, Li X, Guan B, Hicks JL, Lan F, Jenkins RB, Bieberich CJ, De Marzo AM. Decreased NKX3.1 protein expression in focal prostatic atrophy, prostatic intraepithelial neoplasia, and adenocarcinoma: association with gleason score and chromosome 8p deletion. Cancer Res. 2006 Nov 15;66(22):10683-90
Ju JH, Maeng JS, Zemedkun M, Ahronovitz N, Mack JW, Ferretti JA, Gelmann EP, Gruschus JM. Physical and functional interactions between the prostate suppressor
homeoprotein NKX3.1 and serum response factor. J Mol Biol. 2006 Jul 28;360(5):989-99
Li X, Guan B, Maghami S, Bieberich CJ. NKX3.1 is regulated by protein kinase CK2 in prostate tumor cells. Mol Cell Biol. 2006 Apr;26(8):3008-17
Rodriguez Ortner E, Hayes RB, Weissfeld J, Gelmann EP. Effect of homeodomain protein NKX3.1 R52C polymorphism on prostate gland size. Urology. 2006 Feb;67(2):311-5
Simmons SO, Horowitz JM. Nkx3.1 binds and negatively regulates the transcriptional activity of Sp-family members in prostate-derived cells. Biochem J. 2006 Jan 1;393(Pt 1):397-409
Zheng SL, Ju JH, Chang BL, Ortner E, Sun J, Isaacs SD, Sun J, Wiley KE, Liu W, Zemedkun M, Walsh PC, Ferretti J, Gruschus J, Isaacs WB, Gelmann EP, Xu J. Germ-line mutation of NKX3.1 cosegregates with hereditary prostate cancer and alters the homeodomain structure and function. Cancer Res. 2006 Jan 1;66(1):69-77
Bowen C, Stuart A, Ju JH, Tuan J, Blonder J, Conrads TP, Veenstra TD, Gelmann EP. NKX3.1 homeodomain protein binds to topoisomerase I and enhances its activity. Cancer Res. 2007 Jan 15;67(2):455-64
Mogal AP, van der Meer R, Crooke PS, Abdulkadir SA. Haploinsufficient prostate tumor suppression by Nkx3.1: a role for chromatin accessibility in dosage-sensitive gene regulation. J Biol Chem. 2007 Aug 31;282(35):25790-800
Abate-Shen C, Shen MM, Gelmann E. Integrating differentiation and cancer: the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis. Differentiation. 2008 Jul;76(6):717-27
Holmes KA, Song JS, Liu XS, Brown M, Carroll JS. Nkx3-1 and LEF-1 function as transcriptional inhibitors of estrogen receptor activity. Cancer Res. 2008 Sep 15;68(18):7380-5
Markowski MC, Bowen C, Gelmann EP. Inflammatory cytokines induce phosphorylation and ubiquitination of prostate suppressor protein NKX3.1. Cancer Res. 2008 Sep 1;68(17):6896-901
Zhang Y, Fillmore RA, Zimmer WE. Structural and functional analysis of domains mediating interaction between the bagpipe homologue, Nkx3.1 and serum response factor. Exp Biol Med (Maywood). 2008 Mar;233(3):297-309
This article should be referenced as such:
Song LN, Gelmann EP. NKX3-1 (NK3 homeobox 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):246-248.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 249
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
PLXNB1 (plexin B1) José Javier Gómez-Román, Montserrat Nicolas Martínez, Servando Lazuén Fernández, José
Fernando Val-Bernal
Department of Anatomical Pathology, Marques de Valdecilla University Hospital, Medical Faculty,
University of Cantabria, Santander, Spain (JJGR, MN, SL, JFVB)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/PLXNB1ID43413ch3p21.html DOI: 10.4267/2042/44702
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: KIAA0407; MGC149167;
OTTHUMP00000164806; PLEXIN-B1; PLXN5; SEP
HGNC (Hugo): PLXNB1
Location: 3p21.31
Local order: The Plexin B1 gene is located between
FBXW12 and CCDC51 genes.
Note
Size: 26,200 bases.
Orientation: minus strand.
DNA/RNA
Description
Functioning gene. 21.00 kb; 37 Exons.
Transcription
7097.00 bp; Number of transcripts: 1; Type:
Messenger.
Two alternatively truncated spliced variant, coding
secreted proteins (lacking the part of the extracellular
domains).
Pseudogene
No.
Protein
Description
2135 Amino acids (AA). Plexins are receptors for axon
molecular guidance molecules semaphorins. Plexin
signalling is important in pathfinding and patterning of
both neurons and developing blood vessels. Plexin-B1
is a surface cell receptor. When it binds to its ligand
SEMA4D it activates several pathways by binding of
cytoplasmic ligands, like RHOA activation and
subsequent changes of the actin cytoskeleton, axon
guidance, invasive growth and cell migration.
It monomers and heterodimers with PLXNB2 after
proteolytic processing. Binds RAC1 that has been
activated by GTP binding.
It binds PLXNA1 and by similarity ARHGEF11,
ARHGEF12, ERBB2, MET, MST1R, RND1, NRP1
and NRP2.
This family features the C-terminal regions of various
plexins. The cytoplasmic region, which has been called
a SEX domain in some members of this family is
involved in downstream signalling pathways, by
interaction with proteins such as Rac1, RhoD, Rnd1
and other plexins.
Three copies of a cysteine rich repeat are found in
Plexin. The function of the repeat is unknown.
Expression
It is highly expressed in fetal kidney, digestive system
(from esophagus to colon), thyroid, prostate and
trachea and at slightly lower levels in fetal brain, lung,
PLXNB1 (plexin B1) Gómez-Román JJ, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 250
female reproductive system (breast, uterus and ovary) and liver.
Plexin B1 policlonal antibody in foetal human central nervous system. Positive staining in developing neurons.
Localisation
Three isoforms have been identified: The isoform 1 is
located in cell membrane and the isoforms 2 and 3 are
secreted proteins.
Function
Plexin B1 has several molecular functions, like a
receptor activity, transmembrane receptor activity,
protein binding, semaphorin receptor and semaphorin
receptor binding. It is implicated in the next biological
processes: Signal transduction, intracellular signalling
cascade, multicellular organismal development, cell
migration and posi-tive regulation of axonogenesis.
Homology
It belongs to the plexin family and it contains 3
IPT/TIG domains and one Sema domain.
Mutations
Somatic
Wong et al. (2007) identified 13 different somatic
mutations in the cytoplasmic domain of the PLXNB1
gene in prostate cancer tissue. Mutations were found in
8 (89%) of 9 prostate cancer bone metastases, in 7
(41%) of 17 lymph node meta-stases, and in 41 (46%)
of 89 primary cancers. Forty percent of prostate cancers
contained the same mutation, and the majority of the
primary tumors showed overexpression of the plexin-
B1 protein. In vitro functional expression studies of the
3 most common mutations showed that the mutant
proteins resulted in increased cell motility, inva-sion,
adhesion, and lamellipodia extension compared to
wildtype. The mutations acted by hindering RAC1 and
RRAS binding and GTP activity.
Implicated in
Breast cancer
Prognosis
Loss of protein Plexin B1 expression is associated with
poor outcome in breast cancer ER (estrogen positive)
patients.
PLXNB1 (plexin B1) Gómez-Román JJ, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 251
Renal cell carcinoma
Note
By reverse transcription-polymerase chain reaction
plexin B1 is expressed in nonneoplastic renal tissue,
and it is severely downregulated in clear cell renal
carcinomas. By immunohistochemistry on tissue
microarrays it was shown that plexin B1 protein is
absent in more than 80% of renal cell carcinomas.
Otherwise, all kinds of renal tubules showed strong
membrane reactivity.
When plexin B1 expression is induced with an
expression vector in the renal adenocarcinoma cell line
ACHN, a marked reduction in proliferation rate is
found.
Prostate carcinoma
Note
13 somatic missense mutations in the cytoplasmic
domain of the Plexin-B1 gene have been reported.
Mutations were found in cancer bone metastases,
lymph node metastases, and in primary cancers.
Forty percent of prostate cancers contained the same
mutation. Overexpression of the Plexin-B1 protein was
found in the majority of primary tumors. The mutations
hinder Rac and R-Ras binding and R-RasGAP activity,
resulting in an increase in cell motility, invasion,
adhesion, and lamellipodia.
Plexin B1 in normal kidney tissue. Tubular cortical and medular cells reactive The same immunostaining after blocking peptide incubation.
PLXNB1 (plexin B1) Gómez-Román JJ, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 252
Plexin B1 loss of expression in three cases of renal cell carcinoma (clear cell upper right and left), and papillary (bottom right). One case of renal clear cell carcinoma with PlexinB1 expression (bottom left).
Osteoarthritis
Note
Using semi-quantitative reverse transcription
polymerase chain reaction (RT-PCR) analysis, plexin
B1 (PLXNB1) was confirmed to be consis-tently
expressed at lower levels in osteoarthritis.
Disease
Degenerative bone disease.
References Maestrini E, Tamagnone L, Longati P, Cremona O, Gulisano M, Bione S, Tamanini F, Neel BG, Toniolo D, Comoglio PM. A family of transmembrane proteins with homology to the MET-hepatocyte growth factor receptor. Proc Natl Acad Sci U S A. 1996 Jan 23;93(2):674-8
Fujii T, Nakao F, Shibata Y, Shioi G, Kodama E, Fujisawa H, Takagi S. Caenorhabditis elegans PlexinA, PLX-1, interacts with transmembrane semaphorins and regulates epidermal morphogenesis. Development. 2002 May;129(9):2053-63
Lorenzato A, Olivero M, Patanè S, Rosso E, Oliaro A, Comoglio PM, Di Renzo MF. Novel somatic mutations of the MET oncogene in human carcinoma metastases activating cell motility and invasion. Cancer Res. 2002 Dec 1;62(23):7025-30
Oinuma I, Katoh H, Harada A, Negishi M. Direct interaction of Rnd1 with Plexin-B1 regulates PDZ-RhoGEF-mediated Rho
activation by Plexin-B1 and induces cell contraction in COS-7 cells. J Biol Chem. 2003 Jul 11;278(28):25671-7
Usui H, Taniguchi M, Yokomizo T, Shimizu T. Plexin-A1 and plexin-B1 specifically interact at their cytoplasmic domains. Biochem Biophys Res Commun. 2003 Jan 24;300(4):927-31
Conrotto P, Corso S, Gamberini S, Comoglio PM, Giordano S. Interplay between scatter factor receptors and B plexins controls invasive growth. Oncogene. 2004 Jul 1;23(30):5131-7
Oinuma I, Ishikawa Y, Katoh H, Negishi M. The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras. Science. 2004 Aug 6;305(5685):862-5
Swiercz JM, Kuner R, Offermanns S. Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2. J Cell Biol. 2004 Jun 21;165(6):869-80
Torres-Vázquez J, Gitler AD, Fraser SD, Berk JD, Van N Pham, Fishman MC, Childs S, Epstein JA, Weinstein BM. Semaphorin-plexin signaling guides patterning of the developing vasculature. Dev Cell. 2004 Jul;7(1):117-23
Basile JR, Afkhami T, Gutkind JS. Semaphorin 4D/plexin-B1 induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway. Mol Cell Biol. 2005 Aug;25(16):6889-98
Conrotto P, Valdembri D, Corso S, Serini G, Tamagnone L, Comoglio PM, Bussolino F, Giordano S. Sema4D induces angiogenesis through Met recruitment by Plexin B1. Blood. 2005 Jun 1;105(11):4321-9
PLXNB1 (plexin B1) Gómez-Román JJ, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 253
Basile JR, Gavard J, Gutkind JS. Plexin-B1 utilizes RhoA and Rho kinase to promote the integrin-dependent activation of Akt and ERK and endothelial cell motility. J Biol Chem. 2007 Nov 30;282(48):34888-95
Harduf H, Goldman S, Shalev E. Human uterine epithelial RL95-2 and HEC-1A cell-line adhesiveness: the role of plexin B1. Fertil Steril. 2007 Jun;87(6):1419-27
Tong Y, Chugha P, Hota PK, Alviani RS, Li M, Tempel W, Shen L, Park HW, Buck M. Binding of Rac1, Rnd1, and RhoD to a novel Rho GTPase interaction motif destabilizes dimerization of the plexin-B1 effector domain. J Biol Chem. 2007 Dec 21;282(51):37215-24
Wong OG, Nitkunan T, Oinuma I, Zhou C, Blanc V, Brown RS, Bott SR, Nariculam J, Box G, Munson P, Constantinou J, Feneley MR, Klocker H, Eccles SA, Negishi M, Freeman A, Masters JR, Williamson M. Plexin-B1 mutations in prostate cancer. Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19040-5
Bouguet-Bonnet S, Buck M. Compensatory and long-range changes in picosecond-nanosecond main-chain dynamics upon complex formation: 15N relaxation analysis of the free and bound states of the ubiquitin-like domain of human plexin-
B1 and the small GTPase Rac1. J Mol Biol. 2008 Apr 11;377(5):1474-87
Gómez Román JJ, Garay GO, Saenz P, Escuredo K, Sanz Ibayondo C, Gutkind S, Junquera C, Simón L, Martínez A, Fernández Luna JL, Val-Bernal JF. Plexin B1 is downregulated in renal cell carcinomas and modulates cell growth. Transl Res. 2008 Mar;151(3):134-40
Swiercz JM, Worzfeld T, Offermanns S. ErbB-2 and met reciprocally regulate cellular signaling via plexin-B1. J Biol Chem. 2008 Jan 25;283(4):1893-901
Tong Y, Hota PK, Hamaneh MB, Buck M. Insights into oncogenic mutations of plexin-B1 based on the solution structure of the Rho GTPase binding domain. Structure. 2008 Feb;16(2):246-58
This article should be referenced as such:
Gómez-Román JJ, Nicolas Martínez M, Lazuén Fernández S, Val-Bernal JF. PLXNB1 (plexin B1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):249-253.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 254
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
RUVBL1 (RuvB-like 1 (E. coli)) Valérie Haurie, Aude Grigoletto, Jean Rosenbaum
INSERM U889, Universite Victor Segalen Bordeaux 2, 146 rue Leo Saignat, 33076 Bordeaux, France (VH,
AG, JR)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/RUVBL1ID44415ch3q21.html DOI: 10.4267/2042/44703
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: ECP54; INO80H; NMP238; PONTIN;
Pontin52; RVB1; TAP54-alpha; TIH1; TIP49; TIP49A
HGNC (Hugo): RUVBL1
Location: 3q21.3
DNA/RNA
Description
11 exons spamming 42840bp, 1371bp open reading
frame.
Transcription
1785bp mRNA.
Protein
Description
456 amino acids, 50.2 kDa. RUVBL1 belongs to the
AAA+ ATPase superfamily (ATPases associa-ted with
diverse cellular activities) sharing conserved Walker A
and B motifs, arginine fingers, and sensor domains.
The structure of RuvBL1 has been determined by X-ray
crystallography and published in 2006 (Matias et al.,
2006).
The monomers contain three domains, of which the
first and the third are involved in ATP binding and
hydrolysis. The second domain is a DNA/RNA-binding
domain as demonstrated by structural homology and
nucleic acid binding assays. RUVBL1 assembles into
an hexameric structure with a central channel. Pure
RUVBL1 displays a marginal ATPase activity in vitro
and no detectable helicase activity (Matias et al., 2006).
RUVBL1 interacts with RUVBL2 to form a dodecamer
(Puri et al., 2007). This RUVBL1/ RUVBL2 complex
displays a significant ATPase activity and is likely one
of the functional forms of the proteins.
Sumoylation of RUVBL1 was reported in metastatic
prostate cancer cells (Kim et al., 2007).
Expression
Expression is ubiquitous but especially abundant in
heart, skeletal muscle and testis (Salzer et al., 1999).
RUVBL1 is overexpressed in several tumors : liver (Li
et al., 2005), colon (Carlson et al., 2003; Lauscher et
al., 2007), lymphoma (Nishiu et al., 2002), non-small
cell lung (Dehan et al., 2007). Overexpressions of
RUVBL1 in a large number of cancers and its possible
role in human cancers have been reported (reviewed in
Huber et al., 2008).
Localisation
Cytoplasm and nucleus.
RUVBL1 (RuvB-like 1 (E. coli)) Haurie V, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 255
Function
RUVBL1 plays roles in essential signaling path-ways
such as the c-Myc and beta-catenin pathways.
RUVBL1 appears notably required for the trans-
forming activity of c-myc (Wood et al., 2000), beta-
catenin (Feng et al., 2003) and of the viral oncoprotein
E1A (Dugan et al., 2002).
RUVBL1 participates in the remodelling of chromatin
as a member of several complexes such as TRRAP,
several distinct HAT complexes and BAF53 (Wood et
al., 2000; Park et al., 2002; Feng et al., 2003).
It is also involved in transcriptional regulation
(reviewed in Gallant, 2007), DNA repair (Gospodinov
et al., 2008), snoRNP biogenesis (Watkins et al., 2002),
and telomerase activity (Venteicher et al., 2008).
RUVBL1 has a mitosis-specific function in regulating
microtubule assembly (Ducat et al., 2008).
RUVBL1 has been found expressed on the cell surface
where it participates in the activation of plasminogen
(Hawley et al., 2001).
Implicated in
Colon cancer
Disease
By immunohistochemistry, RUVBL1 expression was
found higher in 22 out of 26 cases where information
was available (Lauscher et al., 2007). The staining was
increased at the invasive margin of the tumors.
Increased RUVBL1 transcripts levels were also
reported in a smaller series (Carlson et al., 2003).
Large B cell lymphoma
Disease
Microarray analysis has identified an over-expression
of RUVBL1 in Advanced lymphomas as compared
with localized lymphomas (Nishiu et al., 2002).
Non Small cell lung cancer
Disease
Microarray analysis and subsequent RT-PCR have
shown an overexpression of RUVBL1 in NSCLC
(Dehan et al., 2007).
Cytogenetics
There is a frequent amplification of 3q21 in the same
samples (Dehan et al., 2007).
Hepatocellular carcinoma
Disease
Proteomic analysis found an overexpression of
RUVBL1 in 4 out of 10 cases (Li et al., 2005).
Autoimmune diseases
Disease
Auto-antibodies to RUVBL1 were found in the serum
of patients with polymyositis/dermato-myositis and
autoimmune hepatitis (Makino et al., 1998).
References Makino Y, Mimori T, Koike C, Kanemaki M, Kurokawa Y, Inoue S, Kishimoto T, Tamura T. TIP49, homologous to the bacterial DNA helicase RuvB, acts as an autoantigen in human. Biochem Biophys Res Commun. 1998 Apr 28;245(3):819-23
Salzer U, Kubicek M, Prohaska R. Isolation, molecular characterization, and tissue-specific expression of ECP-51 and ECP-54 (TIP49), two homologous, interacting erythroid cytosolic proteins. Biochim Biophys Acta. 1999 Sep 3;1446(3):365-70
Wood MA, McMahon SB, Cole MD. An ATPase/helicase complex is an essential cofactor for oncogenic transformation by c-Myc. Mol Cell. 2000 Feb;5(2):321-30
Hawley SB, Tamura T, Miles LA. Purification, cloning, and characterization of a profibrinolytic plasminogen-binding protein, TIP49a. J Biol Chem. 2001 Jan 5;276(1):179-86
Dugan KA, Wood MA, Cole MD. TIP49, but not TRRAP, modulates c-Myc and E2F1 dependent apoptosis. Oncogene. 2002 Aug 29;21(38):5835-43
Nishiu M, Yanagawa R, Nakatsuka S, Yao M, Tsunoda T, Nakamura Y, Aozasa K. Microarray analysis of gene-expression profiles in diffuse large B-cell lymphoma: identification of genes related to disease progression. Jpn J Cancer Res. 2002 Aug;93(8):894-901
Park J, Wood MA, Cole MD. BAF53 forms distinct nuclear complexes and functions as a critical c-Myc-interacting nuclear cofactor for oncogenic transformation. Mol Cell Biol. 2002 Mar;22(5):1307-16
Watkins NJ, Dickmanns A, Lührmann R. Conserved stem II of the box C/D motif is essential for nucleolar localization and is required, along with the 15.5K protein, for the hierarchical assembly of the box C/D snoRNP. Mol Cell Biol. 2002 Dec;22(23):8342-52
Carlson ML, Wilson ET, Prescott SM. Regulation of COX-2 transcription in a colon cancer cell line by Pontin52/TIP49a. Mol Cancer. 2003 Dec 15;2:42
Feng Y, Lee N, Fearon ER. TIP49 regulates beta-catenin-mediated neoplastic transformation and T-cell factor target gene induction via effects on chromatin remodeling. Cancer Res. 2003 Dec 15;63(24):8726-34
Li C, Tan YX, Zhou H, Ding SJ, Li SJ, Ma DJ, Man XB, Hong Y, Zhang L, Li L, Xia QC, Wu JR, Wang HY, Zeng R. Proteomic analysis of hepatitis B virus-associated hepatocellular carcinoma: Identification of potential tumor markers. Proteomics. 2005 Mar;5(4):1125-39
Matias PM, Gorynia S, Donner P, Carrondo MA. Crystal structure of the human AAA+ protein RuvBL1. J Biol Chem. 2006 Dec 15;281(50):38918-29
Dehan E, Ben-Dor A, Liao W, Lipson D, Frimer H, Rienstein S, Simansky D, Krupsky M, Yaron P, Friedman E, Rechavi G, Perlman M, Aviram-Goldring A, Izraeli S, Bittner M, Yakhini Z, Kaminski N. Chromosomal aberrations and gene expression profiles in non-small cell lung cancer. Lung Cancer. 2007 May;56(2):175-84
Gallant P. Control of transcription by Pontin and Reptin. Trends Cell Biol. 2007 Apr;17(4):187-92
Kim JH, Lee JM, Nam HJ, Choi HJ, Yang JW, Lee JS, Kim MH, Kim SI, Chung CH, Kim KI, Baek SH. SUMOylation of pontin chromatin-remodeling complex reveals a signal integration code in prostate cancer cells. Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20793-8
RUVBL1 (RuvB-like 1 (E. coli)) Haurie V, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 256
Lauscher JC, Loddenkemper C, Kosel L, Gröne J, Buhr HJ, Huber O. Increased pontin expression in human colorectal cancer tissue. Hum Pathol. 2007 Jul;38(7):978-85
Puri T, Wendler P, Sigala B, Saibil H, Tsaneva IR. Dodecameric structure and ATPase activity of the human TIP48/TIP49 complex. J Mol Biol. 2007 Feb 9;366(1):179-92
Ducat D, Kawaguchi S, Liu H, Yates JR 3rd, Zheng Y. Regulation of microtubule assembly and organization in mitosis by the AAA+ ATPase Pontin. Mol Biol Cell. 2008 Jul;19(7):3097-110
Huber O, Ménard L, Haurie V, Nicou A, Taras D, Rosenbaum J. Pontin and reptin, two related ATPases with multiple roles in cancer. Cancer Res. 2008 Sep 1;68(17):6873-6
Venteicher AS, Meng Z, Mason PJ, Veenstra TD, Artandi SE. Identification of ATPases pontin and reptin as telomerase components essential for holoenzyme assembly. Cell. 2008 Mar 21;132(6):945-57
Gospodinov A, Tsaneva I, Anachkova B. RAD51 foci formation in response to DNA damage is modulated by TIP49. Int J Biochem Cell Biol. 2009 Apr;41(4):925-33
This article should be referenced as such:
Haurie V, Grigoletto A, Rosenbaum J. RUVBL1 (RuvB-like 1 (E. coli)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):254-256.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 257
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
RUVBL2 (RuvB-like 2 (E. coli)) Aude Grigoletto, Valérie Haurie, Jean Rosenbaum
INSERM U889, Universite Victor Segalen Bordeaux 2, 146 rue Leo Saignat, 33076 Bordeaux, France (AG,
VH, JR)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/RUVBL2ID42185ch19q13.html DOI: 10.4267/2042/44704
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: CGI-46; ECP51; INO80J; REPTIN;
RVB2; Reptin52; Rvb2; TAP54-beta; TIH2; TIP48;
TIP49B
HGNC (Hugo): RUVBL2
Location: 19q13.33
DNA/RNA
Description
15 exons, 14 introns (Parfait et al., 2000).
Transcription
1518bp mRNA with 463aa open reading frame.
Protein
Description
463 amino acids, 52 kDa.
RUVBL2 belongs to the AAA+ ATPase super-family
(ATPases associated with diverse cellular activities)
sharing conserved Walker A and B motifs, arginine
fingers, and sensor domains. The monomers contain
two domains, which are involved in ATP binding and
hydrolysis respectively. RUVBL2 assembles into an
hexameric structure with a central channel.
RUVBL2 interacts with RUVBL1 to form a dodecamer
(Puri et al., 2007). This RUVBL1/ RUVBL2 complex
displays a significant ATPase activity and is likely one
of the functional forms of the proteins. Sumoylation of
RUVBL2 has been reported on
Lys456 in invasive prostate cancer cells (Kim et al.,
2006).
RUVBL2 is phosphorylated on an ATM/ATR
consensus site following DNA damage (Matsuoka et
al., 2007).
Expression
Expression of RUVBL2 is ubiquitous but especially
abundant in thymus and testis (Salzer et al., 1999;
Parfait et al., 2000).
RUVBL2 is overexpressed in hepatocellular carci-
noma (Rousseau et al., 2007). Overexpression of
RUVBL2 in several cancers and its possible role in
human cancers has been reported (reviewed in Huber et
al., 2008).
Localisation
Cytoplasm and nucleus.
Function
RUVBL2 interacts with c-myc (Wood et al., 2000) and
also modulates transcriptional regulation by the beta-
catenin/TCF-LEF complex (Bauer et al., 2000) and
ATF2 (Cho et al., 2001). RUVBL2 participates in the
remodelling of chromatin as a member of several
complexes such as TIP60 (Ikura et al., 2000), INO80
(Jin et al., 2005), SRCAP (Cai et al., 2005).
It is also involved in transcriptional regulation
(reviewed in Gallant, 2007), DNA repair (Gospodinov
et al., 2008), snoRNP biogenesis (Watkins et al., 2002),
and telomerase activity (Venteicher et al., 2008).
RUVBL2 silencing in fibroblasts induces a senescent
phenotype (Chan et al., 2005).
Implicated in
Hepatocellular carcinoma (HCC)
Disease
RUVBL2 (RuvB-like 2 (E. coli)) Grigoletto A, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 258
RUVBL2 was found to be overexpressed in 75% of
cases in a series of 96 human HCC studied with real-
time RT-PCR (Rousseau et al., 2007). It was also
increased in a smaller 15 cases series (Iizuka et al.,
2006). No mutations in the coding sequence were
identified (Rousseau et al., 2007).
Prognosis
Overexpression of RUVBL2 was an independent factor
of poor prognosis (Rousseau et al., 2007).
Oncogenesis
RUVBL2 depletion with siRNAs led to HCC cell
growth arrest and apoptosis, whereas over-expression
in HCC cells allowed these cells to give rise to more
progressive tumors in xenografts than control cells
(Rousseau et al., 2007).
Colon cancer
Disease
RUVBL2 was overexpressed in a series of 18 colon
cancers (Graudens et al., 2006).
Melanoma
Disease
RUVBL2 was overexpressed in a series of 45
melanomas (Talantov et al., 2005).
Bladder carcinoma
Disease
RUVBL2 was overexpressed in a series of 108 bladder
carcinomas (Sanchez-Carbayo et al., 2006).
Prostate cancer
Oncogenesis
In conjunction with beta-catenin, RUVBL2 represses
the expression of the anti-metastasis gene KAI-1 (Kim
et al., 2005) and is involved in the invasive phenotype
of cultured prostate cancer cells (Kim et al., 2006).
References Salzer U, Kubicek M, Prohaska R. Isolation, molecular characterization, and tissue-specific expression of ECP-51 and ECP-54 (TIP49), two homologous, interacting erythroid cytosolic proteins. Biochim Biophys Acta. 1999 Sep 3;1446(3):365-70
Bauer A, Chauvet S, Huber O, Usseglio F, Rothbächer U, Aragnol D, Kemler R, Pradel J. Pontin52 and reptin52 function as antagonistic regulators of beta-catenin signalling activity. EMBO J. 2000 Nov 15;19(22):6121-30
Ikura T, Ogryzko VV, Grigoriev M, Groisman R, Wang J, Horikoshi M, Scully R, Qin J, Nakatani Y. Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell. 2000 Aug 18;102(4):463-73
Parfait B, Giovangrandi Y, Asheuer M, Laurendeau I, Olivi M, Vodovar N, Vidaud D, Vidaud M, Bièche I. Human TIP49b/RUVBL2 gene: genomic structure, expression pattern, physical link to the human CGB/LHB gene cluster on chromosome 19q13.3. Ann Genet. 2000 Apr-Jun;43(2):69-74
Wood MA, McMahon SB, Cole MD. An ATPase/helicase complex is an essential cofactor for oncogenic transformation by c-Myc. Mol Cell. 2000 Feb;5(2):321-30
Cho SG, Bhoumik A, Broday L, Ivanov V, Rosenstein B, Ronai Z. TIP49b, a regulator of activating transcription factor 2 response to stress and DNA damage. Mol Cell Biol. 2001 Dec;21(24):8398-413
Watkins NJ, Dickmanns A, Lührmann R. Conserved stem II of the box C/D motif is essential for nucleolar localization and is required, along with the 15.5K protein, for the hierarchical assembly of the box C/D snoRNP. Mol Cell Biol. 2002 Dec;22(23):8342-52
Cai Y, Jin J, Florens L, Swanson SK, Kusch T, Li B, Workman JL, Washburn MP, Conaway RC, Conaway JW. The mammalian YL1 protein is a shared subunit of the TRRAP/TIP60 histone acetyltransferase and SRCAP complexes. J Biol Chem. 2005 Apr 8;280(14):13665-70
Chan HM, Narita M, Lowe SW, Livingston DM. The p400 E1A-associated protein is a novel component of the p53 --> p21 senescence pathway. Genes Dev. 2005 Jan 15;19(2):196-201
Jin J, Cai Y, Yao T, Gottschalk AJ, Florens L, Swanson SK, Gutiérrez JL, Coleman MK, Workman JL, Mushegian A, Washburn MP, Conaway RC, Conaway JW. A mammalian chromatin remodeling complex with similarities to the yeast INO80 complex. J Biol Chem. 2005 Dec 16;280(50):41207-12
Kim JH, Kim B, Cai L, Choi HJ, Ohgi KA, Tran C, Chen C, Chung CH, Huber O, Rose DW, Sawyers CL, Rosenfeld MG, Baek SH. Transcriptional regulation of a metastasis suppressor gene by Tip60 and beta-catenin complexes. Nature. 2005 Apr 14;434(7035):921-6
Talantov D, Mazumder A, Yu JX, Briggs T, Jiang Y, Backus J, Atkins D, Wang Y. Novel genes associated with malignant melanoma but not benign melanocytic lesions. Clin Cancer Res. 2005 Oct 15;11(20):7234-42
Weiske J, Huber O. The histidine triad protein Hint1 interacts with Pontin and Reptin and inhibits TCF-beta-catenin-mediated transcription. J Cell Sci. 2005 Jul 15;118(Pt 14):3117-29
Graudens E, Boulanger V, Mollard C, Mariage-Samson R, Barlet X, Grémy G, Couillault C, Lajémi M, Piatier-Tonneau D, Zaborski P, Eveno E, Auffray C, Imbeaud S. Deciphering cellular states of innate tumor drug responses. Genome Biol. 2006;7(3):R19
Iizuka N, Tsunedomi R, Tamesa T, Okada T, Sakamoto K, Hamaguchi T, Yamada-Okabe H, Miyamoto T, Uchimura S, Hamamoto Y, Oka M. Involvement of c-myc-regulated genes in hepatocellular carcinoma related to genotype-C hepatitis B virus. J Cancer Res Clin Oncol. 2006 Jul;132(7):473-81
Kim JH, Choi HJ, Kim B, Kim MH, Lee JM, Kim IS, Lee MH, Choi SJ, Kim KI, Kim SI, Chung CH, Baek SH. Roles of sumoylation of a reptin chromatin-remodelling complex in cancer metastasis. Nat Cell Biol. 2006 Jun;8(6):631-9
Sanchez-Carbayo M, Socci ND, Lozano J, Saint F, Cordon-Cardo C. Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. J Clin Oncol. 2006 Feb 10;24(5):778-89
Gallant P. Control of transcription by Pontin and Reptin. Trends Cell Biol. 2007 Apr;17(4):187-92
Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 2007 May 25;316(5828):1160-6
Puri T, Wendler P, Sigala B, Saibil H, Tsaneva IR. Dodecameric structure and ATPase activity of the human TIP48/TIP49 complex. J Mol Biol. 2007 Feb 9;366(1):179-92
Rousseau B, Ménard L, Haurie V, Taras D, Blanc JF, Moreau-Gaudry F, Metzler P, Hugues M, Boyault S, Lemière S, Canron
RUVBL2 (RuvB-like 2 (E. coli)) Grigoletto A, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 259
X, Costet P, Cole M, Balabaud C, Bioulac-Sage P, Zucman-Rossi J, Rosenbaum J. Overexpression and role of the ATPase and putative DNA helicase RuvB-like 2 in human hepatocellular carcinoma. Hepatology. 2007 Oct;46(4):1108-18
Huber O, Ménard L, Haurie V, Nicou A, Taras D, Rosenbaum J. Pontin and reptin, two related ATPases with multiple roles in cancer. Cancer Res. 2008 Sep 1;68(17):6873-6
Venteicher AS, Meng Z, Mason PJ, Veenstra TD, Artandi SE. Identification of ATPases pontin and reptin as telomerase components essential for holoenzyme assembly. Cell. 2008 Mar 21;132(6):945-57
Gospodinov A, Tsaneva I, Anachkova B. RAD51 foci formation in response to DNA damage is modulated by TIP49. Int J Biochem Cell Biol. 2009 Apr;41(4):925-33
This article should be referenced as such:
Grigoletto A, Haurie V, Rosenbaum J. RUVBL2 (RuvB-like 2 (E. coli)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):257-259.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 260
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
SH3GL2 (SH3-domain GRB2-like 2) Chinmay Kr Panda, Amlan Ghosh, Guru Prasad Maiti
Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata 700026, India (CKP,
AG, GPM)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/SH3GL2ID44345ch9p22.html DOI: 10.4267/2042/44705
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: CNSA2; EEN-B1; Endophilin-1;
FLJ20276; FLJ25015; OTTHUMP00000021084;
SH3D2A; SH3P4
HGNC (Hugo): SH3GL2
Location: 9p22.2
Local order: Next to ADAMTSL1 and FAN154A.
DNA/RNA
Description
10 exons; spans 217.93kb.
Transcription
mRNA of 2483 and 2417bp (there are two transcripts).
Protein
Description
352 amino acids; 39.96kDa and 330 amino acids;
37.51kDa.
Expression
Highest expression found in brain followed by pituitary
gland and kidney. Expression has also been reported in
bladder, eye, heart, cervix, breast, head and neck
tissues etc.
Localisation
Cytoplasmic (diffuse cytoplasmic distribution in resting
cells and a colocalization with EGF receptor in
endocytic vesicles after EGF stimulation).
Function
SH3GL2 is a presynaptic protein that binds to dynamin,
a GTPase that is implicated in endo-cytosis and
recycling of synaptic vesicles. SH3GL2 by its LPAAT
activity may induce negative membrane curvature by
converting an inverted cone shaped lipid to a cone
shaped lipid in the cytoplasmic leaflet of the bilayer.
Through this action, SH3GL2 works with dynamin to
mediate synaptic vesicle invagination from the plasma
membrane and fission. SH3GL2 in complex with CBL
and CIN85 participates in activated EGF receptor
(Stimulated by EGF) endocytosis from the membrane
surface and its subsequent lysosomal degradation.
The SH3 domain of SH3GL2 binds to a 24 amino acid
proline rich domain (PRD) in the third intracellular
loop of the G-protein coupled-1-adrenergic receptor.
SH3GL2 overexpression increased isoproterenol-
induced receptor inter-nalization by 25% and decreased
coupling of receptor to the G-protein.
The SH3 domain of SH3GL2 also binds to a proline
rich domain within the cytoplasmic tail of metallo-
protease disintegrins, transmembrane glycoproteins
acting in cell adhesion and growth factor signaling.
SH3GL2 binds preferentially to the pro-form found in
the trans-Golgi network. Therefore SH3GL2 binding
may regulate intracellular transit and maturation of
metalloprotease disintegrin.
Rat germinal centre kinse-like kinase (rGLK), a
serine/threonine cytosolic kinase, interacted with
SH3GL2. rGLK modulated c-Jun N-terminal kinase
(JNK) activity by phosphorylation and binds to the
SH3 domain of SH3GL2 through a C-terminal proline
rich domain. Coexpression of rGLK and full length
SH3GL2 increased JNK activity two fold, whereas
coexpression with the SH3 domain of SH3GL2
abrogated rGLK-induced JNK activation. SH3GL2,
therefore, modulated the mitogen-activated protein
kinase pathway through physical association with
rGLK.
SH3GL2 (SH3-domain GRB2-like 2) Panda CK, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 261
Homology
SH3GL2 contains a C-terminal SH3 domain, which
shares 92% and 84% amino acid sequence homology
with the SH3 domain of SH3GL3 and SH3GL1,
respectively. The SH3 domain of SH3GL2 also shows
high homology to the C-terminal SH3 domain of
GRB2.
Mutations
Somatic
In SH3GL2, mutation in SH3 domain has only been
reported.
Implicated in
Sporadic cancer
Disease
Reduced expressions of SH3GL2 due to different types
of molecular alterations are involved in tumor
formation in head and neck, breast and gastric tissues.
Prognosis
The prognostic significance of down regulation of
SH3GL2 in sporadic tumors is not understood clearly.
Cytogenetics
Chromosomal deletions, chromosomal gain or
amplification and chromosomal breakpoints are
frequent.
Oncogenesis
LOH on 9p22 is one of the most frequent events
identified in head and neck tumor, breast carcinoma,
pituitary adenoma, neuroblastoma etc. However,
promoter methylation appears to be another common
mechanism of SH3GL2 inactivation.
Alzheimer disease
Disease
The increased expression level of SH3GL2 in neuron is
linked to an increase in the activation of the stress
kinase c-Jun N-terminal kinase with the subsequent
death of the neuron.
Prognosis
SH3GL2 overexpression is now considered as a new
indicator of the progression of Alzhemier disease.
Cytogenetics
Increase in aneuploidy or aberration, but chromosomal
loss or gain in aneuploid cell was not specific. In some
forms of Alzheimer disease, a specific type of
aneuploidy-trisomy 21 mosaicism has been reported.
References Giachino C, Lantelme E, Lanzetti L, Saccone S, Bella Valle G, Migone N. A novel SH3-containing human gene family preferentially expressed in the central nervous system. Genomics. 1997 May 1;41(3):427-34
Howard L, Nelson KK, Maciewicz RA, Blobel CP. Interaction of the metalloprotease disintegrins MDC9 and MDC15 with two SH3 domain-containing proteins, endophilin I and SH3PX1. J Biol Chem. 1999 Oct 29;274(44):31693-9
Schmidt A, Wolde M, Thiele C, Fest W, Kratzin H, Podtelejnikov AV, Witke W, Huttner WB, Söling HD. Endophilin I mediates synaptic vesicle formation by transfer of arachidonate to lysophosphatidic acid. Nature. 1999 Sep 9;401(6749):133-41
Tang Y, Hu LA, Miller WE, Ringstad N, Hall RA, Pitcher JA, DeCamilli P, Lefkowitz RJ. Identification of the endophilins (SH3p4/p8/p13) as novel binding partners for the beta1-adrenergic receptor. Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12559-64
Huttner WB, Schmidt A. Lipids, lipid modification and lipid-protein interaction in membrane budding and fission--insights from the roles of endophilin A1 and synaptophysin in synaptic vesicle endocytosis. Curr Opin Neurobiol. 2000 Oct;10(5):543-51
Ramjaun AR, Angers A, Legendre-Guillemin V, Tong XK, McPherson PS. Endophilin regulates JNK activation through its interaction with the germinal center kinase-like kinase. J Biol Chem. 2001 Aug 3;276(31):28913-9
Reutens AT, Begley CG. Endophilin-1: a multifunctional protein. Int J Biochem Cell Biol. 2002 Oct;34(10):1173-7
Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY, Dikic I. Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors. Nature. 2002 Mar 14;416(6877):183-7
Verstreken P, Kjaerulff O, Lloyd TE, Atkinson R, Zhou Y, Meinertzhagen IA, Bellen HJ. Endophilin mutations block clathrin-mediated endocytosis but not neurotransmitter release. Cell. 2002 Apr 5;109(1):101-12
Chen Y, Deng L, Maeno-Hikichi Y, Lai M, Chang S, Chen G, Zhang JF. Formation of an endophilin-Ca2+ channel complex is critical for clathrin-mediated synaptic vesicle endocytosis. Cell. 2003 Oct 3;115(1):37-48
Hirayama S, Bajari TM, Nimpf J, Schneider WJ. Receptor-mediated chicken oocyte growth: differential expression of endophilin isoforms in developing follicles. Biol Reprod. 2003 May;68(5):1850-60
Otsuki M, Itoh T, Takenawa T. Neural Wiskott-Aldrich syndrome protein is recruited to rafts and associates with endophilin A in response to epidermal growth factor. J Biol Chem. 2003 Feb 21;278(8):6461-9
Masuda M, Takeda S, Sone M, Ohki T, Mori H, Kamioka Y, Mochizuki N. Endophilin BAR domain drives membrane curvature by two newly identified structure-based mechanisms. EMBO J. 2006 Jun 21;25(12):2889-97
Shang C, Fu WN, Guo Y, Huang DF, Sun KL. Study of the SH3-domain GRB2-like 2 gene expression in laryngeal carcinoma. Chin Med J (Engl). 2007 Mar 5;120(5):385-8
Potter N, Karakoula A, Phipps KP, Harkness W, Hayward R, Thompson DN, Jacques TS, Harding B, Thomas DG, Palmer RW, Rees J, Darling J, Warr TJ. Genomic deletions correlate with underexpression of novel candidate genes at six loci in pediatric pilocytic astrocytoma. Neoplasia. 2008 Aug;10(8):757-72
Ren Y, Xu HW, Davey F, Taylor M, Aiton J, Coote P, Fang F, Yao J, Chen D, Chen JX, Yan SD, Gunn-Moore FJ. Endophilin I expression is increased in the brains of Alzheimer disease patients. J Biol Chem. 2008 Feb 29;283(9):5685-91
Sinha S, Chunder N, Mukherjee N, Alam N, Roy A, Roychoudhury S, Kumar Panda C. Frequent deletion and
SH3GL2 (SH3-domain GRB2-like 2) Panda CK, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 262
methylation in SH3GL2 and CDKN2A loci are associated with early- and late-onset breast carcinoma. Ann Surg Oncol. 2008 Apr;15(4):1070-80
Ghosh A, Ghosh S, Maiti GP, Sabbir MG, Alam N, Sikdar N, Roy B, Roychoudhury S, Panda CK. SH3GL2 and CDKN2A/2B loci are independently altered in early dysplastic lesions of head and neck: correlation with HPV infection and tobacco habit. J Pathol. 2009 Feb;217(3):408-19
This article should be referenced as such:
Panda CK, Ghosh A, Maiti GP. SH3GL2 (SH3-domain GRB2-like 2). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):260-262.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 263
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
TOPORS (topoisomerase I binding, arginine/serine-rich) Jafar Sharif, Asami Tsuboi, Haruhiko Koseki
Developmental Genetics Group, RIKEN Center for Allergy and Immunology (RCAI), Suehirocho 1-7-22,
Tsurumi-ku, Yokohama-shi, Kanagawa-ken, Japan 230-0045 (JS, AT, HK)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/TOPORSID42663ch9p21.html DOI: 10.4267/2042/44706
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: EC 6.3.2.-; LUN;
OTTHUMP00000021182; OTTHUMP00000021184;
OTTHUMP00000045227; P53BP3; RP31; TP53BPL;
p53BP3
HGNC (Hugo): TOPORS
Location: 9p21.1
DNA/RNA
Description
Spans approximately 8kbs of DNA in the reverse strand
of chromosome 9.
Transcription
Two splicing variants.
Transcript 1 (ENST00000360538): Transcript length
4145 bps, three exons, first one non-coding.
Transcript 2 (ENST00000379858): Transcript length
3,621 bps, two exons, first one non-coding.
Pseudogene
None reported.
Protein
Description
TOPORS transcript 1 encodes a protein containing
1,045 amino acids (ENSP00000353735).
TOPORS transcript 2 encodes a protein containing 980
amino acids (ENSP00000369187).
The 1045aa human TOPORS contains a RING family
zinc-finger domain and a leucine zipper (LZ) domain in
the N-terminal. It also possesses a C-terminal bipartite
nuclear localization signal (NLS), five sequences rich
in proline, glutamine, serine and threonine (PEST
sequences) and an arginine rich domain.
Expression
Widely expressed.
Localisation
Nucleus.
The two splicing variants of TOPORS are shown. Transcript 1 (ENST00000360538) has three exons, the first one non-coding. Transcript 2 (ENST00000379858) has two exons, the first one non-coding. The coding regions are shown in yellow boxes and the non-coding regions (untranslated regions, UTRs) are shown in open boxes.
TOPORS (topoisomerase I binding, arginine/serine-rich) Sharif J, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 264
Homology between murine Topors and human TOPORS is shown. The N-terminal Ring-finger (RF, red) and leucine zipper (LZ, green) domains show 93% homology and the C-terminal nuclear localization signal (NLS, blue) domain shows 90% homology between mouse and human. The P53 binding regions of TOPORS, located inside the NLS domain, are highlighted with red lines.
Function
The RING finger protein TOPORS contains a RING
family zinc-finger domain, a putative leucine zipper
(LZ) domain, five sequences rich in proline, glutamine,
serine and threonine (PEST sequences), an
arginine/serine (RS) domain and a bipartite nuclear
localization signal (NLS). TOPORS was first identified
as a human topoisomerase I-interacting protein by yeast
two-hybrid screening (Haluska et al., 1999). TOPORS
is localized in the nucleus and has been reported to be
closely associated with the PML bodies (Weger et al.,
2003; Rasheed et al., 2002). An important role of
TOPORS is its ability to interact with the tumor
suppressor protein P53 (Zhou et al., 1999). Forced
expression of murine Topors during DNA damage
stabilizes p53, enhances the p53-dependent
transcriptional activities of waf1, MDM2 and Bax
promoters and elevates the level of endogenous p21waf1
mRNA (Lin et al., 2005). These findings suggest an
anti-oncogenic role for TOPORS. Indeed, it was shown
that TOPORS expression is decreased or undetectable
in colon adenocarcinomas relative to normal colon
tissue, and the protein level of TOPORS is undetected
in several colon cancer cell lines (Saleem et al., 2004).
Repression of TOPORS expression was also reported
in progression and development of non-small cell lung
cancer (Oyanagi et al., 2004).
Furthermore, loss of heterozygosity in the region 9p21,
the chromosomal locus harboring TOPORS, has been
frequently associated with different malignancies (Puig
et al., 2005). A high-resolution genomewide mapping
study identified deletion of the TOPORS genomic
locus in human glial tumors, suggesting a possible role
for TOPORS in gliomagenesis (Bredel et al., 2005). A
missense mutation in the TOPORS gene was
implicated in autosomal dominant pericentral retinal
dystrophy, showing that mutations in the TOPORS
gene can lead to genetic disorders (Selmer et al., 2009).
Concomitant with these observations, point mutations
and small insertions and deletions in the TOPORS gene
was found to cause approximately 1% of autosomal
dominant retinitis pigmentosa (Bowne et al., 2008).
Another study reported that mutations in TOPORS
cause autosomal dominant retinitis pigmentosa with
perivascular retinal pigment epithelium atrophy
(Chakarova et al., 2007).
Valuable information on the cellular roles for TOPORS
came through several biochemical studies. It was
shown that in the nucleus TOPORS undergoes SUMO-
1 modifications (Weger et al., 2003). Interestingly,
TOPORS itself has the ability to sumoylate other
proteins by functioning as a SUMO-1 E3 ligase. For
example, TOPORS can sumoylate p53 and the
chromatin modifying protein Sin3A (Shinbo et al.,
2005; Weger et al., 2005; Pungaliya et al., 2007).
Furthermore, TOPORS induce the accumulation of
polysumoylated forms of DNA topoisomerase I in vitro
and in vivo (Hammer et al., 2007). Intriguingly, apart
from its role as a SUMO-1 E3 ligase, TOPORS can
also function as an E3 ubiquitin ligase. In fact,
TOPORS was the first example of a protein that
possesses dual-roles as an E3 ligase for sumoylation
and ubiquitination of other proteins. It was reported
that Topors works as an E3 ubiquitin ligase with
specific E2 enzymes to ubiquitinate the p53 protein and
the prostrate tumor suppressor protein NKX3.1
(Rajendra et al., 2004; Guan et al., 2008). Intense
investigations have been undertaken in recent years to
elucidate the mechanisms of molecules that have dual
E3 ligase activities for sumoylation and ubiquitination
such as TOPORS. These studies have discovered a new
family of proteins, designated as the small ubiquitin-
related modifier (SUMO)-targeted ubiquitin ligases
(STUbLs), which directly links sumoylation and
ubiquitination (Perry et al., 2008). It has been
suggested that similar to STUbLs, TOPORS may be
recruited to its targets through SUMO-associated
interactions and stimulate their ubiquitination in a
RING finger-dependent manner (Perry et al., 2008).
Furthermore, TOPORS has been connected with
transcriptional regulation because of its role as an E3
ubiquitin ligase. In drosophila, the homolog of human
TOPORS (dTopors) ubiquitinates the Hairy
transcriptional repressor, suggesting that TOPORS
could be involved in regulating other transcription
factors as well (Secombe et al., 2004). Indeed, it was
shown that TOPORS interacts with the adeno-
associated virus type 2 (AAV-2) Rep78/68 proteins and
enhances the expression of a Rep78/68 dependent
AAV-2 gene in the absence of the helper virus (Weger
et al., 2002). Finally, it was shown that drosophila
dTopors was required for the nuclear organization of a
chromatin insulator, suggesting a role for TOPORS in
regulation of the chromatin (Capelson et al., 2005).
Homology
Widely conserved among different species. Murine
Topors shows high similarity with human TOPORS.
TOPORS (topoisomerase I binding, arginine/serine-rich) Sharif J, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 265
Mutations
Germinal
TOPORS has been implicated in autosomal dominant
pericentral retinal dystrophy (adPRD), an atypical form
of retinitis pigmentosa. Retinitis pigmentosa is the
collective name for a group of genetically induced eye
disorders that are frequenctly associated with night
blindness and tunnel vision. The TOPORS gene was
sequenced in 19 affected members of a large
Norwegian family. A novel missense mutation,
c.1205a>c, resulting in an amino acid substitution
p.Q402P, was found in all of the cases. Furthermore,
the mutation showed complete co-segregation with the
disease in the family, with the LOD score of 7.3. This
mutation was not detected in 207 unrelated and healthy
Norwegian subjects (Selmer et al., 2009). A separate
study showed that mutations in the TOPORS gene are
responsible for autosomal dominant retinitis
pigmentosa (adRP). Mutations that included an
insertion and a deletion were identified in two adRP-
affected families (Chakarova et al., 2007). Finally,
another recent study investigated whether mutation(s)
in the TOPORS gene is associated with autosomal
dominant retinitis pigmentosa (adRP). The frequency
of TOPORS mutation was analyzed in an adRP cohort
of 215 families and two different mutations, namely,
p.Glu808X and p.Arg857GlyfsX9, were identified.
This study concluded that point mutations and small
insertions or deletions in TOPORS may cause
approximately 1% of adRP (Bowne et al., 2008).
Implicated in
Non-small cell lung cancer (NSCLC)
Disease
Non-small cell lung cancer (NSCLC) is the major form
of lung cancer, with a frequency of 80~90% of all lung
carcinomas. NSCLCs are usually classified into three
groups, namely, squamous cell carcinoma,
adenocarcinoma and large-cell carci-noma. The
squamous cell carcinoma is linked with smoking and
accounts for approximately 25~30% of all lung
cancers, which are usually found in the middle of the
lungs or near a bronchus. Adenocarci-noma is
frequently spotted in the outer part of the lungs and is
thought to be responsible for ~40% of all lung cancers.
About 10~15% of lung cancers are large-cell
carcinomas, which can start in any part of the lung and
has the ability to grow and spread quickly, making this
type of lung cancers difficult to treat.
Oncogenesis
Expression of TOPORS was found to be signifi-cantly
repressed in lung cancer tissues compared to normal
lung tissues. TOPORS gene expression was slightly
down-regulated along with progression of primary
tumors, and strongly downregulated along with nodal
metastases. Interestingly, in normal tissues TOPORS
gene expression was down-regulated in smokers
(Oyanagi et al., 2004). These findings show that there
is a reverse correlation between NSCLC and TOPORS
expression and suggest that TOPORS may act as a
tumor sup-pressor gene for lung cancers.
Glial brain tumor
Disease
Glial brain tumors arise from glial cells and are highly
lethal. Glial brain tumors include astrocytomas,
oligodendrogliomas and oligoastro-cytomas.
Oncogenesis
A recent study investigated copy number alterations of
42,000 mapped human cDNA clones in a series of 54
gliomas of varying histogenesis and tumor grade by
comparative genomic hybridization technology. This
study reported a set of genetic alterations
predominantly associated with either astrocytic or
oligodendrocytic tumor phenotype. Among these
genetic alterations, a minimally deleted region
containing the TOPORS gene was identified,
suggesting a role for TOPORS in gliomagenesis
(Bredel et al., 2005).
Colon cancer
Disease
Cancerous growth in colon, rectum or the appendix are
collectively addressed as colon cancer or colorectal
cancer. This is the third most frequent form of cancer
and a major cause of cancer-related death all over the
world.
Oncogenesis
TOPORS expression is decreased or undetected in
colon adenocarcinomas compared to normal colon
tissues. Furthermore, TOPORS protein is not detectable
in several colon cancer cell lines, suggesting an anti-
oncogenic role for TOPORS (Saleem et al., 2004).
Autosomal dominant retinitis pigmentosa (adRP)
Disease
Autosomal dominant retinitis pigmentosa (adRP) is a
form of retinitis pigmentosa, a collective title for a
group of genetically induced eye disorders that are
frequenctly associated with night blindness and tunnel
vision.
Prognosis
Mutations and small insertions or deletions of the
TOPORS gene have been associated with adRP.
TOPORS has been associated with autosomal dominant
pericentral retinal dystrophy (adPRD), which has a
favorable prognosis compared to classical retinitis
pigmentosa (RP). A novel mis-sense mutation,
c.1205a>c, resulting in an amino acid substitution
p.Q402P, was observed in all affected members of a
large Norweigian family (Selmer et al., 2009). In
another study, an adRP cohort of 215 families was
investigated and two different mutations, namely,
TOPORS (topoisomerase I binding, arginine/serine-rich) Sharif J, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 266
p.Glu808X and p.Arg857GlyfsX9, were identified
(Bowne at al., 2008). TOPORS has also been
implicated in autosomal dominant retinitis pigmentosa
with perivascular retinal pigment atrophy, a disorder
that showed a distinct phenotype at the earlier stage of
the disease, with an unusual perivascular cuff of retinal
pigment epithelium atrophy, which was found
surrounding the superior and inferior arcades in the
retina. This study reported mutations in the TOPORS
gene that included an insertion and a deletion was
identified in two adRP-affected families (Chakarova et
al., 2007).
References Puig S, Ruiz A, Lázaro C, Castel T, Lynch M, Palou J, Vilalta A, Weissenbach J, Mascaro JM, Estivill X. Chromosome 9p deletions in cutaneous malignant melanoma tumors: the minimal deleted region involves markers outside the p16 (CDKN2) gene. Am J Hum Genet. 1995 Aug;57(2):395-402
Haluska P Jr, Saleem A, Rasheed Z, Ahmed F, Su EW, Liu LF, Rubin EH. Interaction between human topoisomerase I and a novel RING finger/arginine-serine protein. Nucleic Acids Res. 1999 Jun 15;27(12):2538-44
Zhou R, Wen H, Ao SZ. Identification of a novel gene encoding a p53-associated protein. Gene. 1999 Jul 22;235(1-2):93-101
Rasheed ZA, Saleem A, Ravee Y, Pandolfi PP, Rubin EH. The topoisomerase I-binding RING protein, topors, is associated with promyelocytic leukemia nuclear bodies. Exp Cell Res. 2002 Jul 15;277(2):152-60
Weger S, Hammer E, Heilbronn R. Topors, a p53 and topoisomerase I binding protein, interacts with the adeno-associated virus (AAV-2) Rep78/68 proteins and enhances AAV-2 gene expression. J Gen Virol. 2002 Mar;83(Pt 3):511-6
Oyanagi H, Takenaka K, Ishikawa S, Kawano Y, Adachi Y, Ueda K, Wada H, Tanaka F. Expression of LUN gene that encodes a novel RING finger protein is correlated with development and progression of non-small cell lung cancer. Lung Cancer. 2004 Oct;46(1):21-8
Rajendra R, Malegaonkar D, Pungaliya P, Marshall H, Rasheed Z, Brownell J, Liu LF, Lutzker S, Saleem A, Rubin EH. Topors functions as an E3 ubiquitin ligase with specific E2 enzymes and ubiquitinates p53. J Biol Chem. 2004 Aug 27;279(35):36440-4
Saleem A, Dutta J, Malegaonkar D, Rasheed F, Rasheed Z, Rajendra R, Marshall H, Luo M, Li H, Rubin EH. The topoisomerase I- and p53-binding protein topors is differentially expressed in normal and malignant human tissues and may function as a tumor suppressor. Oncogene. 2004 Jul 8;23(31):5293-300
Secombe J, Parkhurst SM. Drosophila Topors is a RING finger-containing protein that functions as a ubiquitin-protein isopeptide ligase for the hairy basic helix-loop-helix repressor protein. J Biol Chem. 2004 Apr 23;279(17):17126-33
Bredel M, Bredel C, Juric D, Harsh GR, Vogel H, Recht LD, Sikic BI. High-resolution genome-wide mapping of genetic alterations in human glial brain tumors. Cancer Res. 2005 May 15;65(10):4088-96
Capelson M, Corces VG. The ubiquitin ligase dTopors directs the nuclear organization of a chromatin insulator. Mol Cell. 2005 Oct 7;20(1):105-16
Lin L, Ozaki T, Takada Y, Kageyama H, Nakamura Y, Hata A, Zhang JH, Simonds WF, Nakagawara A, Koseki H. topors, a p53 and topoisomerase I-binding RING finger protein, is a coactivator of p53 in growth suppression induced by DNA damage. Oncogene. 2005 May 12;24(21):3385-96
Shinbo Y, Taira T, Niki T, Iguchi-Ariga SM, Ariga H. DJ-1 restores p53 transcription activity inhibited by Topors/p53BP3. Int J Oncol. 2005 Mar;26(3):641-8
Weger S, Hammer E, Heilbronn R. Topors acts as a SUMO-1 E3 ligase for p53 in vitro and in vivo. FEBS Lett. 2005 Sep 12;579(22):5007-12
Chakarova CF, Papaioannou MG, Khanna H, Lopez I, Waseem N, Shah A, Theis T, Friedman J, Maubaret C, Bujakowska K, Veraitch B, Abd El-Aziz MM, Prescott de Q, Parapuram SK, Bickmore WA, Munro PM, Gal A, Hamel CP, Marigo V, Ponting CP, Wissinger B, Zrenner E, Matter K, Swaroop A, Koenekoop RK, Bhattacharya SS. Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy. Am J Hum Genet. 2007 Nov;81(5):1098-103
Hammer E, Heilbronn R, Weger S. The E3 ligase Topors induces the accumulation of polysumoylated forms of DNA topoisomerase I in vitro and in vivo. FEBS Lett. 2007 Nov 27;581(28):5418-24
Pungaliya P, Kulkarni D, Park HJ, Marshall H, Zheng H, Lackland H, Saleem A, Rubin EH. TOPORS functions as a SUMO-1 E3 ligase for chromatin-modifying proteins. J Proteome Res. 2007 Oct;6(10):3918-23
Bowne SJ, Sullivan LS, Gire AI, Birch DG, Hughbanks-Wheaton D, Heckenlively JR, Daiger SP. Mutations in the TOPORS gene cause 1% of autosomal dominant retinitis pigmentosa. Mol Vis. 2008 May 19;14:922-7
Guan B, Pungaliya P, Li X, Uquillas C, Mutton LN, Rubin EH, Bieberich CJ. Ubiquitination by TOPORS regulates the prostate tumor suppressor NKX3.1. J Biol Chem. 2008 Feb 22;283(8):4834-40
Perry JJ, Tainer JA, Boddy MN. A SIM-ultaneous role for SUMO and ubiquitin. Trends Biochem Sci. 2008 May;33(5):201-8
Selmer KK, Grøndahl J, Riise R, Brandal K, Braaten O, Bragadottir R, Undlien DE. Autosomal dominant pericentral retinal dystrophy caused by a novel missense mutation in the TOPORS gene. Acta Ophthalmol. 2010 May;88(3):323-8
This article should be referenced as such:
Sharif J, Tsuboi A, Koseki H. TOPORS (topoisomerase I binding, arginine/serine-rich). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):263-266.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 267
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
TRPV6 (transient receptor potential cation channel, subfamily V, member 6) Yoshiro Suzuki, Matthias A Hediger
Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern,
Switzerland (YS, MAH)
Published in Atlas Database: March 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/TRPV6ID44425ch7q34.html DOI: 10.4267/2042/44707
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: CaT1; ECaC2; CATL; ABP/ZF;
LP6728; ZFAB
HGNC (Hugo): TRPV6
Location: 7q34
Local order: Colocalized with another Ca2+
-selective
epithelial channel gene, TRPV5.
DNA/RNA
Description
TRPV6 gene consists of 15 exons and 14 introns
including a coding, and a 5'-/3'- non-coding region.
The regions encoding the ankyrin repeats, 6 trans-
membrane domains and a pore region are indicated.
Several VDREs (vitamin D responsive element) have
been identified in its promoter region.
A haplotype containing 3 non-synonymous
polymorphisms (C157R+M378V+M681T) repre-sent a
recent positive selection in human evolution. The same
haplotype seems to be associated with renal calcium
stone formation.
Transcription
There is an alterative splice variant which missed 25-
192 (a.a.). In EST database, there seems to be at least
one more variant using different exon 1 (V2) and a
variant starting from another site (P3) just upstream of
exon 2 (V3).
Schematic representation of human TRPV6 gene and neighbouring genes.
Genomic structure of human TRPV6. The coding region is shown by open bars. The non-translated regions are shown by filled bars.
TRPV6 (transient receptor potential cation channel, subfamily V, member 6) Suzuki Y, Hediger MA
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 268
Protein
Schematic representation of TRPV6 protein. Four subunits makes one channel pore. Several ankyrin repeats, one N-
glycosylation site and several calmodulin binding sites (CaM) are indicated.
Description
Glycosylated membrane protein (725 a.a., MW ~70
kDa) with 6 transmembrane regions and a pore-forming
loop. N- and C-terminal tails are in cytoplasmic side.
This protein forms a Ca2+-
selective ion channel in the
plasma membrane. TRPV6 interacts with
calmodulin which contribute to the intracellular
Ca2+
-dependent inactivation to avoid an increase
of free Ca2+
concentration. The ankyrin repeats
may play a role in the interaction between
subunits. TRPV6 can form a homo-tetramer as
well as a hetero-tetramer with TRPV5, which
exhibits distinct channel properties.
Expression
Highly expressed in placenta, moderately expressed in
exocrine pancreas, mammary gland and salivary gland.
Highly induced in small intestine under low calcium
conditions or by 1,25-dihydroxyvitamin D3 treatment.
Highly induced in prostate, breast and other cancer
tissues during tumor progression.
Localisation
Plasma membrane. Localized in the apical membrane
of the epithelial cells in the duodenum, and
syncytiotrophoblasts in placenta.
Function
Apical Ca2+
entry pathway for total body calcium
homeostasis in the small intestine under the control of
1,25-dihydroxyvitamin D3. TRPV6 likely also be
involved in the placental Ca2+
transport from mother to
fetus to maintain fetal bone mineralization.
TRPV6 may play a role in the Ca2+
entry pathway
essential for keratinocyte differentiation. Although its
exact function in cancer cells and tumor progression is
still under investigation, TRPV6 is involved in an
increase in proliferation and apoptotic resistance in
cancer cells.
Homology
73% identity with human TRPV5. 89% identity with
mouse TRPV6.
Implicated in
Prostate cancer
Oncogenesis
Expression of TRPV6 may be a predictor for prostate
cancer progression since TRPV6 mRNA and protein
levels are elevated in prostatic carcinoma compared to
benign prostatic hyperplasia and positively correlated
with Gleason grade/score in prostatic carcinoma.
TRPV6 is involved in an increase in proliferation and
apoptotic resistance in cancer cells, suggesting that
TRPV6 could be a new therapeutic target for the
treatment for advanced prostate cancer.
Breast cancer
Oncogenesis
TRPV6 mRNA was also found to be increased in breast
cancer tissues compared to normal breast tissues.
TRPV6 could be a prognostic marker for breast cancer
and therapeutic target for breast cancer treatment.
References Hediger MA, Peng JB, Brown EM Inventors.. Compositions Corresponding to a Calcium Transporter and Methods of Making and Using Same. US patent 6,534,642.
Peng JB, Chen XZ, Berger UV, Vassilev PM, Tsukaguchi H, Brown EM, Hediger MA. Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption. J Biol Chem. 1999 Aug 6;274(32):22739-46
Peng JB, Chen XZ, Berger UV, Weremowicz S, Morton CC, Vassilev PM, Brown EM, Hediger MA. Human calcium transport protein CaT1. Biochem Biophys Res Commun. 2000 Nov 19;278(2):326-32
Niemeyer BA, Bergs C, Wissenbach U, Flockerzi V, Trost C. Competitive regulation of CaT-like-mediated Ca2+ entry by protein kinase C and calmodulin. Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3600-5
Peng JB, Brown EM, Hediger MA. Structural conservation of the genes encoding CaT1, CaT2, and related cation channels. Genomics. 2001 Aug;76(1-3):99-109
Peng JB, Zhuang L, Berger UV, Adam RM, Williams BJ, Brown EM, Hediger MA, Freeman MR. CaT1 expression correlates with tumor grade in prostate cancer. Biochem Biophys Res Commun. 2001 Apr 6;282(3):729-34
Van Cromphaut SJ, Dewerchin M, Hoenderop JG, Stockmans I, Van Herck E, Kato S, Bindels RJ, Collen D, Carmeliet P, Bouillon R, Carmeliet G. Duodenal calcium absorption in vitamin D receptor-knockout mice: functional and molecular aspects. Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13324-9
Wissenbach U, Niemeyer BA, Fixemer T, Schneidewind A, Trost C, Cavalie A, Reus K, Meese E, Bonkhoff H, Flockerzi V. Expression of CaT-like, a novel calcium-selective channel,
TRPV6 (transient receptor potential cation channel, subfamily V, member 6) Suzuki Y, Hediger MA
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 269
correlates with the malignancy of prostate cancer. J Biol Chem. 2001 Jun 1;276(22):19461-8
Nilius B, Prenen J, Hoenderop JG, Vennekens R, Hoefs S, Weidema AF, Droogmans G, Bindels RJ. Fast and slow inactivation kinetics of the Ca2+ channels ECaC1 and ECaC2 (TRPV5 and TRPV6). Role of the intracellular loop located between transmembrane segments 2 and 3. J Biol Chem. 2002 Aug 23;277(34):30852-8
Zhuang L, Peng JB, Tou L, Takanaga H, Adam RM, Hediger MA, Freeman MR. Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is aberrantly expressed in human malignancies. Lab Invest. 2002 Dec;82(12):1755-64
Fixemer T, Wissenbach U, Flockerzi V, Bonkhoff H. Expression of the Ca2+-selective cation channel TRPV6 in human prostate cancer: a novel prognostic marker for tumor progression. Oncogene. 2003 Oct 30;22(49):7858-61
Hoenderop JG, Voets T, Hoefs S, Weidema F, Prenen J, Nilius B, Bindels RJ. Homo- and heterotetrameric architecture of the epithelial Ca2+ channels TRPV5 and TRPV6. EMBO J. 2003 Feb 17;22(4):776-85
Moreau R, Simoneau L, Lafond J. Calcium fluxes in human trophoblast (BeWo) cells: calcium channels, calcium-ATPase, and sodium-calcium exchanger expression. Mol Reprod Dev. 2003 Feb;64(2):189-98
Erler I, Hirnet D, Wissenbach U, Flockerzi V, Niemeyer BA. Ca2+-selective transient receptor potential V channel architecture and function require a specific ankyrin repeat. J Biol Chem. 2004 Aug 13;279(33):34456-63
Hoenderop JG, Nilius B, Bindels RJ. Calcium absorption across epithelia. Physiol Rev. 2005 Jan;85(1):373-422
Akey JM, Swanson WJ, Madeoy J, Eberle M, Shriver MD. TRPV6 exhibits unusual patterns of polymorphism and divergence in worldwide populations. Hum Mol Genet. 2006 Jul 1;15(13):2106-13
Meyer MB, Watanuki M, Kim S, Shevde NK, Pike JW. The human transient receptor potential vanilloid type 6 distal promoter contains multiple vitamin D receptor binding sites that mediate activation by 1,25-dihydroxyvitamin D3 in intestinal cells. Mol Endocrinol. 2006 Jun;20(6):1447-61
Bianco SD, Peng JB, Takanaga H, Suzuki Y, Crescenzi A, Kos CH, Zhuang L, Freeman MR, Gouveia CH, Wu J, Luo H, Mauro T, Brown EM, Hediger MA. Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene. J Bone Miner Res. 2007 Feb;22(2):274-85
Lehen'kyi V, Beck B, Polakowska R, Charveron M, Bordat P, Skryma R, Prevarskaya N. TRPV6 is a Ca2+ entry channel essential for Ca2+-induced differentiation of human keratinocytes. J Biol Chem. 2007 Aug 3;282(31):22582-91
Lehen'kyi V, Flourakis M, Skryma R, Prevarskaya N. TRPV6 channel controls prostate cancer cell proliferation via Ca(2+)/NFAT-dependent pathways. Oncogene. 2007 Nov 15;26(52):7380-5
Bolanz KA, Hediger MA, Landowski CP. The role of TRPV6 in breast carcinogenesis. Mol Cancer Ther. 2008 Feb;7(2):271-9
Hughes DA, Tang K, Strotmann R, Schöneberg T, Prenen J, Nilius B, Stoneking M. Parallel selection on TRPV6 in human populations. PLoS One. 2008 Feb 27;3(2):e1686
Stumpf T, Zhang Q, Hirnet D, Lewandrowski U, Sickmann A, Wissenbach U, Dörr J, Lohr C, Deitmer JW, Fecher-Trost C. The human TRPV6 channel protein is associated with cyclophilin B in human placenta. J Biol Chem. 2008 Jun 27;283(26):18086-98
Suzuki Y, Kovacs CS, Takanaga H, Peng JB, Landowski CP, Hediger MA. Calcium channel TRPV6 is involved in murine maternal-fetal calcium transport. J Bone Miner Res. 2008 Aug;23(8):1249-56
Suzuki Y, Landowski CP, Hediger MA. Mechanisms and regulation of epithelial Ca2+ absorption in health and disease. Annu Rev Physiol. 2008;70:257-71
Suzuki Y, Pasch A, Bonny O, Mohaupt MG, Hediger MA, Frey FJ. Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation. Hum Mol Genet. 2008 Jun 1;17(11):1613-8
This article should be referenced as such:
Suzuki Y, Hediger MA. TRPV6 (transient receptor potential cation channel, subfamily V, member 6). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):267-269.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 270
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) Shian-Ying Sung
Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and
Hospital, Taichung, Taiwan (SYS)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/ADAM9ID573ch8p11.html DOI: 10.4267/2042/44708
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: MDC9; Meltrin-gamma; MLTNG;
MCMP; KIAA0021
HGNC (Hugo): ADAM9
Location: 8p11.23
Local order: TACC1 - PLEKHA2 - HTRA4 - TM2D2
- ADAM9 - ADAM32 - ADAM5p - ADAM3A -
ADAM18 - ADAM2; TACC1; 8P11; Transforming,
acidic coiled-coil containing protein 1; PLEKHA2;
8P11.23; Pleckstrin homology domain containing,
family A member 2; HTRA4; 8P11.23; HtrA serine
peptidase 4; TM2D2; 8P11.23; TM2 domain containing
2; ADAM9; 8P11.23; a disintegrin and
metalloproteinase domain 9; ADAM32; 8p11.23;
ADAM metalloproteinase domain 32; ADAM5P;
8p11.23; ADAM metallopeptidase domain 5
pseudogene; ADAM3A; 8p11.23; ADAM
metallopeptidase domain 3A (Cyritestin 1); ADAM18;
8p11.22; ADAM metallopeptidase domain 18;
ADAM2; 8p11.22; ADAM metallopeptidase domain 2.
Note
The ADAM9 gene, a member of the ADAM super-
family has metalloprotease, integrin binding and cell
adhesion capacities. It shown the metallo-protease
domain cleaves insulin beta-chain, TNF-alpha, gelatin,
beta-casein, fibronectin, as well as shedding of EGF,
HB-EGF and FGFR2IIIB. The integrin domain
mediates cellular adhesion through alpha6beta1 and
alphavbeta5 integrins. The cytoplasmic tail of ADAM9
has been reported to interact with endophilin 1
(SH3GL2), SH3PX1 and
mitotic arrest deficient 2beta. ADAM9 has implicated
mediated by stress, such as oxidation during
inflammation and cancer progression.
DNA/RNA
Note
The ADAM9 gene transcript 2 isoforms of mRNA with
altered splicing results the lost of exon 18 in the second
isoform of ADAM9 mRNA and early stop codon.
Description
ADAM9 gene extends 108,276 base pairs with 22
exons which gives rise to 2 different ADAM9 trans-
cripts with differential splicing. The mRNA of
ADAM9 isoform 1 is 4111 base pair and isoform 2 is
4005. ADAM9 isoform 2 lacks exon 18 of iso-form 1
in the coding region, which results in a frameshift and
an early stop codon. The isoform 2 lacks the c-terminal
transmembrane and cyto-plasmic domains and is a
secreted form.
Transcription
Isoform 1 mRNA of ADAM9 (NM_003816) has a size
of 4111 bp, isoform 2 mRNA (NM_001005845) has a
size of 4005 bp. ADAM9 mRNA is equally expressed
in many tissue. Among cancer progression, ADAM9
mRNA is relatively highly expressed in prostate cancer
and breast cancer. However, little is known of
differential expression between different isoform of
ADAM9.
Pseudogene
No pseudogene has reported for ADAM9.
ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) Sung SY
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 271
ADAM9 gene is located on chromosome 8p11.23 spread out on 108,276 deoxynucleotides contained 22 exons. The coding sequence of ADAM9 is 2460 nucleotides. Two isoforms reported, isoform 1 of ADAM9 carried full-length membrane bond ADAM9 and isoform 2 carried soluble form of ADAM9 (sADAM9). The sADAM9 is due to alternative splicing in which lost of exon 18 and results in early stop translation in exon 19.
Protein
Note
Two different isoform of ADAM9 was reported, the
full length and soluble form of ADAM9. Recent report
suggests promoter polymorphisms regulated ADAM9
transcription that plays a protective role against
Alzheimer's disease.
Description
The predicted molecular mass of ADAM9 is about 84
KDa. ADAM9 contained coding sequence of 2460
nucleotides which encoding amino acid of 819
residues. The full length of active ADAM9 contained
several functional regions including metalloproteinase,
disintegrin, cystein rich, EGF-like, transmembrane and
cytoplasmic domains. The pro-domain of ADAM9 was
removed by furin-type convertase during ADAM9
translocated onto membrane and become active form.
Recent reports indicated soluble form of ADAM9
cloned from human cDNA library that showed
increased of cancer invasion in malignant progression.
Expression
ADAM9 is ubiquitously expressed. SAGE analyses of
ADAM9 expression demonstrated that ADAM9 is
expressed in the bone marrow, lymph node, brain,
retina, heart, skin, muscle, lung, prostate, breast and
placenta. Increased expression of ADAM9 was
reported in several cancers, including gastric, breast,
prostate, colon, and pancreatic cancers. Splicing
alteration and lost of exon 18 of ADAM9 causes lost of
transmembrane domain and early stop in soluble form
of ADAM9.
Localisation
Full length has N-terminal signal peptide and a single
hydrophobic region predicted to be transmembrane
domain. Hence, the full length of ADAM9 is localized
to the plasma membrane. Soluble ADAM9 lack the
transmembrane domain and cytoplasmic domain and to
be released out of cell.
Function
1. Ectodomain shedding: Metalloproteinase domain of
ADAM9 is zinc dependent. Metallo-proteinase has
been showed to involve ectodomain shedding (see table
below). One such protein is the heparin-binding EGF-
like growth factor (HB-EGF) and amyloid precursor
protein (APP).
2. Matrix Degradation: purified metalloproteinase
domain of ADAM9 showed the ability to digest
fibronectin, gelatin and beta-casein. Secreted form of
ADAM9 showed the ability to digest laminin and
promote cancer invasion.
3. Cell contact: ADAM9 specifically bind to integrin
alpha6beta1, a laminin receptor, via disintegrin region of
ADAM9 through non-RGD mechanism. ADAM9 also
have been implicated in binding of avbeta5 in divalent
cation dependent condition, suggests ADAM9 can
function as adhesion molecule for cell-cell and cell-
martrix interaction. Secreted form of ADAM9 binds
directly to alpha6beta4 and alpha2beta1 integrin and
ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) Sung SY
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 272
Two isoforms of ADAM9 with their specific function. Soluble form of ADAM9 has function to active APP either on the same cell or neighbor cell.
ability to cleave laminin and promote cancer
progression.
4. Cysteine-Rich domain: The ADAM Cysteine-rich
domain is not found in other organisms, such as virus,
archaeal, bacterial or plant. The function of cysteine-
rich domain might involved in complement the binding
ability of disintegrin-mediated interactions.
TABLE: Substrate and Peptide Sequence Cleaved.
Substrate Peptide sequence cleaved
(*: cleave site)
Amyloid
precursor
protein
EVHH*QKLVFFAE
TNF-a SPLA*QAVRS*SSR
P75 TNF
receptor SMAPGAVH*LPQP
c-kit ligand LPPVA*A*S*SLRND
Insulin B
Chain LVEALY*LVCGERGFFY*TPKA
HB-EGF GLSLPVE*NRLYTYD
Homology
The table below gives homology between the human
ADAM9 and others organisms.
Mutations
Note
Single nucleotide polymorphosim analyses of
chromosome 8 demonstrated about 356 SNP in the
chromosome 8p11.23. Most of them are located in
intron of ADAM9. No mutation was reported in
ADAM9 coding sequence. Recent evidence sug-gests
promoter polymorphisms that may upregulate ADAM9
transcription, such as -1314C has higher of
transcription activities.
ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) Sung SY
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 273
ADAM9 gene promoter region contained 4 polymorphisms: -542C/T, -600A/C, -963A/G and -1314T/C. 1314C showed higher ADAM9 transcription compared to 1314T.
Implicated in
Prostate cancer
Note
ADAM9 has been implicated in prostate cancer
progression and the production of reactive oxygen
species. Large cohort of clinic evaluation demonst-
rated ADAM9 is upregulated in prostate cancer in both
mRNA and protein level. ADAM9 protein expression
can be upregulated by androgen in AR-positive but not
in AR-negative prostate cancer cells that is through
downstream ROS as mediator to induce ADAM9
expression. ADAM9 protein expression is associated
with shortened PSA-relapse-free survival in clinic
evaluation.
Pancreatic cancer
Note
Pancreatic ductal adenocarcinomas showing increased
of ADAM9 expression in microarray analyses and
clinic evaluation that correlated with poor tumor
differentiation and shorter overall survival rate.
Breast cancer
Note
ADAM9 expression is 24% positive in normal breast
tissue and 66% positive in breast carcinomas. Western
blot studies demonstrated multiform of ADAM9 were
expressed in breast carcinoma. In addition, recent study
demonstrated copy number abnormalities occurred in
ADAM9 gene.
Lung cancer
Note
The increased of ADAM9 expression in lung cancer
enhanced cell adhesion and invasion of non-small cell
lung cancer through change adhesion properties and
sensitivity to growth factors, and increase its capacity
of brain metastasis.
Renal cell carcinoma
Note
ADAM9 was implicated increased expression in renal
cell carcinoma and associated with tumor progression.
It also showed higher of ADAM9 expression is
associated with shorten patient survival rate.
Alzheimer's disease
Note
The amyloid precursor protein (APP) of Alzheimer's
disease is a transmembrane protein processed via either
the non-amyloidogenic or amyloidogenic pathways. In
the non-amyloidogenic pathway, alpha-secretase
cleaves APP within the Abeta peptide region releasing
a large soluble fragment sAPPalpha that has
neuroprotective properties. In the amyloidogenic
pathway, beta-secretase and gamma-secretase
sequentially cleave APP to generate the intact Abeta
peptide, which is neurotoxic.
ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) Sung SY
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 274
In ADAM9 expression analyses showed increase in
production of sAPPalpha upon phorbol ester treatment
of cell that co-express of ADAM9 and APP. ADAM9
did not cleave at the Lys16-Leu17 bone but at the
His14-Gln15 bone in the Abeta domain of APP cleave
site. Hence, ADAM9 might play role in protective
against sporadic Alzheimer's disease.
References Shuttleworth A. Violence to healthcare staff must be tackled nationally. Prof Nurse. 1992 Jun;7(9):560
Izumi Y, Hirata M, Hasuwa H, Iwamoto R, Umata T, et al. A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J. 1998 Dec 15;17(24):7260-72
Nelson KK, Schlöndorff J, Blobel CP. Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2beta. Biochem J. 1999 Nov 1;343 Pt 3:673-80
Cao Y, Kang Q, Zhao Z, Zolkiewska A. Intracellular processing of metalloprotease disintegrin ADAM12. J Biol Chem. 2002 Jul 19;277(29):26403-11
Hotoda N, Koike H, Sasagawa N, Ishiura S. A secreted form of human ADAM9 has an alpha-secretase activity for APP. Biochem Biophys Res Commun. 2002 May 3;293(2):800-5
Grützmann R, Foerder M, Alldinger I, Staub E, Brümmendorf T, Röpcke S, Li X, Kristiansen G, Jesnowski R, Sipos B, Löhr M, Lüttges J, Ockert D, Klöppel G, Saeger HD, Pilarsky C. Gene expression profiles of microdissected pancreatic ductal adenocarcinoma. Virchows Arch. 2003 Oct;443(4):508-17
Fischer OM, Hart S, Gschwind A, Prenzel N, Ullrich A. Oxidative and osmotic stress signaling in tumor cells is mediated by ADAM proteases and heparin-binding epidermal growth factor. Mol Cell Biol. 2004 Jun;24(12):5172-83
Grützmann R, Lüttges J, Sipos B, Ammerpohl O, Dobrowolski F, Alldinger I, Kersting S, Ockert D, Koch R, Kalthoff H, Schackert HK, Saeger HD, Klöppel G, Pilarsky C. ADAM9 expression in pancreatic cancer is associated with tumour type and is a prognostic factor in ductal adenocarcinoma. Br J Cancer. 2004 Mar 8;90(5):1053-8
Shintani Y, Higashiyama S, Ohta M, Hirabayashi H, Yamamoto S, Yoshimasu T, Matsuda H, Matsuura N. Overexpression of ADAM9 in non-small cell lung cancer correlates with brain metastasis. Cancer Res. 2004 Jun 15;64(12):4190-6
Asayesh A, Alanentalo T, Khoo NK, Ahlgren U. Developmental expression of metalloproteases ADAM 9, 10, and 17 becomes restricted to divergent pancreatic compartments. Dev Dyn. 2005 Apr;232(4):1105-14
Carl-McGrath S, Lendeckel U, Ebert M, Roessner A, Röcken C. The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer. Int J Oncol. 2005 Jan;26(1):17-24
Mazzocca A, Coppari R, De Franco R, Cho JY, Libermann TA, Pinzani M, Toker A. A secreted form of ADAM9 promotes carcinoma invasion through tumor-stromal interactions. Cancer Res. 2005 Jun 1;65(11):4728-38
Peduto L, Reuter VE, Shaffer DR, Scher HI, Blobel CP. Critical function for ADAM9 in mouse prostate cancer. Cancer Res. 2005 Oct 15;65(20):9312-9
Chin K, DeVries S, Fridlyand J, Spellman PT, et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell. 2006 Dec;10(6):529-41
Hirao T, Nanba D, Tanaka M, Ishiguro H, Kinugasa Y, Doki Y, Yano M, Matsuura N, Monden M, Higashiyama S. Overexpression of ADAM9 enhances growth factor-mediated recycling of E-cadherin in human colon cancer cell line HT29 cells. Exp Cell Res. 2006 Feb 1;312(3):331-9
Sung SY, Kubo H, Shigemura K, Arnold RS, Logani S, et al. Oxidative stress induces ADAM9 protein expression in human prostate cancer cells. Cancer Res. 2006 Oct 1;66(19):9519-26
Mochizuki S, Okada Y. ADAMs in cancer cell proliferation and progression. Cancer Sci. 2007 May;98(5):621-8
Shigemura K, Sung SY, Kubo H, Arnold RS, Fujisawa M, Gotoh A, Zhau HE, Chung LW. Reactive oxygen species mediate androgen receptor- and serum starvation-elicited downstream signaling of ADAM9 expression in human prostate cancer cells. Prostate. 2007 May 15;67(7):722-31
Fritzsche FR, Jung M, Tölle A, Wild P, Hartmann A, et al. ADAM9 expression is a significant and independent prognostic marker of PSA relapse in prostate cancer. Eur Urol. 2008 Nov;54(5):1097-106
Fritzsche FR, Wassermann K, Jung M, Tölle A, Kristiansen I, Lein M, Johannsen M, Dietel M, Jung K, Kristiansen G. ADAM9 is highly expressed in renal cell cancer and is associated with tumour progression. BMC Cancer. 2008 Jun 26;8:179
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This article should be referenced as such:
Sung SY. ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):270-274.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 275
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1) Maria Norlin
Department of Pharmaceutical Biosciences, Division of Biochemistry, University of Uppsala, Sweden (MN)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/CYP7B1ID40255ch8q21.html DOI: 10.4267/2042/44709
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: CBAS3; CP7B; SPG5A; CYP7B
HGNC (Hugo): CYP7B1
Location: 8q21.3
Note
CYP7B1 is a steroid hydroxylase involved in meta-
bolism of sex hormones, oxysterols (a type of
cholesterol derivatives) and neurosteroids.
DNA/RNA
Description
The human CYP7B1 DNA maps to NM_004820
(Entrez-Gene) and spans a region of 202.66 kB.
CYP7B1 is located on chromosome 8 and consists of
six exons.
Transcription
The full length CYP7B1 mRNA is 2,395 bp with an
open reading rame of 1,521 bp.
Pseudogene
No pseudogenes reported.
Protein
Description
The human CYP7B1 protein consists of 506 amino
acids and has a molecular weight of 58,256. The N-
terminal membrane-binding domain (residues 1 to 38)
is highly hydrophobic. The ATG start codon is located
204 nucleotides downstream of the trans-cription start
site (Wu et al., 1999). Similarly as other members of
the cytochrome P450 (CYP) enzyme superfamily,
CYP7B1 contains heme iron as a cofactor. Human
CYP7B1 shares 40% seq-uence identity with human
CYP7A1, the other member of the CYP7 family.
Expression
Expression of CYP7B1 is reported in many human
tissues including brain, kidney, liver, lung, heart,
prostate, testis, ovary, placenta, pancreas, intestine,
colon and thymus (Wu et al., 1999).
Human CYP7B1 gene structure. Exons are represented by red bars with exon numbers at the bottom.
CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1) Norlin M
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 276
Localisation
Most reports indicated localization to the membrane of
the endoplasmic reticulum. There are some data
indicating possible CYP7B1-related activity also in
mitochondria but it is unclear whether this activity
represents CYP7B1 or another enzyme species
(Axelson et al., 1992; Pandak et al., 2002).
Function
CYP7B1 converts a number of steroids into their
7alpha-hydroxyderivatives (Toll et al., 1994; Rose et
al., 1997; Yau et al., 2006; Norlin and Wikvall, 2007).
In addition to 7alpha-hydroxylation, forma-tion of
6alpha, 6beta-, and 7beta-hydroxyderiva-tives also has
been reported for this enzyme. Some well-known
substrates for CYP7B1 are: 27-hydro-xycholesterol and
25-hydroxycholesterol (choles-terol derivatives);
dehydroepiandrosterone (DHEA) and pregnenolone
(sex hormone precursors and neurosteroids); 5alpha-
androstane-3beta,17beta-diol and 5-androstene-
3beta,17beta-diol (estrogen recap-tor ligands). The
catalytic reactions performed by CYP7B1 may lead to
elimination of the steroids from the cell and thereby
reduce the cellular levels of the substrates for this
enzyme. Also, several of the products formed by
CYP7B1 are reported to have physiological effects.
Thus, CYP7B1 may in some cases be part of
biosynthetic pathways to form active compounds.
Homology
The CYP7B1 gene is conserved in chimpanzee, dog,
cow, mouse, rat, chicken, and zebrafish.
Mutations
Germinal
A homozygous mutation in the CYP7B1 gene (R388X)
was identified in an infant boy with defective bile acid
synthesis and severe cholestasis (Setchell et al., 1998).
The patient was the offspring of first cousins.
Mutations in the CYP7B1 gene (S363F, G57R, R417H,
F216S, R388X) have been associated with a form of
hereditary spastic paraplegia (HSP type 5)
characterized by motor neuron degeneration in affected
individuals of several families (Tsaousidou et al.,
2008). S363F and F216S was predicted to affect
phosphorylation of the mature protein. In addition,
studies on non-consanguineous cases of hereditary
spastic para-plegia indicate that a coding CYP7B1
polymor-phism (c.971G>A) is associated with a
phenotype of cerebellar signs believed to complicate a
primary HSP phenotype (Schule et al., 2009).
A functional polymorphism was reported in the human
CYP7B1 promoter consisting of a C-G change located -
104 nucleotides from the trans-cription start site
(Jakobsson et al., 2004). The C-G alteration at -104
creates a putative C/EBPbeta binding site and was
shown to result in higher transcriptional activity. In a
study comparing allele frequency in an Oriental
(Korean) population and a Caucasian (Swedish)
population, the frequency of the uncommon G-allele
was found to be much lower in the Oriental population
(Jakobsson et al., 2004).
Implicated in
Prostate cancer
Note
High expression of CYP7B1 protein is found in high-
grade prostatic intraepithelial neoplasia (PIN) and
adenocarcinomas (Olsson et al., 2007). Local
methylation of the CYP7B1 promoter is suggested to
be important for regulation of CYP7B1 in human
prostate tissue. In addition, a functional C-G
polymorphism in the CYP7B1 promoter has been
associated with a different allele frequency in two
ethnic populations with great differences in the
incidence of prostate cancer (Swedes and Koreans)
(Jakobsson et al., 2004). A connection between
CYP7B1 and prostate cancer may be related to the
action of estrogen receptor beta (ERbeta), since
metabolism by CYP7B1 is reported to affect the levels
of ligands for ERbeta, which is believed to have anti-
proliferative effects (Weihua et al., 2002; Martin et al.,
2004). Sex hormones are important for growth of
prostate and other tissues, both during normal and
malignant conditions. A potential role for CYP7B1 in
tissue growth is supported by data indicating that the
Akt/PI3K (phosphoinositide 3-kinase) cascade, a
signalling pathway important for cellular growth,
affects the CYP7B1 gene (Tang et al., 2008). In human
prostate cancer LNCaP cells, CYP7B1 promoter
activity is affected by both androgens and estrogens,
suggesting important functions in hormonal signalling
(Tang and Norlin, 2006).
Spastic Paraplegia Type 5A
Note
Mutations in the coding region of the CYP7B1 gene
has been found in patients with spastic paraplegia type
5, an upper-motor-neuron degenerative disease which
affects lower limb movement and results in extremity
weakness and spasticity, sometimes accompanied by
additional symptoms. Hereditary spastic paraplegia
(HSP) is characterized by axonal degeneration of
neurons in the corticospinal tracts and dorsal columns.
Sequence alterations in CYP7B1, believed to affect the
functionality of the enzyme, have been associated with
a pure form of autosomal-recessive HSP in several
families (Tsaousidou et al., 2008). The association of
an abnormal CYP7B1 gene with this neurodegene-
rative condition suggest that the pathogenic basis for
this disease is related either to effects on cholesterol
homeostasis in the brain (i e on CYP7B1-mediated
control of the levels of 27-hydroxycholesterol) or to
effects on the metabolism of dehydroepiandrosterone
and other neurosteroids.
CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1) Norlin M
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 277
Congenital Bile Acid Defect Type 3 (CBAS3)
Note
A mutation in the CYP7B1 gene was linked to
defective bile acid production, cholestasis and liver
cirrhosis in an infant boy who died at the age of < 1
year due to complications following liver trans-
plantation (Setchell et al., 1998). Other symptoms
included hepatosplenomegaly, jaundice and increased
bleeding. The pathological findings were consistent
with accumulation of hepatotoxic unsaturated
monohydroxy bile acids. The patient had 4,500 times
higher levels of 27-hydroxycholes-terol than normal
and liver samples showed no 27-hydroxycholesterol
7alpha-hydroxylase activity. Failure to detect CYP7A1-
mediated 7alpha-hydroxylase activity in this patient as
well as in other infants of the same age led the authors
to suggest that CYP7B1 may be more important for
bile acid synthesis in early life than in adulthood
(Setchell et al., 1998).
Alzheimer's Disease
Note
Some patients with Alzheimer's disease, a progress-sive
neurodegenerative disease that strongly impairs
cognition and memory, are reported to have altered
levels of CYP7B1 expression and/or CYP7B1-formed
metabolites. Some studies indi-cate reduced brain
expression of CYP7B1 in Alzheimer's disease (Yau et
al., 2003) whereas others report increased CYP7B1-
formed metabo-lites in serum from patients with this
disease (Attal-Khemis et al., 1998). The potential
role(s) of CYP7B1 in connection with Alzheimer's
disease remains unclear. Alzheimer's disease is
associated with build-up of neuritic plaques and
neurofibrillary tangles and progressive loss of neurons
and synapses in several parts of the brain. The etiology
of Alzheimer's disease is not well understood and the
underlying mechanisms are most likely complex. It has
been suggested that disturbed metabolism of
neurosteroids and/or other brain lipids may be one of
the contributing factors (Yau et al., 2003; Bjorkhem et
al., 2006). In some types of brain cells, CYP7B1-
dependent hydroxylation is the main metabolic fate for
neurosteroids dehydro-epiandrosterone and
pregnenolone. Also, the levels of CYP7B1 are higher in
the hippocampus than in other parts of the brain,
supporting a potential role for this enzyme related to
memory and cognition (Yau et al., 2003).
Rheumatoid Arthritis and Inflammation
Note
Increased production of the CYP7B1-formed
metabolite 7alpha-hydroxy-DHEA has been suggested
to contribute to the chronic inflammation observed in
patients with rheumatoid arthritis (Dulos et al., 2005).
Rheumatoid arthritis is a chronic inflammatory disorder
with unclear etiology characterized by joint
inflammation and progressive destruction of the joints.
Other tissues also may be affected. Studies in a mouse
model for collagen-induced arthritis indicate
correlation of increased CYP7B1 activity with disease
progression (Dulos et al., 2004). In humans, CYP7B1 is
found in synovial tissues (connective tissues
surrounding the joints) from patients with rheumatoid
arthritis and CYP7B1 levels are up-regulated by
proinflammatory cytokines in human synoviocytes
(Dulos et al., 2005). Chronic inflam-matory diseases
including rheumatoid arthritis are known to be
associated with changes in levels of several steroids. It
has been proposed that the CYP7B1-formed 7alpha-
hydroxy-DHEA might counteract the
immunosuppressive effects of gluco-corticoids, which
are used in treatment of rheuma-toid arthritis.
References Axelson M, Shoda J, Sjövall J, Toll A, Wikvall K. Cholesterol is converted to 7 alpha-hydroxy-3-oxo-4-cholestenoic acid in liver mitochondria. Evidence for a mitochondrial sterol 7 alpha-hydroxylase. J Biol Chem. 1992 Jan 25;267(3):1701-4
Toll A, Wikvall K, Sudjana-Sugiaman E, Kondo KH, Björkhem I. 7 alpha hydroxylation of 25-hydroxycholesterol in liver microsomes. Evidence that the enzyme involved is different from cholesterol 7 alpha-hydroxylase. Eur J Biochem. 1994 Sep 1;224(2):309-16
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Attal-Khémis S, Dalmeyda V, Michot JL, Roudier M, Morfin R. Increased total 7 alpha-hydroxy-dehydroepiandrosterone in serum of patients with Alzheimer's disease. J Gerontol A Biol Sci Med Sci. 1998 Mar;53(2):B125-32
Setchell KD, Schwarz M, O'Connell NC, Lund EG, Davis DL, Lathe R, Thompson HR, Weslie Tyson R, Sokol RJ, Russell DW. Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease. J Clin Invest. 1998 Nov 1;102(9):1690-703
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Weihua Z, Lathe R, Warner M, Gustafsson JA. An endocrine pathway in the prostate, ERbeta, AR, 5alpha-androstane-3beta,17beta-diol, and CYP7B1, regulates prostate growth. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13589-94
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This article should be referenced as such:
Norlin M. CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):275-278.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 279
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
EPHA3 (EPH receptor A3) Brett Stringer, Bryan Day, Jennifer McCarron, Martin Lackmann, Andrew Boyd
Leukaemia Foundation Research Laboratory, Queensland Institute of Medical Research, 300 Herston Road,
Brisbane Queensland 4006, Australia (BS, BD, JM, AB); Department of Biochemistry and Molecular
Biology, PO Box 13D, Monash University, Clayton Victoria 3800, Australia (ML); Department of Medicine,
University of Queensland, St Lucia Queensland 4067, Australia (AB)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/EPHA3ID40463ch3p11.html DOI: 10.4267/2042/44710
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: EC 2.7.10.1; ETK; ETK1; EphA3;
HEK; HEK4; TYRO4
HGNC (Hugo): EPHA3
Location: 3p11.2
Local order: (tel) C3orf38 (ENSG00000179021) ->,
949,562bp, EPHA3 (374,609bp) ->, 720,071bp, <-
AC139337.5 (ENSG00000189002) (cen)
Note
EPHA3 is flanked by two gene deserts.
DNA/RNA
Note
EPHA3 spans the human tile path clones CTD-
2532M17, RP11-784B9 and RP11-547K2.
Description
EPHA3 consists of 17 exons and 16 introns and spans
375kb of genomic DNA. It is the second largest of the
EPH genes after EPHA6.
Figure 1: Chromosomal location of EPHA3 (based on Ensembl Homo sapiens version 53.36o (NCBI36)). Figure 2: Genomic neighbourhood of EPHA3 (based on Ensembl Homo sapiens version 53.36o (NCBI36)).
EPHA3 (EPH receptor A3) Stringer B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 280
Figure 3: Genomic organisation of EPHA3.
Transcription
Two alternatively spliced transcript variants have been
described (NM_005233.5, a 5,807 nucleotide mRNA
and NM_182644.2, a 2,684 nucleotide mRNA). The
shorter transcript results in truncation within the
extracellular domain of EphA3 and is predicted to
produce a soluble protein. The 5' end of EPHA3 is
associated with a CpG island, a feature common to all
EPH genes. The EPHA3 promoter also lacks a TATA
box and transcription initiates from multiple start sites.
Pseudogene
None identified.
Protein
Note
The Eph receptors constitute the largest of the 20
subfamilies of human receptor tyrosine kinases. The
founding member of this group was isolated originally
from an erythropoietin producing hepato-ma cell line.
Figure 4: Domain organisation of EphA3.
Description
The EPHA3 gene encodes a 983 amino acid protein
with a calculated molecular weight of 110.1kDa and an
isoelectric point of 6.7302. Amino acids 1-20 constitute
a signal peptide. The predicted mole-cular mass of the
translated protein minus the signal peptide is 92.8kDa.
The 521 amino acid extra-cellular domain contains five
potential sites for N-glycosylation such that EphA3 is
typically detected as a 135kDa glycoprotein. This
mature isoform of EphA3 is a single-pass
transmembrane receptor tyrosine kinase. At its N-
terminus is a 174 amino acid ligand binding domain, a
14 amino acid EGF-like domain and two membrane
proximal fibro-nectin type III repeats. Amino acids 21-
376 of the extracellular domain also are rich in cysteine
residues. The intracellular domain contains the tyrosine
kinase domain and a sterile alpha motif. EphA3 lacks a
PDZ domain interacting motif present in EphA7,
EphB2, EphB3, EphB5 and EphB6. Activation of the
EphA3 receptor tyrosine kinase domain is associated
with two tyrosine residues in the juxtamembrane region
(Y596, Y602) that are sites of autophosphorylation and
interact with the kinase domain to modulate its activity.
EphA3 belongs to an evolutionarily ancient subfamily
of receptor tyrosine kinases with mem-bers being
present in sponges, worms and fruit flies. The
expansion in the number of Eph receptor-encoding
genes along with genes encoding their ligands, the
ephrins (Eph receptor interacting proteins), is proposed
to have contributed to the increase in complexity of the
bilaterian body plan. Genes encoding EphA3 are found
in the genomes of representative members of at least
five of the seven classes of vertebrates including bony
fish (zebrafish, pufferfish, medaka), amphibians
(African clawed frog), reptiles (green anole lizard),
birds (chicken) and mammals (platypus, possum,
human).
Fourteen Eph receptors have been identified in
vertebrates. These are subdivided into either EphA
(EphA1, EphA2, EphA3, EphA4, EphA5, EphA6,
EphA7, EphA8, EphA10) or EphB (EphB1, EphB2,
EphB3, EphB4, EphB6) subclasses which differ
primarily in the structure of their ligand binding
domains. EphA receptors also exhibit greater affinity
for binding GPI-linked ephrin-A ligands while EphB
receptors bind transmembrane ephrin-B ligands. While
interactions are somewhat promis-cuous, and some
cross-class binding occurs, each Eph receptor displays
distinct affinity for the different ephrin ligands. The
high affinity ligands for EphA3 are ephrin-A2 and
ephrin-A5. EphA3 also binds ephrin-A3 and ephrin-A4
with lower affinity.
Eph-ephrin binding involves contact between cells.
Upon binding, receptor-ligand dimers form
heterotetramers, which further assemble into higher
order signalling clusters. Several moieties in the EphA3
receptor extracellular region mediate ephrin binding. A
high-affinity binding site in the N-terminal ephrin
binding domain mediates inter-cellular Eph-ephrin
interaction. Two additional lower-affinity ephrin-
binding sites, one in the ephrin-binding domain and the
other in the cysteine-rich region, are involved in
clustering of Eph-ephrin complexes.
Following ephrin-A5-mediated EphA3 receptor
clustering, intracellular signalling by EphA3 receptors
is initiated by autophosphorylation of three defined
tyrosine residues, two in the highly conserved
juxtamembrane region and the third in the activation
loop of the kinase domain (Y779). Rapid reorganisation
of the actin and myosin cytoskeleton follows, leading
to retraction of cellular protrusions, membrane
blebbing and cell detachment, following association of
the adaptor protein CrkII with tyrosine phosphorylated
EphA3 and activation of RhoA signalling.
Such Eph-ephrin interaction triggers bidirectional
signalling, that is signalling events within both Eph-
and ephrin-bearing cells, an unusual phenomenon for
receptor tyrosine kinases, most of which interact with
soluble ligands. Subsequently, depending on the
cellular context (including the identity of the
interacting Eph-ephrin receptor-ligand pairs, their
relative levels on interacting cells, the presence of
additional Ephs and ephrins and their alternative
EPHA3 (EPH receptor A3) Stringer B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 281
isoforms, and the net effect of interaction with
additional signalling pathways) this either results in
repulsion or promotes adhesion of the interacting cells.
Cellular repulsion and the termination of Eph-ephrin
signalling require disruption of the receptor-ligand
complex. This is brought about either by enzymatic
cleavage of the tethered ephrin ligand in cis or in trans
or by endocytosis of Eph-ephrin complexes. EphA3-
ephrin-A2 receptor-ligand complexes are shed from
ephrin-A2 bearing cells following receptor-ligand
binding when ADAM10 (a disintegrin and
metalloprotease 10), associated with ephrin-A2, cleaves
ephrin-A2. Conversely, intercellular EphA3-ephrin-A5
receptor-ligand complexes are broken when EphA3-
associated ADAM10 cleaves ephrin-A5 on opposing
cells, following binding to EphA3. The post-cleavage
ephrin-A5-EphA3 complex is then endocytosed by the
EphA3-expressing cell.
While cellular repulsion is often the outcome of Eph-
ephrin interaction, in some circumstances adhesion
may persist. For example, ADAM10 has been observed
not to cleave ephrin-A5 following EphA3-ephrin-A5
interaction involving LK63 cells in which high
intracellular protein tyrosine phosphatase activity also
appears to counter ephrin-A5 stimulated
phosphorylation of EphA3, holding the receptor in an
inactive, unphosphorylated state. Also cis interaction
between EphA3 and ephrin-A2 expressed on the same
cell surface has been reported to block EphA3
activation by ephrins acting in trans, the cis interaction
site being independent of the ligand binding domain.
Another mechanism that may favour stable cell-cell
adhesion involves truncated Eph receptor isoforms
acting in a dominant negative manner. While activation
of full length EphA7 by ephrin-A5 results in cellular
repulsion, ephrin-A5-induced phosphorylation of
EphA7 is inhibited by two EphA7 splice variants with
truncated kinase domains and adhesion results. A splice
variant of EPHA3 also has been reported and is
predicted to give rise to a soluble isoform of EphA3.
Whether this soluble variant of EphA3, which is
truncated before the transmembrane domain, functions
in a similar manner to the shorter EphA7 isoforms has
not been established.
While important details of EphA3 signalling have been
determined, more complete understanding of EphA3
activity will require knowledge of the full complement
of EphA3 interacting proteins. Substrates that are
targets for the tyrosine kinase activity of EphA3 have
yet to be defined and potential mediators or modulators
of EphA3 signalling output such as Src family kinases,
additional phosphotyrosine binding adaptors, SAM
domain interacting factors, interaction with other
receptor kinases and crosstalk with other signalling
pathways, and the regulatory role of phosphatases all
remain to be explored. Based on the range of
interacting proteins identified for other Eph receptors
(some common to more than one Eph, others
apparently unique to individual Ephs) additional
effectors of EphA3 signalling output are likely.
Expression
EphA3 was first identified as an antigen expressed at
high levels (10,000-20,000 copies per cell) on the
surface of the LK63 pre-B cell acute lymphoblastic
leukaemia cell line. It also was found to be expressed
by JM, HSB-2 and MOLT-4 T-cell leukaemic cell
lines, in CD28-stimulated Jurkat cells, and in 16 of 42
cases of primary T-cell lymphoma (but not normal
peripheral T lymphocytes nor in any subset of thymus-
derived developing T cells), as well as at low frequency
in acute myeloid leukaemia and chronic lymphocytic
leukaemia EphA3 is not expressed by many other
haematopoietic cell lines.
Subsequently, EphA3 expression has been shown to be
most abundant, and also highly regulated both
temporally and spatially, during vertebrate
development. Prominent EphA3 expression occurs in
the neural system, including the retinal ganglion cells
of the embryonic retina in a graded distribution from
anterior/nasal (lowest) to posterior /temporal (highest);
the cerebrum, thalamus, striatum, olfactory bulb,
anterior commissure, and corpus callosum of the
forebrain; and the medial motor column ventral motor
neurons of the spinal cord; and extraneurally by
mesodermally-derived tissues including the paraxial
musculature, tongue musculature, submucosa of the
soft palate, capsule of the submandibular gland, cortical
rim of bone, thymic septae, media of the pharynx,
trachea, great vessels, small intestine and portal vein,
cardiac valves, and the renal medulla. In adult tissues
EphA3 expression is more restricted and detected at
significantly lower levels than during early
development.
Localisation
Isoform 1: Cell membrane; single-pass type I
membrane protein.
Isoform 2: Secreted.
Function
Eph receptors modulate cell shape and movement
through reorganisation of the cytoskeleton and changes
in cell-cell and cell-substrate adhesion, and are
involved in many cellular migration, sorting (tissue
patterning) and guidance events, most often during
development, and in particular involving the nervous
system. There is evidence too that Eph receptor
signalling influences cell proliferation and cell-fate
determination and growing recognition that Eph
receptors function in adult tissue homeostasis.
EphA3 is thought to play a role in retinotectal mapping,
the tightly patterned projection of retinal ganglion cell
axons from the retina to the optic tectum (or superior
colliculus in mammals). In chicks, posterior retinal
ganglion axons expressing highest levels of EphA3
project to the anterior tectum where the graded
EPHA3 (EPH receptor A3) Stringer B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 282
expression of ephrin-A2 and ephrin-A5 is lowest and
are excluded from projecting more posteriorly where
ephrin-A2/A5 expression is highest. More direct
evidence of non-redundant function for EphA3 has
come from phenotypic analysis of EphA3 knockout
mice. Approximately 70-75% of EphA3 null mice die
within 48 hours of birth with post-mortem evidence of
pulmonary oedema secondary to cardiac failure. These
mice exhibit hypoplastic atrioventricular endocardial
cushions and subsequent atri-oventricular valve and
atrial membranous septal defects, with endocardial
cushion explants from these mice giving rise to fewer
migrating cells arising from epithelial to mesenchymal
trans-formation. Expression of EphA3 in the spinal
cord appears to be redundant as axial muscle targeting
by medial motor column motor axons and the
organisation of the motor neuron columns is not
altered. EphA4 is the only other EphA receptor also
expressed by developing spinal cord motor neurons and
in mice lacking EphA3 and EphA4 these receptors
together repel axial motor axons from neighbouring
ephrin-A-expressing sensory axons, inhibiting
intermingling of motor and sensory axons and
preventing mis-projection of motor axons into the
dorsal root ganglia. In contrast to the chick, EphA3 is
not expressed by mouse retinal ganglion cells. Instead
the closely related receptors EphA5 and EphA6 (see
homology below) are expressed in a low nasal to high
temporal gradient. However, if EphA3 is ectopically
expressed in retinal ganglion cells in mice these axons
project to more rostral positions in the superior
colliculus.
A function for soluble EphA3 has not been reported
although potentially this isoform might play a role in
promoting cell adhesion (see above) or act as a tumour
suppressor protein (see below).
Homology
Phylogenetic tree for the Eph receptors. Amino acid
sequences used for this compilation were EphA1
(NP_005223), EphA2 (NM_004431), EphA3
(NP_005224), EphA4 (NP_004429), EphA5
(NM_004439), EphA6 (ENSP00000374323), EphA7
(NP_004431), EphA8 (NP_065387), EphA10
(NP_001092909), EphB1 (NP_004432), EphB2
(NP_004433), EphB3 (NP_004434), EphB4
(NP_004435) and EphB6 (NP_004436).
Mutations
Note
Seven nonsynonymous single nucleotide polymer-
phisms (all missense) are recorded in the dbSNP
database for EPHA3. Recognised allelic variation
occurs for the following EphA3 amino acids: I564V
(rs56081642), C568S (rs56077781), L590P
(rs56081642), T608A (rs17855794), G777A
(rs34437982), W924R (rs35124509) and H914R
(rs17801309).
Germinal
To date no germinal mutations in EPHA3 have been
associated with disease.
Somatic
Somatic mutations in EPHA3 have been detected in
lung adenocarcinoma (T166N, G187R, S229Y,
W250R, M269I, N379K, T393K, A435S, D446Y,
Figure 6: Sites of somatic mutations in EphA3 identified in lung adenocarcinoma colorectal carcinoma, glioblastoma multiforme and metastatic melanoma.
EPHA3 (EPH receptor A3) Stringer B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 283
S449F, G518L, T660K, D678E, R728L, K761N,
G766E, T933M), colorectal carcinoma (T37K, N85S,
I621L, S792P, D806N), glioblastoma multi-forme
(K500N, A971P) and metastatic melanoma (G228R).
Implicated in
Prostate cancer
Note
EPHA3 was among the genes whose expression was
upregulated during androgen-independent progresssion
in an LNCaP in vitro cell model of prostate cancer.
Melanoma
Note
A melanoma patient with an especially favourable
evolution of disease, associated with a very strong and
sustained anti-tumour cytotoxic T lymphocyte
response, was found to have a lytic CD4 clone that
recognised an EphA3 antigen presented by the HLA
class II molecule HLA- DRB1*1101. 94% (75 of 80) of
melanomas examined expressed EphA3 in contrast to
normal melanocytes which do not express detectable
EphA3.
Lung cancer, Sarcoma, and Renal cell carcinoma
Note
44% (11 of 25) of small cell lung cancer, 24% (10 of
41) of non-small cell lung cancer, 58% (17 of 29) of
sarcomas, and 31% (12 of 38) of renal cell carcinomas
expressed EphA3 at levels significantly higher than the
corresponding normal tissues.
Breakpoints
Note
No reported breakpoints identified to date nor
recognised fusion proteins involving EphA3.
To be noted
Note
Soluble forms of EphA3 appear to inhibit tumour
angiogenesis and tumour progression suggesting that
specific inhibition by soluble EphA3 may be
therapeutically useful.
The IIIA4 monoclonal antibody originally raised
against LK63 human acute pre-B leukemia cells and
used to affinity isolate EphA3 binds the native EphA3
globular ephrin-binding domain with sub-nanomolar
affinity (KD ~5x10-10
mol/L). Like ephrin-A5, pre-
clustered IIIA4 effectively triggers EphA3 activation,
contraction of the cytoskeleton, and cell rounding.
Moreover, radio-metal conju-gates of ephrin-A5 and
IIIA4 retain their EphA3-binding affinity, and in mouse
xenografts localise to, and are internalised rapidly into
EphA3-positive, human tumours.
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Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE. The consensus coding sequences of human breast and colorectal cancers. Science. 2006 Oct 13;314(5797):268-74
Wood LD, Calhoun ES, Silliman N, Ptak J, Szabo S, Powell SM, Riggins GJ, Wang TL, Yan H, Gazdar A, Kern SE, Pennacchio L, Kinzler KW, Vogelstein B, Velculescu VE. Somatic mutations of GUCY2F, EPHA3, and NTRK3 in human cancers. Hum Mutat. 2006 Oct;27(10):1060-1
Balakrishnan A, Bleeker FE, Lamba S, Rodolfo M, Daniotti M, Scarpa A, van Tilborg AA, Leenstra S, Zanon C, Bardelli A. Novel somatic and germline mutations in cancer candidate genes in glioblastoma, melanoma, and pancreatic carcinoma. Cancer Res. 2007 Apr 15;67(8):3545-50
Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR.
EPHA3 (EPH receptor A3) Stringer B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 285
Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8;446(7132):153-8
Himanen JP, Saha N, Nikolov DB. Cell-cell signaling via Eph receptors and ephrins. Curr Opin Cell Biol. 2007 Oct;19(5):534-42
Stephen LJ, Fawkes AL, Verhoeve A, Lemke G, Brown A. A critical role for the EphA3 receptor tyrosine kinase in heart development. Dev Biol. 2007 Feb 1;302(1):66-79
Davis TL, Walker JR, Loppnau P, Butler-Cole C, Allali-Hassani A, Dhe-Paganon S. Autoregulation by the juxtamembrane region of the human ephrin receptor tyrosine kinase A3 (EphA3). Structure. 2008 Jun;16(6):873-84
Dereeper A, Guignon V, Blanc G, Audic S, Buffet S, Chevenet F, Dufayard JF, Guindon S, Lefort V, Lescot M, Claverie JM, Gascuel O. Phylogeny.fr: robust phylogenetic analysis for the non-specialist. Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W465-9
Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez-Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X,
Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba II, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis WD, Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, Lander ES, Gibbs RA, Meyerson M, Wilson RK. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008 Oct 23;455(7216):1069-75
Gallarda BW, Bonanomi D, Müller D, Brown A, Alaynick WA, Andrews SE, Lemke G, Pfaff SL, Marquardt T. Segregation of axial motor and sensory pathways via heterotypic trans-axonal signaling. Science. 2008 Apr 11;320(5873):233-6
Pasquale EB. Eph-ephrin bidirectional signaling in physiology and disease. Cell. 2008 Apr 4;133(1):38-52
Singh AP, Bafna S, Chaudhary K, Venkatraman G, Smith L, Eudy JD, Johansson SL, Lin MF, Batra SK. Genome-wide expression profiling reveals transcriptomic variation and perturbed gene networks in androgen-dependent and androgen-independent prostate cancer cells. Cancer Lett. 2008 Jan 18;259(1):28-38
Wimmer-Kleikamp SH, Nievergall E, Gegenbauer K, Adikari S, Mansour M, Yeadon T, Boyd AW, Patani NR, Lackmann M. Elevated protein tyrosine phosphatase activity provokes Eph/ephrin-facilitated adhesion of pre-B leukemia cells. Blood. 2008 Aug 1;112(3):721-32
This article should be referenced as such:
Stringer B, Day B, McCarron J, Lackmann M, Boyd A. EPHA3 (EPH receptor A3). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):279-285.
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OPEN ACCESS JOURNAL AT INIST-CNRS
JAZF1 (JAZF zinc finger 1) Hui Li, Jeffrey Sklar
University of Virginia Medical School, Charlottesville, VA 22908, USA (HL), Department of Pathology,
Yale University, New haven, CT, USA (HL, JS)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/JAZF1ID41036ch7p15.html DOI: 10.4267/2042/44711
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: TIP27; ZNF802; DKFZp761K2222
HGNC (Hugo): JAZF1
Location: 7p15.2
Metaphase FISH using as probe YAC908B12, which encompasses the entire JAZF1 at 7p15.2.
DNA/RNA
Description
5 exons; spans 350kb.
Transcription
Major transcript: 2,980bp; coding sequence: 52-783.
Protein
Description
243 amino acids.
Expression
Expressed in all the tissues tested with variable level.
The tissues or organs that express JAZF1 include
cerebellum, lung, thymus, liver, kidney,
stomach/esophagus, skeleton muscle, skin and eye.
Localisation
Mostly nucleus.
Function
JAZF1 has three C2H2-type zinc fingers. It is mostly
detected within the nucleus, with lesser amounts found
in the cytoplasm. JAZF1 copurifies with chromatin,
and presumably has DNA-binding properties. It has
been reported to interact with TAK1 and function as a
transcriptional repressor of the TAK1 gene.
SNPs in intron 1 of JAZF1 has been reported to be
associated with type 2 diabetes and body height.
SNPs in intron 2 of JAZF1 have been reported to be
associated with reduced prevalence of prostate cancer.
Chimeric JAZF1-JJAZ1 protein (amino acid sequence
of the first three exons of JAZF1 joined to sequence of
the last 15 exons of JJAZ1) resulting from trans-
splicing of precursor mRNAs and identical to a product
generated from the JAZF1-JJAZ1 gene fusion in
endometrial tumors has been found in normal
endometrium.
Homology
Unkown.
Mutations
Somatic
JAZF1 has been identified at the breakpoints of a
recurrent chromosomal translocation, the
JAZF1 (JAZF zinc finger 1) Li H, Sklar J
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 287
t(7;17)(p15;q21), in endometrial stromal tumors
(benign nodules and sarcomas). The translocation leads
to a JAZF1-JJAZ1 fusion gene. This gene fusion is
detected in about 50% of endometrial stromal sarcomas
and most endometrial stromal nodules.
Another common chromosomal translocation in
endometrial stroma sarcomas, the t(6;7)(p21;p15),
results in a JAZF1-PHF1 fusion. About 25-30% of
endometrial stromal sarcomas are reported to contain
this fusion. The sites of fusion within JAZF1 RNA to
JJAZ1 and PHF1 RNA sequence are the same. Both
JJAZ1(also called SUZ12) and PHF1 belong to the
Polycomb group (PcG) gene family.
Implicated in
t(7;17)(p15;q21) / endometrial stromal nodule and endometrial sarcoma
Disease
Endometrial stroma nodule and sarcoma.
Cytogenetics
t(7;17)(p15;q21)
Hybrid/Mutated gene
JAZF1-JJAZ1
Abnormal protein
JAZF1-JJAZ1
Oncogenesis
The fusion protein protects cells from hypoxia-induced
apoptosis, and also promotes proliferation when the
wild-type allele of JJAZ1 is silenced (as it is in
endometrial stromal sarcomas carrying the
t(7;17)(p15;q21)).
t(6;7)(p21;p15)/ endometrial stroma sarcoma
Disease
Endometrial stroma sarcoma.
Cytogenetics
t(6;7)(p21;p15)
Hybrid/Mutated gene
JAZF1-PHF1
Abnormal protein
JAZF1-PHF1
Oncogenesis
The function of the JAZF1-PHF1 fusion is not
currently known.
Prostate carcinoma
Oncogenesis
A SNIP in intron 2 of JAZF1 is associated with a
somewhat decreased risk of prostate cancer, especially
cancers that have been classified as being less
aggressive. The mechanism by which polymer-phisms
alter the susceptibility toward prostate cancer is not
currently known.
Breakpoints
References Koontz JI, Soreng AL, Nucci M, Kuo FC, Pauwels P, van Den Berghe H, Dal Cin P, Fletcher JA, Sklar J. Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6348-53
Micci F, Panagopoulos I, Bjerkehagen B, Heim S. Consistent rearrangement of chromosomal band 6p21 with generation of fusion genes JAZF1/PHF1 and EPC1/PHF1 in endometrial stromal sarcoma. Cancer Res. 2006 Jan 1;66(1):107-12
Li H, Ma X, Wang J, Koontz J, Nucci M, Sklar J. Effects of rearrangement and allelic exclusion of JJAZ1/SUZ12 on cell proliferation and survival. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):20001-6
Nucci MR, Harburger D, Koontz J, Dal Cin P, Sklar J. Molecular analysis of the JAZF1-JJAZ1 gene fusion by RT-PCR and fluorescence in situ hybridization in endometrial stromal neoplasms. Am J Surg Pathol. 2007 Jan;31(1):65-70
Frayling TM, Colhoun H, Florez JC. A genetic link between type 2 diabetes and prostate cancer. Diabetologia. 2008 Oct;51(10):1757-60
Frayling TM, Colhoun H, Florez JC. A genetic link between type 2 diabetes and prostate cancer. Diabetologia. 2008 Oct;51(10):1757-60
Li H, Wang J, Mor G, Sklar J. A neoplastic gene fusion mimics trans-splicing of RNAs in normal human cells. Science. 2008 Sep 5;321(5894):1357-61
Thomas G, Jacobs KB, Yeager M, Kraft P, Wacholder S, Orr N, Yu K, Chatterjee N, Welch R, Hutchinson A, Crenshaw A, Cancel-Tassin G, Staats BJ, Wang Z, Gonzalez-Bosquet J, Fang J, Deng X, Berndt SI, Calle EE, Feigelson HS, Thun MJ, Rodriguez C, Albanes D, Virtamo J, Weinstein S, Schumacher FR, Giovannucci E, Willett WC, Cussenot O, Valeri A, Andriole GL, Crawford ED, Tucker M, Gerhard DS, Fraumeni JF Jr, Hoover R, Hayes RB, Hunter DJ, Chanock SJ. Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet. 2008 Mar;40(3):310-5
Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, de Bakker PI, Abecasis GR, Almgren P, Andersen G, Ardlie K, Boström KB, Bergman RN, Bonnycastle LL, Borch-Johnsen K, Burtt NP, Chen H, Chines PS, Daly MJ, Deodhar P, Ding CJ, Doney AS, Duren WL, Elliott KS, Erdos MR, Frayling TM,
JAZF1 (JAZF zinc finger 1) Li H, Sklar J
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 288
Freathy RM, Gianniny L, Grallert H, Grarup N, Groves CJ, Guiducci C, Hansen T, Herder C, Hitman GA, Hughes TE, Isomaa B, Jackson AU, Jørgensen T, Kong A, Kubalanza K, Kuruvilla FG, Kuusisto J, Langenberg C, Lango H, Lauritzen T, Li Y, Lindgren CM, Lyssenko V, Marvelle AF, Meisinger C, Midthjell K, Mohlke KL, Morken MA, Morris AD, Narisu N, Nilsson P, Owen KR, Palmer CN, Payne F, Perry JR, Pettersen E, Platou C, Prokopenko I, Qi L, Qin L, Rayner NW, Rees M, Roix JJ, Sandbaek A, Shields B, Sjögren M, Steinthorsdottir V, Stringham HM, Swift AJ, Thorleifsson G, Thorsteinsdottir U, Timpson NJ, Tuomi T, Tuomilehto J, Walker M, Watanabe RM, Weedon MN, Willer CJ, Illig T, Hveem K, Hu FB, Laakso M, Stefansson K, Pedersen O, Wareham NJ, Barroso I, Hattersley AT, Collins FS, Groop L, McCarthy MI, Boehnke M, Altshuler D. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet. 2008 May;40(5):638-45
Johansson A, Marroni F, Hayward C, Franklin CS, Kirichenko AV, Jonasson I, Hicks AA, Vitart V, Isaacs A, Axenovich T, Campbell S, Dunlop MG, Floyd J, Hastie N, Hofman A, Knott S, Kolcic I, Pichler I, Polasek O, Rivadeneira F, Tenesa A, Uitterlinden AG, Wild SH, Zorkoltseva IV, Meitinger T, Wilson JF, Rudan I, Campbell H, Pattaro C, Pramstaller P, Oostra BA, Wright AF, van Duijn CM, Aulchenko YS, Gyllensten U. Common variants in the JAZF1 gene associated with height identified by linkage and genome-wide association analysis. Hum Mol Genet. 2009 Jan 15;18(2):373-80
Waters KM, Le Marchand L, Kolonel LN, Monroe KR, Stram DO, Henderson BE, Haiman CA. Generalizability of associations from prostate cancer genome-wide association studies in multiple populations. Cancer Epidemiol Biomarkers Prev. 2009 Apr;18(4):1285-9
This article should be referenced as such:
Li H, Sklar J. JAZF1 (JAZF zinc finger 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):286-288.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 289
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
LPAR1 (lysophosphatidic acid receptor 1) Mandi M Murph, Harish Radhakrishna
University of Georgia College of Pharmacy, Department of Pharmaceutical and Biomedical Sciences, 250 W
Green Street, Rm 376 Athens, Georgia 30602 USA (MMM); Global Research & Technology, The Coca-
Cola Company, 1 Coca-Cola Plaza Atlanta, GA 30313 USA (HR)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/LPAR1ID40405ch9q31.html DOI: 10.4267/2042/44712
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: EDG2; GPR26; LPA-1; LPA1;
Mrec1.3; VZG1; edg-2; rec.1.3; vzg-1
HGNC (Hugo): LPAR1
Location: 9q31.3
DNA/RNA
Note
mRNA length 3104 or 3182 bp, depending on
alternative splicing.
Protein
Description
LPAR1 is an abbreviation for the LPA1 receptor, the
first receptor cloned and identified from a growing
number of LPA receptors that includes the Edg-family
and the purinergic receptors.
Expression
LPAR1 is ubiquitously expressed throughout cells and
tissues in the body.
High level of expression is found in amygdale,
Figure of the LPAR1, a G protein-coupled receptor, spanning the plasma membrane seven times. The receptor has three numbered extracellular and intracellular loops that are involved in signal transduction. Also shown are the amino terminus and carboxyl terminal tail. Three regions of the carboxyl terminal tail have been shown to be important for the LPAR1 signaling and receptor regulation. LPAR1 contains a canonical Type 1 PDZ binding domain (a.a. 362-364) at the extreme C-terminus. This domain has been shown to be required for LPA-induced cell proliferation and activation of Rho family GTPases via PDZ-Rho guanine nucleotide exchange factors. Further upstream in the carboxyl terminal tail, LPAR1 contains a di-leucine sequence (a.a. 351 and 352), which is required for phorbol ester-
LPAR1 (lysophosphatidic acid receptor 1) Murph MM, Radhakrishna H
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 290
induced internalization. Still further upstream lies a serine-rich cluster (a.a. 341-347) that is required for beta-arrestin association, which is critical for signal attenuation and receptor endocytosis.
prefrontal cortex, caudate nucleus, hypothalamus,
medulla oblongata, olfactory bulb, parietal lobe, spinal
cord and thalamus.
Moderately high level of expression is found in
adipocytes, cingulated cortex, occipital lobe, pons,
whole brain, globus pallidus, subthalamic nucleus,
temporal lobe, appendix, monocytes and smooth
muscle.
Slightly above median level of expression is found in
bronchial epithelial cells, cerebellum peduncies, dorsal
root ganglia, ciliary ganglion, uterus, uterus corpus,
atrioventricular node, fetal lung, fetal thyroid, skeletal
muscle, cardiac myocytes, salivary gland, tongue and
lymph node. It is also expressed in tissues during
neuronal development. The expression of LPAR1 is
increased in blister skin compared to normal skin. The
mRNA of LPAR1 is significantly increased 8 days after
unilateral uretheral obstruction in mice kidneys where
expression is higher in the medulla than the cortex. The
expression of LPAR1 is variable in cancer.
Localisation
It is a requirement of G protein-coupled receptor
functioning that receptors are embedded into
membranes for proper structure. The LPAR1 spans the
plasma membrane seven times in a barrel conformation
with three extracellular and three intracellular loops. At
steady state, LPAR1 is located on the plasma
membrane at the cell surface until it binds LPA, which
triggers dynamin2-dependent, clathrin-mediated
endocytosis into the cell. LPAR1 requires membrane
cholesterol for association with beta-arrestin, which
targets the receptor to clathrin-coated pits for
internalization. In addition to LPA, phorbol ester
stimulation of protein kinase C also induces
internalization of LPAR1, but this does not require
beta-arrestin. Rather, phorbol ester-dependent
internalization of LPAR1 requires AP-2 clathrin
adaptors. The LPAR1 is subsequently sorted through
Rab-5 dependent early and recycling endosomes before
it is recycled back to the cell surface or degraded in
lysosomes.
The receptor may also be localized to the nuclear
membrane in the cell. Some evidence indicates that a
portion of the total cellular LPAR1 localizes to the
nuclear membrane in PC12 cells, micro-vascular
endothelial cells, and human bronchial epithelial cells.
The exact function of this nuclear LPAR1 pool is not
known.
Function
The LPAR1 binds LPA and initiates G protein-
dependent signal transduction cascades throughout the
cell that result in a number of functional outcomes,
depending on the specific cell or tissue type. The G
alpha proteins involved are Gi, Gq and G 12/13. The
receptor has critical functions that have been elucidated
through gene knock-out studies in mice. LPAR1-null
mice have deficiencies in olfactory development that
impairs their ability to locate maternal nipples and
initiate suckling required for survival. The lack of
olfactant detection leads to 50% lethality among pups.
Other LPAR1-null mice demonstrate alterations in
neurotransmitters that mimic models of schizophrenia.
LPAR1-null mice are 10-15% shorter than wild-type
mice and have gross anatomical defects due to bone
development, including incisor overgrowth that affects
ability to feed. The LPAR1 functions in normal cortical
development and commits cortical neuroblasts to
differentiate through the neural lineage. It may also
play a role in the formation of dendritic spine synapses.
Through autotoxin-generated LPA, LPAR1 mediates
neuropathic pain induced by nerve injury. Activation of
the LPAR1 functions in the inflammatory response;
receptor activation stimulates the recruitment of
macrophages.
The LPAR1 positively regulates motility in a variety of
cell types, exerting a dominant signal in the absence of
LPAR4.
Homology
The LPAR1 has significant homology with LPAR2
(57%) and LPAR3 (51%), members of the original or
classical endothelial differentiation gene (Edg) family.
It has approximately 33-38% homology with individual
sphingosine 1-phosphate receptors and no significant
homology with the purinergic family of receptors that
also bind LPA.
Mutations
Note
There are several single nucleotide polymorphisms
(SNPs) reported within the LPAR1 gene and several of
these are associated with altered phenotype and disease
states.
A functional SNP located in the promoter region of the
gene (-2,820G/A; rs10980705) is associated with
increased susceptibility to knee osteoarthritis in
Japanese by showing an increase in binding and
activity.
A change in amino acid sequence at position 125 from
glutamine to glutamate in the LPAR1 will result in the
ability of the receptor to recognize both S1P and LPA.
A change in amino acid sequence at position 236 from
threonine to lysine in the LPAR1 will result in the
enhanced activation of serum response factor.
Mutations in the LPAR1 were detected in a small
percentage of adenomas and adenocarcinomas of rats
given BHP in their drinking water. Missense mutations
in the LPAR1 were detected in rat hepatocellular
carcinomas induced by N-nitroso-diethylamine and
choline-deficient l-amino acid-defined diets.
Deletion of the PDZ domain of the receptor prevents
signal attenuation that controls LPA-mediated receptor
activation and cell proliferation.
LPAR1 (lysophosphatidic acid receptor 1) Murph MM, Radhakrishna H
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 291
Implicated in
Various cancers
Note
Overexpression of the LPAR1 in mice contributes to
the tumorigenicity and aggressiveness of ovarian
cancer.
Prognosis
Upregulation of the LPAR1 appears to enhance tumor
progression in the previous examples.
Oncogenesis
The LPAR1 is a proto-oncogene contributing to the
metastatic potential of breast cancers and may require
signals from ErbB2/HER2 dimerization. In a study
designed to assess the functional conseq-uences of
overexpression as it relates to breast carcinogenesis,
1000 selected/suspected cDNAs were inserted into
immortalized MCF-10A cells and a derivative cell line,
MCF-10A.B2 expressing an inducibly active variant of
ErbB2. The study examined three assays (cell
proliferation, migration and 3-D matrigel acinar
morphogenesis) and the LPAR1 scored positive in all
three; thus, it was determined to be a proto-oncogene in
this disease. Several observations are of interest: first,
the LPAR1 induced migration in the absence of ErbB2
activation but not in the absence of dimerization which
suggests that the LPAR1 may require weak signals
from ligand-independent dimerization of ErbB2 to
induce migration; second, in the acinar morphogenesis
assay, phenotypical changes of cells with the LPAR1
included the formation of features of invasive tumor
cells, such as disorganized acinar structure, large
structures and protrusive behavior; third, the LPAR1
was capable of establishing abnormal 3-D
morphogenesis in the absence of conditions to dimerize
ErbB2.
Lung injury
Note
The LPAR1 mediates fibroblast migration and
recruitment in the injured lung. The chemotactic
activity of fibroblasts is dependent on LPAR1
expression.
Disease
Pulmonary fibrosis
The concentration of LPA is elevated in broncho-
alveolar lavage samples from patients with idio-pathic
pulmonary fibrosis. The fibroblasts of these patients
require expression of LPAR1 for the chemotactic
activity present in this pathology. Data suggests that
LPAR1-null mice are substantially protected from
fibroblast accumulation. This corresponds to lung
injury where aberrant wound-healing responses
exacerbate pulmonary fibrosis pathogenesis.
Prognosis
LPAR1 links lung injury with pulmonary fibrosis
development.
References Contos JJ, Fukushima N, Weiner JA, Kaushal D, Chun J. Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior. Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13384-9
Wang DA, Lorincz Z, Bautista DL, Liliom K, Tigyi G, Parrill AL. A single amino acid determines lysophospholipid specificity of the S1P1 (EDG1) and LPA1 (EDG2) phospholipid growth factor receptors. J Biol Chem. 2001 Dec 28;276(52):49213-20
Gobeil F Jr, Bernier SG, Vazquez-Tello A, Brault S, Beauchamp MH, Quiniou C, Marrache AM, Checchin D, Sennlaub F, Hou X, Nader M, Bkaily G, Ribeiro-da-Silva A, Goetzl EJ, Chemtob S. Modulation of pro-inflammatory gene expression by nuclear lysophosphatidic acid receptor type-1. J Biol Chem. 2003 Oct 3;278(40):38875-83
Harrison SM, Reavill C, Brown G, Brown JT, Cluderay JE, Crook B, Davies CH, Dawson LA, Grau E, Heidbreder C, Hemmati P, Hervieu G, Howarth A, Hughes ZA, Hunter AJ, Latcham J, Pickering S, Pugh P, Rogers DC, Shilliam CS, Maycox PR. LPA1 receptor-deficient mice have phenotypic changes observed in psychiatric disease. Mol Cell Neurosci. 2003 Dec;24(4):1170-9
Murph MM, Scaccia LA, Volpicelli LA, Radhakrishna H. Agonist-induced endocytosis of lysophosphatidic acid-coupled LPA1/EDG-2 receptors via a dynamin2- and Rab5-dependent pathway. J Cell Sci. 2003 May 15;116(Pt 10):1969-80
Avendaño-Vázquez SE, García-Caballero A, García-Sáinz JA. Phosphorylation and desensitization of the lysophosphatidic acid receptor LPA1. Biochem J. 2005 Feb 1;385(Pt 3):677-84
Roberts C, Winter P, Shilliam CS, Hughes ZA, Langmead C, Maycox PR, Dawson LA. Neurochemical changes in LPA1 receptor deficient mice--a putative model of schizophrenia. Neurochem Res. 2005 Mar;30(3):371-7
Yamada T, Ohoka Y, Kogo M, Inagaki S. Physical and functional interactions of the lysophosphatidic acid receptors with PDZ domain-containing Rho guanine nucleotide exchange factors (RhoGEFs). J Biol Chem. 2005 May 13;280(19):19358-63
Pilpel Y, Segal M. The role of LPA1 in formation of synapses among cultured hippocampal neurons. J Neurochem. 2006 Jun;97(5):1379-92
Waters CM, Saatian B, Moughal NA, Zhao Y, Tigyi G, Natarajan V, Pyne S, Pyne NJ. Integrin signalling regulates the nuclear localization and function of the lysophosphatidic acid receptor-1 (LPA1) in mammalian cells. Biochem J. 2006 Aug 15;398(1):55-62
Witt AE, Hines LM, Collins NL, Hu Y, Gunawardane RN, Moreira D, Raphael J, Jepson D, Koundinya M, Rolfs A, Taron B, Isakoff SJ, Brugge JS, LaBaer J. Functional proteomics approach to investigate the biological activities of cDNAs implicated in breast cancer. J Proteome Res. 2006 Mar;5(3):599-610
Fukushima N, Shano S, Moriyama R, Chun J. Lysophosphatidic acid stimulates neuronal differentiation of cortical neuroblasts through the LPA1-G(i/o) pathway. Neurochem Int. 2007 Jan;50(2):302-7
Murph MM, Hurst-Kennedy J, Newton V, Brindley DN, Radhakrishna H. Lysophosphatidic acid decreases the nuclear localization and cellular abundance of the p53 tumor suppressor in A549 lung carcinoma cells. Mol Cancer Res. 2007 Nov;5(11):1201-11
LPAR1 (lysophosphatidic acid receptor 1) Murph MM, Radhakrishna H
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 292
Pradère JP, Klein J, Grès S, Guigné C, Neau E, Valet P, Calise D, Chun J, Bascands JL, Saulnier-Blache JS, Schanstra JP. LPA1 receptor activation promotes renal interstitial fibrosis. J Am Soc Nephrol. 2007 Dec;18(12):3110-8
Estivill-Torrús G, Llebrez-Zayas P, Matas-Rico E, Santín L, Pedraza C, De Diego I, Del Arco I, Fernández-Llebrez P, Chun J, De Fonseca FR. Absence of LPA1 signaling results in defective cortical development. Cereb Cortex. 2008 Apr;18(4):938-50
Lee Z, Cheng CT, Zhang H, Subler MA, Wu J, Mukherjee A, Windle JJ, Chen CK, Fang X. Role of LPA4/p2y9/GPR23 in negative regulation of cell motility. Mol Biol Cell. 2008 Dec;19(12):5435-45
Mototani H, Iida A, Nakajima M, Furuichi T, Miyamoto Y, Tsunoda T, Sudo A, Kotani A, Uchida A, Ozaki K, Tanaka Y, Nakamura Y, Tanaka T, Notoya K, Ikegawa S. A functional SNP in EDG2 increases susceptibility to knee osteoarthritis in Japanese. Hum Mol Genet. 2008 Jun 15;17(12):1790-7
Murakami M, Shiraishi A, Tabata K, Fujita N. Identification of the orphan GPCR, P2Y(10) receptor as the sphingosine-1-phosphate and lysophosphatidic acid receptor. Biochem Biophys Res Commun. 2008 Jul 11;371(4):707-12
Murph MM, Nguyen GH, Radhakrishna H, Mills GB. Sharpening the edges of understanding the structure/function of the LPA1 receptor: expression in cancer and mechanisms of regulation. Biochim Biophys Acta. 2008 Sep;1781(9):547-57
Pradère JP, Gonzalez J, Klein J, Valet P, Grès S, Salant D, Bascands JL, Saulnier-Blache JS, Schanstra JP. Lysophosphatidic acid and renal fibrosis. Biochim Biophys Acta. 2008 Sep;1781(9):582-7
Urs NM, Kowalczyk AP, Radhakrishna H. Different mechanisms regulate lysophosphatidic acid (LPA)-dependent versus phorbol ester-dependent internalization of the LPA1 receptor. J Biol Chem. 2008 Feb 29;283(9):5249-57
Yu S, Murph MM, Lu Y, Liu S, Hall HS, Liu J, Stephens C, Fang X, Mills GB. Lysophosphatidic acid receptors determine tumorigenicity and aggressiveness of ovarian cancer cells. J Natl Cancer Inst. 2008 Nov 19;100(22):1630-42
Obo Y, Yamada T, Furukawa M, Hotta M, Honoki K, Fukushima N, Tsujiuchi T. Frequent mutations of lysophosphatidic acid receptor-1 gene in rat liver tumors. Mutat Res. 2009 Jan 15;660(1-2):47-50
Yamada T, Obo Y, Furukawa M, Hotta M, Yamasaki A, Honoki K, Fukushima N, Tsujiuchi T. Mutations of lysophosphatidic acid receptor-1 gene during progression of lung tumors in rats. Biochem Biophys Res Commun. 2009 Jan 16;378(3):424-7
This article should be referenced as such:
Murph MM, Radhakrishna H. LPAR1 (lysophosphatidic acid receptor 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):289-292.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 293
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OPEN ACCESS JOURNAL AT INIST-CNRS
PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) Montserrat Sanchez-Cespedes
Programa d'Epigenetica i Biologia del Cancer-PEBC, Institut d'Investigacions Biomediques Bellvitge
(IDIBELL), Hospital Durant i Reynals, Avinguda Gran Via de l'Hospitalet, 199-203 08907-L'Hospitalet de
Llobregat-Barcelona, Spain (MSC)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/PIK3CAID415ch3q26.html DOI: 10.4267/2042/44713
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: EC 2.7.1.153; MGC142161;
MGC14216
PI3K; p110-alpha
HGNC (Hugo): PIK3CA
Location: 3q26.32
Local order: centromere-KCNMB2-ZMAT3-
BC032034-PIK3CA-KCNMB3-ZNF639-MFN1-
GNB4- telomere
DNA/RNA
Relative size of the 21 exons of PIK3CA. The entire exon 1 is UTR (untranslated region). Exon numeration corresponds to the prevalent transcript (NM-006218).
Description
The PIK3CA gene spans a total genomic size of 86,190
bases and is composed of 21 exons, 20 of them coding
exons of varying lengths. Putative pseudogenes of
PIK3CA have been described on chromosomes 16 (gi
28913054) and 22q11.2
(gi 5931525), the later one in the Cat Eye Syndrome
region. These regions are highly homolog to the
sequences of exons 9 and 11-13 of the PIK3CA gene.
Transcription
The human PIK3CA transcript has an open reading
frame of 3,207-bp, predicting a protein of 1,068 amino
acid residues.
Protein
Description
The PIK3CA gene encodes the p110alpha protein
which is a catalytic subunit of the class I PI 3-kinases
(PI3K). Class I PI3K are heterodimeric molecules
composed of a catalytic subunit, a p110, and a
regulatory subunit. There are three possible calatytic
subunits p110alpha, beta or delta.
Expression
Widely expressed.
Localisation
The p110alpha localizes in the cytoplasm.
p110alpha conserved domains. Through its adaptor binding domain p110alpha interacts with the regulatory subunit. C2 domain, protein-kinase-C-homology-2 domain.
PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) Sanchez-Cespedes M
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 294
Function
Class I PI 3-kinases (PI3K) are linked to many cellular
functions, including cell growth, prolifera-tion,
differentiation, motility, survival and intra-cellular
trafficking. PI3K convert PI(4,5)P2 to PI(3,4,5)P3 on
the inner leaflet of the plasma membrane. The
PI(3,4,)P3 provokes the recruitment to cellular
membranes of a variety of signalling proteins,
containing PX domain, pleckstrin homo-logy domains
(PH domains), FYVE domains and other
phosphoinositide-binding domains. One of these is the
protein kinase B (PKB/AKT) a very well known
protein that is activated as a result of its translocation to
the cell membrane where it is then phosphorylated and
activated by another kinase, called phosphoinositide
dependent kinase 1 (PDK1). The phosphorylation of
AKT leads to the activation of the TSC/mTOR
pathway. PTEN, a tumor suppressor inactivated in
many cancers counteracts the action of PI3K by
dephosphoryla-ting the phosphoinositide-3,4,5-
trisphosphate (PIP3) (Lee et al., 2007).The PI3K are
inhibited by the drugs wortmannin and LY294002
although to various degree of sensitivity among the
different classes.
Mutations
Somatic
Somatic mutations at the PIK3CA gene have been
found in tumors and thus, it can be considered a bona
fide oncogene (Samuels et al., 2004). Most of the
mutations cluster in hotspots within the helical or the
catalytic domains.
Implicated in
A wide variety of human cancers
Note
(For example, colon, breast, endometrial, ovarian,
brain, lung, thyroid, head and neck and stomach).
PIK3CA mutations lead to constitutive activation of
p110alpha enzymatic activity, stimulate AKT
signaling, and allow growth factor-independent growth
(Bader et al., 2005). In addition, when expressed in
normal cells, these mutations allow anchorage-
independent growth, further attesting to their important
role in cancer development (Kang et al., 2005).
PIK3CA somatic mutations are frequent in a variety of
human primary tumors and cancer cell lines such as,
among others, those of the colon, breast, and stomach
(Samuels et al., 2004). However, in other tumors, i.e.
those of the lung, head and neck, brain, endometrium,
ovary, prostate, osteosarcoma and pancreas,
hematopoietic malignancies, PIK3CA mutations are not
as common (Angulo et al., 2008; Qiu et al., 2006;
Muller et al., 2007; Samuels et al., 2004; Schonleben et
al., 2006). PIK3CA gene amplifica-
tion has also been proposed as a mechanism for
oncogene activation in some tumors (Angulo et al.,
2008). Because PIK3CA is now considered an
important oncogene implicated in the development of a
wide variety of human cancers, efforts are now being
directed towards the development of mole-cules that
inhibit the activity of PI3K (Garcia-Echeverria et al.,
2008). These could be efficient in the treatment of
those tumors carrying constitutive activation of PI3K
pathway. PTEN is a well known tumor suppressor that
counteracts the action of PI3K by dephosphorylating
the phosphoinositide-3,4,5-trisphosphate (PIP3). Thus,
the treatment with drugs that inhibit p110alpha activity
would be also potentially efficient in patients whose
tumors carry genetic alterations at PTEN.
It has recently been reported that activation of the PI3K
pathway in breast tumors with concomitant ERBB2
gene amplification, either through PIK3CA mutations
or PTEN inactivation, underlies trastuzumab resistance.
These findings may provide a biomarker to identify
patients unlikely to respond to trastuzumab-based
therapy (Berns et al., 2007).
To be noted
Note
Recent evidence has shown that the PIK3CA gene is
mutated and amplified in a range of human cancers.
Due to that p110alpha is believed to be a promising
drug target. A number of pharmaceutical companies are
currently designing and charactering potential
p110alpha isoform specific inhibitors.
References Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004 Apr 23;304(5670):554
Bader AG, Kang S, Zhao L, Vogt PK. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer. 2005 Dec;5(12):921-9
Kang S, Bader AG, Vogt PK. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):802-7
Qiu W, Schönleben F, Li X, Ho DJ, Close LG, Manolidis S, Bennett BP, Su GH. PIK3CA mutations in head and neck squamous cell carcinoma. Clin Cancer Res. 2006 Mar 1;12(5):1441-6
Schönleben F, Qiu W, Ciau NT, Ho DJ, Li X, Allendorf JD, Remotti HE, Su GH. PIK3CA mutations in intraductal papillary mucinous neoplasm/carcinoma of the pancreas. Clin Cancer Res. 2006 Jun 15;12(12):3851-5
Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, Bernards R. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007 Oct;12(4):395-402
PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) Sanchez-Cespedes M
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 295
Lee JY, Engelman JA, Cantley LC. Biochemistry. PI3K charges ahead. Science. 2007 Jul 13;317(5835):206-7
Müller CI, Miller CW, Hofmann WK, Gross ME, Walsh CS, Kawamata N, Luong QT, Koeffler HP. Rare mutations of the PIK3CA gene in malignancies of the hematopoietic system as well as endometrium, ovary, prostate and osteosarcomas, and discovery of a PIK3CA pseudogene. Leuk Res. 2007 Jan;31(1):27-32
Angulo B, Suarez-Gauthier A, Lopez-Rios F, Medina PP, Conde E, Tang M, Soler G, Lopez-Encuentra A, Cigudosa JC, Sanchez-Cespedes M. Expression signatures in lung cancer reveal a profile for EGFR-mutant tumours and identify selective
PIK3CA overexpression by gene amplification. J Pathol. 2008 Feb;214(3):347-56
Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene. 2008 Sep 18;27(41):5511-26
This article should be referenced as such:
Sanchez-Cespedes M. PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):293-295.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 296
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
SFRP4 (Secreted Frizzled-Related Protein 4) Kendra S Carmon, David S Loose
University of Texas Health Science Center Houston, Houston, TX 77030, USA (KSC, DSL)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/SFRP4ID42277ch7p14.html DOI: 10.4267/2042/44714
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: FRP-4; sFRP-4; FRPHE; MGC26498;
LOC6424
HGNC (Hugo): SFRP4
Location: 7p14.1
Local order: According to NCBI, SFRP4 is telomeric
to EPDR1 (7p14.1) ependymin related protein 1
(zebrafish) and STARD3NL (7p14-p13) StAR-related
lipid transfer domain containing 3 N-terminal like and
centromeric to TXNDC3 (7p14.1) thioredoxin domain
containing 3 (spermatozoa) and GPR141 (7p14.1) G
protein-coupled receptor 141.
DNA/RNA
Description
The SFRP4 gene spans 10.99 kb on the short arm of
chromosome 7 and is transcribed from the minus strand
in the centromere-to-telomere orientation. The gene is
encoded by six exons with the trans-lation initiation
codon in the first exon.
Transcription
The SFRP4 mRNA transcript is 2974 bp, 1041 bp are
coding sequence. Ensembl data predicts a second
transcript from the SFRP4 gene, lacking the 81 bp exon
2, although this has not been demons-trated.
Protein
Description
SFRP4 protein is comprised of 346 amino acids with a
predicted molecular weight of 39.9 kDa and an actual
molecular weight of approximately 50-55 kDa.
SFRP4 belongs to a family of five SFRPs; these
proteins fold into two independent domains. The N-
terminus contains a secretion signal peptide followed
by a ~120 amino acid cysteine-rich domain (CRD). The
CRD is 30-50% identical to the extracellular putative
Wnt-binding domain of frizzled (Fzd) receptors and is
characterized by the presence of ten cysteine residues at
conserved positions.
Diagram illustrates SFRP4 gene that contains a total of six exons.
SFRP4 (Secreted Frizzled-Related Protein 4) Carmon KS, Loose DS
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 297
Diagram illustrates the full length SFRP4 protein which contains a signal peptide sequence of 20-30 amino acids, a cysteine-rich domain (CRD) of approximately 120 amino acids, and a netrin-related motif (NTR) domain. Conserved cysteines of the CRD are indicated by *.
These cysteines form a pattern of disulfide bridges. The
C-terminal portion of the SFRP protein is characterized
by segments of positively charged residues that appear
to confer heparin-binding properties in at least two
SFRPs (SFRP1 and SFRP3) and contains a netrin-
related motif (NTR) with six cysteine residues that
most likely form three disulfide bridges. NTR domains
with similar features are found in a wide range of
unrelated proteins, including Netrin-1, tissue inhibitors
of metallo-proteinases (TIMPs), complement proteins
and type I procollagen C-proteinase enhancer proteins
(PCOLCEs). The six conserved cysteines in the NTR
of SFRP4 share a similar spacing to SFRP3, whereas
those of the SFRP1/SFRP2/SFRP5 subgroup are
distinctively different, indicating a disparity in disulfide
bond formation. Uniquely, SFRP4 contains two
additional cysteine residues. The overall function of the
NTR is unknown, yet there is some evidence that the
NTR may also play a role in Wnt binding. This implies
that multiple Wnt binding sites may exist on SFRP
molecules and/or that SFRPs exhibit differential
affinities for Wnt ligands according to the different
SFRP conformational and post-translational
modifications.
Expression
SFRP4 is expressed in various normal tissues including
endometrium (specifically stromal cells with higher
expression during proliferative phase of menstrual
cycle), ovary, kidney, heart, brain, mammary gland,
cervix, pancreas, stomach, colon, lung, skeletal muscle,
testis, eye, bone, prostate, and liver.
Localisation
Secreted from cell; extracellular matrix; bound to
plasma membrane.
Function
Since SFRPs share a similar CRD with the Fzd family
of receptors; it is believed that SFRPs may act as
soluble modulators that compete with Fzd to bind the
Wnt ligands, thereby altering the Wnt signal. Individual
SFRPs also have distinct binding specificity for distinct
Wnt ligands. Reports have demonstrated that SFRP4
binds Wnt7a and there is conflicting data for SFRP4
binding to Wnt3a. SFRP4 expression is regulated by
estrogen and progesterone and may act as a regulator of
adult uterine morphology and function. SFRP4 has
been shown to increase apoptosis during ovulation.
Transgenic studies have found that SFRP4 decreases
bone formation and inhibits osteoblast proliferation by
attenuating canonical/beta-catenin-Wnt signaling.
SFRP4 reportedly exhibits phospha-turic effects by
specifically inhibiting sodium-dependent phosphate
uptake.
Homology
Of the five human SFRPs (SFRP1, SFRP2, SFRP3,
SFRP4, SFRP5), SFRP4 shares most significant
homology with SFRP3.
Mutations
Note
It was reported that the T allele of the SFRP4 gene
polymorphism ARG262 (CGC to CGT) of exon4 is
associated with decreased bone mineral density in post-
menopausal Japanese women.
Implicated in
Endometrial Carcinoma
Note
SFRP4 was more frequently down-regulated in
(microsatellite instability). MSI cancers as compared
with (microsatellite stable) MSS endo-metrioid
endometrial cancers. Expression of SFRP4 is decreased
in both low-grade endometrial stromal sarcoma and
undifferentiated endometrial sarcoma.
Malignant Pleural Mesothelioma
Note
SFRP4 promoter is frequently methylated in this cancer
leading to inhibition of expression and is associated
with abnormal growth; restoration of SFRP4 results in
growth suppression and apoptosis in mesothelioma cell
lines.
Tumor-induced osteomalacia
Note
Tumor-induced osteomalacia is a disorder in which
there is an increase in renal phosphate excretion and a
reduction in serum phosphate levels leading to
hyperphosphaturia, hypophosphatemia and rickets.
SFRP4 (Secreted Frizzled-Related Protein 4) Carmon KS, Loose DS
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 298
CLUSTAL alignment of the 5 human SFRPs.
SFRP4 is highly expressed in such tumors and
functions as a circulating phosphaturic factor that
antagonizes renal Wnt-signaling.
Breast Cancer
Note
Studies have found evidence for SFRP4 overexpression
in breast cancer.
Pancreatic Cancer
Note
SFRP4 found to be significantly hypermethylated in the
tumors of cancer patients versus matched adjacent
tissue controls.
Gastric Carcinoma
Note
The SFRP4 was highly methylated in gastric carcinoma
samples with greater instance in H. pylori positive
patients.
Prostate Cancer
Note
SFRP4 is overexpressed in prostate cancers and
SFRP4 (Secreted Frizzled-Related Protein 4) Carmon KS, Loose DS
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 299
functions to inhibit cell proliferation and metastatic
potential.
Prognosis
Increased expression of membranous SFRP4 is
associated with a good prognosis in human localized
androgen-dependent prostate cancer, suggesting a role
for sFRP4 in early stage disease.
B-cell chronic lymphocytic leukemia
Note
SFRP4 was found to be frequently methylated and
downregulated in CLL samples.
Colorectal Carcinoma
Note
SFRP4 expression was shown to be up-regulated in
colorectal cancer.
Esophageal Adenocarcinoma
Note
SFRP4 mRNA and protein expression were
significantly decreased due to hypermethylation in
esophageal adenocarcinoma and Barrett's esophagus
patients.
References Finch PW, He X, Kelley MJ, Uren A, Schaudies RP, Popescu NC, Rudikoff S, Aaronson SA, Varmus HE, Rubin JS. Purification and molecular cloning of a secreted, Frizzled-related antagonist of Wnt action. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6770-5
Abu-Jawdeh G, Comella N, Tomita Y, Brown LF, Tognazzi K, Sokol SY, Kocher O. Differential expression of frpHE: a novel human stromal protein of the secreted frizzled gene family, during the endometrial cycle and malignancy. Lab Invest. 1999 Apr;79(4):439-47
Bafico A, Gazit A, Pramila T, Finch PW, Yaniv A, Aaronson SA. Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling. J Biol Chem. 1999 Jun 4;274(23):16180-7
Bányai L, Patthy L. The NTR module: domains of netrins, secreted frizzled related proteins, and type I procollagen C-proteinase enhancer protein are homologous with tissue inhibitors of metalloproteases. Protein Sci. 1999 Aug;8(8):1636-42
Dennis S, Aikawa M, Szeto W, d'Amore PA, Papkoff J. A secreted frizzled related protein, FrzA, selectively associates with Wnt-1 protein and regulates wnt-1 signaling. J Cell Sci. 1999 Nov;112 ( Pt 21):3815-20
Uren A, Reichsman F, Anest V, Taylor WG, Muraiso K, Bottaro DP, Cumberledge S, Rubin JS. Secreted frizzled-related protein-1 binds directly to Wingless and is a biphasic modulator of Wnt signaling. J Biol Chem. 2000 Feb 11;275(6):4374-82
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Roszmusz E, Patthy A, Trexler M, Patthy L. Localization of disulfide bonds in the frizzled module of Ror1 receptor tyrosine kinase. J Biol Chem. 2001 May 25;276(21):18485-90
Yamaguchi TP. Heads or tails: Wnts and anterior-posterior patterning. Curr Biol. 2001 Sep 4;11(17):R713-24
Chong JM, Uren A, Rubin JS, Speicher DW. Disulfide bond assignments of secreted Frizzled-related protein-1 provide insights about Frizzled homology and netrin modules. J Biol Chem. 2002 Feb 15;277(7):5134-44
Fujita M, Ogawa S, Fukuoka H, Tsukui T, Nemoto N, Tsutsumi O, Ouchi Y, Inoue S. Differential expression of secreted frizzled-related protein 4 in decidual cells during pregnancy. J Mol Endocrinol. 2002 Jun;28(3):213-23
Berndt T, Craig TA, Bowe AE, Vassiliadis J, Reczek D, Finnegan R, Jan De Beur SM, Schiavi SC, Kumar R. Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. J Clin Invest. 2003 Sep;112(5):785-94
Drake JM, Friis RR, Dharmarajan AM. The role of sFRP4, a secreted frizzled-related protein, in ovulation. Apoptosis. 2003 Aug;8(4):389-97
Ace CI, Okulicz WC. Microarray profiling of progesterone-regulated endometrial genes during the rhesus monkey secretory phase. Reprod Biol Endocrinol. 2004 Jul 7;2:54
Fujita M, Urano T, Shiraki M, Momoeda M, Tsutsumi O, Hosoi T, Orimo H, Ouchi Y, Inoue S.. Association of a single nucleotide polymorphism in the secreted frizzled-related protein 4 (sFRP4) gene with bone mineral density. Ger. Geront. Int. 2004; 4 (3): 175-180.
Horvath LG, Henshall SM, Kench JG, Saunders DN, Lee CS, Golovsky D, Brenner PC, O'Neill GF, Kooner R, Stricker PD, Grygiel JJ, Sutherland RL. Membranous expression of secreted frizzled-related protein 4 predicts for good prognosis in localized prostate cancer and inhibits PC3 cellular proliferation in vitro. Clin Cancer Res. 2004 Jan 15;10(2):615-25
Hrzenjak A, Tippl M, Kremser ML, Strohmeier B, Guelly C, Neumeister D, Lax S, Moinfar F, Tabrizi AD, Isadi-Moud N, Zatloukal K, Denk H. Inverse correlation of secreted frizzled-related protein 4 and beta-catenin expression in endometrial stromal sarcomas. J Pathol. 2004 Sep;204(1):19-27
Lee AY, He B, You L, Dadfarmay S, Xu Z, Mazieres J, Mikami I, McCormick F, Jablons DM. Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma. Oncogene. 2004 Aug 26;23(39):6672-6
He B, Lee AY, Dadfarmay S, You L, Xu Z, Reguart N, Mazieres J, Mikami I, McCormick F, Jablons DM. Secreted frizzled-related protein 4 is silenced by hypermethylation and induces apoptosis in beta-catenin-deficient human mesothelioma cells. Cancer Res. 2005 Feb 1;65(3):743-8
Risinger JI, Maxwell GL, Chandramouli GV, Aprelikova O, Litzi T, Umar A, Berchuck A, Barrett JC. Gene expression profiling of microsatellite unstable and microsatellite stable endometrial cancers indicates distinct pathways of aberrant signaling. Cancer Res. 2005 Jun 15;65(12):5031-7
Zou H, Molina JR, Harrington JJ, Osborn NK, Klatt KK, Romero Y, Burgart LJ, Ahlquist DA. Aberrant methylation of secreted frizzled-related protein genes in esophageal adenocarcinoma and Barrett's esophagus. Int J Cancer. 2005 Sep 10;116(4):584-91
Berndt TJ, Bielesz B, Craig TA, Tebben PJ, Bacic D, Wagner CA, O'Brien S, Schiavi S, Biber J, Murer H, Kumar R. Secreted frizzled-related protein-4 reduces sodium-phosphate co-transporter abundance and activity in proximal tubule cells. Pflugers Arch. 2006 Jan;451(4):579-87
Feng Han Q, Zhao W, Bentel J, Shearwood AM, Zeps N, Joseph D, Iacopetta B, Dharmarajan A. Expression of sFRP-4
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and beta-catenin in human colorectal carcinoma. Cancer Lett. 2006 Jan 8;231(1):129-37
Liu TH, Raval A, Chen SS, Matkovic JJ, Byrd JC, Plass C. CpG island methylation and expression of the secreted frizzled-related protein gene family in chronic lymphocytic leukemia. Cancer Res. 2006 Jan 15;66(2):653-8
Turashvili G, Bouchal J, Burkadze G, Kolar Z. Wnt signaling pathway in mammary gland development and carcinogenesis. Pathobiology. 2006;73(5):213-23
Wawrzak D, Métioui M, Willems E, Hendrickx M, de Genst E, Leyns L. Wnt3a binds to several sFRPs in the nanomolar range. Biochem Biophys Res Commun. 2007 Jun 15;357(4):1119-23
Bu XM, Zhao CH, Zhang N, Gao F, Lin S, Dai XW. Hypermethylation and aberrant expression of secreted frizzled-related protein genes in pancreatic cancer. World J Gastroenterol. 2008 Jun 7;14(21):3421-4
Carmon KS, Loose DS. Secreted frizzled-related protein 4 regulates two Wnt7a signaling pathways and inhibits proliferation in endometrial cancer cells. Mol Cancer Res. 2008 Jun;6(6):1017-28
Kang GH, Lee S, Cho NY, Gandamihardja T, Long TI, Weisenberger DJ, Campan M, Laird PW. DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis. Lab Invest. 2008 Feb;88(2):161-70
Nakanishi R, Akiyama H, Kimura H, Otsuki B, Shimizu M, Tsuboyama T, Nakamura T. Osteoblast-targeted expression of Sfrp4 in mice results in low bone mass. J Bone Miner Res. 2008 Feb;23(2):271-7
This article should be referenced as such:
Carmon KS, Loose DS. SFRP4 (Secreted Frizzled-Related Protein 4). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):296-300.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 301
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)) Stephen Hiscox
Welsh School of Pharmacy, Redwood Building, Cardiff University, Cardiff, UK (SH)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/SRCID448ch20q11.html DOI: 10.4267/2042/44715
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: ASV (Avian Sarcoma Virus); SRC1; c-
SRC; p60-Src; pp60c-Src
HGNC (Hugo): SRC
Location: 20q11.23
Note
The Src kinase proto-oncogene has a high degree of
similarity to the v-src gene of Rous sarcoma virus,
although the C-terminal domain of v-Src is trunca-ted
and lacks the regulatory Tyr527 and therefore is not
subjected to downregulation by Csk. Src kinase is
implicated in the regulation of embryonic development,
cell differentiation and proliferation. Src has been
suggested to play a key role in cancer, where it may
facilitate tumour spread through promotion of tumour
cell invasion.
DNA/RNA
Note
The gene consists of 14 exons. Two isoforms have been
described differing in their 5' UTRs. Variant 1
represents the longer transcript although both isoforms
1 and 2 encode the same protein.
Description
Size: 61.33 Kb, 14 exons. mRNA: 4145 bases.
Protein
Note
Src can be phosphorylated on Tyr-530 by CSK (c-Src
kinase). The phosphorylated form is termed pp60c-src.
Phosphorylation of this tyrosine allows facilitates
interaction between the C-terminal tail and the SH2
domain, maintaining Src in an inactive formation.
Protein Translation:
MGSNKSKPKDASQRRRSLEPAENVHGAGGGAFP
ASQTPSKPASADGHRGPSAAFAPAAAEPKLFGGF
NSSDTVTSPQRAGPLAGGVTTFVALYDYESRTET
DLSFKKGERLQIVNNTEGDWWLAHSLSTGQTGY
IPSNYVAPSDSIQAEEWYFGKITRREGQGCFGEV
WMGTWNGTTRVAIKTLKPGTMSPEAFLQEAQV
MKKLRHEKLVQLYAVVSEEPIYIVTEYMSKGSLL
DFLKGETGKYLRLPQLVDMAAQIASGMAYVER
MNYVHRDLRAANILVGENLVCKVADFGLARLIE
DNEYTARQGAKFPIKWTAPEAALYGRFTIKSDV
WSFGILLTELTTKGRVPYPGMVNREVLDQVERG
YRMPCPPECPESLHDLMCQCWRKEPEERPTFEYL
QAFLEDYFTSTEPQYQPGENL
Note: This variant (isoform 1) represents the longer Src
transcript although both isoforms 1 and 2 encode the
same protein as the difference is in the 5' UTR.
SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)) Hiscox S
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 302
Linear representation of the protein structure of human Src family members, showing the six distinct domains. N and C denote N- and C-termini respectively. Location of major regulatory phosphorylation sites and the myristolation signal sequence are shown.
Description
Size: 536 amino acids; 59.835 KDa.
Src is 59.6 KDa in size and has a domain structure
comprised of six distinct functional regions (see figure
above). These include an N-terminal SH4 domain that
contains a lipid-modification sequence allowing
targeting of Src to cellular membranes, and an adjacent,
poorly-conserved region thus being unique to each Src
family member. SH3 and SH2 domains adjacent to the
N-terminus facilitate protein-protein interactions
between Src and its interacting proteins whilst the SH1
domain allows ATP and substrate binding and has
tyrosine kinase activity; autophosphorylation of Y419
within this domain is required for the maximum kinase
activity of Src. The negative regulatory tail of Src
contains a tyrosine at 530, the phosphorylation of
which promotes a conformational change to produce an
inactive Src molecule. Sequences within the C-
terminus of Src have been recently identified to
facilitate protein-protein interactions have been shown
to regulate Src function in addition to its kinase
activity.
Expression
Ubiquitously expressed but with particularly high
levels in brain tissue, osteoclasts and platelets.
Localisation
Predominantly cytoplasmic and/or plasma mem-brane,
the latter due to myristolation of the N-terminus.
Activated Src has also been reported in the cell nucleus
in some tumour tissues.
Function
Src can interact with a diverse array of cellular factors
allowing it to regulate a variety of normal and
oncogenic processes that ultimately result in cell
proliferation, differentiation, survival, adhe-sion,
motility, invasion and angiogenesis (Thomas and
Brugge, 1997; Summy and Gallick, 2003). Such
interacting partners include receptor tyrosine kinases
(e.g. the EGF receptor family (Biscardi et al., 1998)),
integrins (Galliher and Schiemann, 2006; Huveneers et
al., 2007), cell-cell adhesion molecules (Giehl and
Menke, 2008), in addition to STATs (Silva, 2004),
FAK (Brunton and Frame, 2008), the adaptor protein
p130Cas (Chang et al., 2008) and GPCRs (McGarrigle
and Huang, 2007). Importantly, Src can also interact
with the oestrogen receptor (Weatherman, 2008), where
it has been shown to be pivotal in both non-genomic
ER activation of signalling pathways and gene
transcription events. The ability of Src to function as
both an effector and regulator of receptor-induced
signalling allows it to mediate cross-talk between
normally distinct signalling pathways and thus regulate
a wide variety of both normal and oncogenic processes,
including proliferation, differentiation, survival,
adhesion, motility, invasion and angiogenesis.
Homology
c-Src is the prototypic member of a family of nine non-
receptor tyrosine kinases which share the same domain
structure (Src, Fyn, Yes, Lyn, Lck, Hck, Blk, Fgr and
Frk) (Erpel and Courtneidge, 1995) and are expressed
in vertebrates. All Src family members have the same
basic structure of an N-terminal, unique domain
containing a myristylation site and frequently a
palmitoylation site; regulatory SH3 and SH2 domains;
a catalytic domain that has its active site wedged
between the two lobes of the molecule, and a C-
terminal regulatory tail that contains the hallmark
regulatory tyrosine residue (Tyr527 in Src). The
activity of Src family kinases is suppressed upon
phosphorylation of Tyr527, allowing binding of the C-
terminal domain to the SH2 domain. The SH2 and SH3
domains bind phosphotyrosine and proline-rich
peptides, respectively; through these interactions, they
participate in intra- and intermolecular regulation of
kinase activity, as well as localization and substrate
recognition. Differences in the SH2 linker sequences
within Src family kinases correlate with the division of
the Src kinase family into two separate subfamilies:
Group A: Src, Fyn, Yes, Fgr and Group B: Lyn, Hck,
Lck and Blk. Frk forms a separate but linked subfamily
but with homologues also found in invertebrates. Src
family members, with the exception of Src, Fyn and
Yes, exhibit tissue-restricted distribution, being found
primarily in cells of a haematopoietic nature. Below is
a table constructed from Src homology analysis
performed by CluSTr:
Src family
member % identity* % similarity**
Fyn 75 10
Yes 73 9
Fgr 66 11
Lck 60 17
Lyn 60 17
Hck 57 17
SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)) Hiscox S
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 303
Blk 62 13
*Percent identity between Src and protein; defined as: (Same AAs/Length of Protein 1) X100% **Percent similarity between Src and protein; defined as: (Sim. AAs/Length of Protein 1) X100%
Mutations
Somatic
The SRC family of kinases is rarely mutated in primary
human tumours, although apparently scarce, a
truncating and activating mutation in Src (at aa 531)
has been described for a small subset of advanced-stage
colorectal cancers (Irby et al., 1999).
Implicated in
Cancer
Note
Elevated Src expression and/or activity has been
reported in many different cancer types, where it may
associate with poor clinical prognosis (Irby and
Yeatman, 2000). Increased Src kinase activity in cancer
is likely to arise from the deregulation of Src
expression and/or activation mechanisms rather than
the presence of activating mutations, since genetic
mutations of this kind are rarely reported for Src (see
above). Whereas constitutively activated forms of Src
are transforming, wild-type Src has a relatively low
transformation potential suggesting that Src may act to
facilitate intracellular signalling through regulation,
either directly or indirectly, of other signalling proteins.
Colorectal cancer
Disease
Increased Src activity has been widely described in
colorectal tumour tissue compared with normal
epithelia and within colon polyps, particularly those
displaying a malignant phenotype (DeSeau et al., 1987;
Cartwright et al., 1994). In colorectal cancer tissue
studies, elevated Src kinase activity is associated with a
poor clinical outcome (Aligayer et al., 2002). In vitro
studies suggest that in colon cancer, Src may contribute
more to disease spread than to increased proliferation
(Jones et al., 2002).
Breast cancer
Disease
Src kinase activity is increased in breast cancer tissue
compared to normal tissues (Verbeek et al., 1996). In
vivo animal models suggest that Src activity is elevated
in breast tumours over-expressing HER2 and
interaction between Src and erbB family members may
promote the develop-ment of a more aggressive disease
clinically (Biscardi et al., 2000; Tan et al., 2005).
Physical interactions between Src and growth factor
receptors are reported in breast cancer tissues and cells,
particularly with receptor tyrosine kinases of the EGFR
family allowing Src to regulate signal-ling pathways
that may contribute to aggressive breast cancer cell
behaviour. Src is also intimately involved with Her2
pathway signalling in breast cancer, the result of which
is the promotion of an invasive phenotype (Vadlamudi
et al., 2003; Tan et al., 2005).
Oestrogenic signalling plays a critical role in promoting
breast cancer cell growth where ligand-induced
activation of oestrogen receptors (ERs) results in gene
transcription mediated by the ER, in complex with
various co-activators/co-repressor molecules. In such
cases, Src is able to potentiate ER-mediated, AF-1
dependent gene transcription through indirect
phosphorylation of nuclear ER via ERK1/ERK2 (Feng
et al., 2001) and Akt (Campbell et al., 2001; Shah et al.,
2005) and through regulation of FAK-p130CAS-JNK
signalling pathway activity and the subsequent
activation of co-activator molecules including CBP
(PAG1) and GRIP1 (NCOA2). Furthermore, Src
appears to mediate non-genomic ER signalling through
ERK and Akt pathways (Castoria et al., 2001; Wessler
et al., 2006) to regulate cellular proliferation and
survival (Castoria et al., 1999; Migliaccio et al., 2000).
That Src is involved in both EGFR/Her2 and ER
signalling has led to Src being implicated in growth
factor-ER cross talk mechanisms in breast cancer and
the development of endocrine resistance (Arpino et al.,
2008; Massarweh and Schiff, 2006; Hiscox et al., 2006;
Hiscox et al., 2009).
Hematopoietic cancers
Disease
The majority of Src family kinases are highly expressed
in cells of a hematopoietic origin where they are
suggested to regulate growth and prolifera-tion. Src
itself is, along with related family kinase members, are
implicated in imatinib-resistant, BCR-ABL-expressing
CML (Li, 2008).
Other tumour types
Disease
Src protein and activity have been identified as being
increased in a number of other tumour types including
gastric, pancreatic, lung and ovarian tumours compared
to normal tissue suggesting a possible role for Src in
these tumours.
References DeSeau V, Rosen N, Bolen JB. Analysis of pp60c-src tyrosine kinase activity and phosphotyrosyl phosphatase activity in human colon carcinoma and normal human colon mucosal cells. J Cell Biochem. 1987 Oct;35(2):113-28
Cartwright CA, Coad CA, Egbert BM. Elevated c-Src tyrosine kinase activity in premalignant epithelia of ulcerative colitis. J Clin Invest. 1994 Feb;93(2):509-15
Erpel T, Courtneidge SA. Src family protein tyrosine kinases and cellular signal transduction pathways. Curr Opin Cell Biol. 1995 Apr;7(2):176-82
SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)) Hiscox S
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 304
Verbeek BS, Vroom TM, Adriaansen-Slot SS, Ottenhoff-Kalff AE, Geertzema JG, Hennipman A, Rijksen G. c-Src protein expression is increased in human breast cancer. An immunohistochemical and biochemical analysis. J Pathol. 1996 Dec;180(4):383-8
Thomas SM, Brugge JS. Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol. 1997;13:513-609
Biscardi JS, Belsches AP, Parsons SJ. Characterization of human epidermal growth factor receptor and c-Src interactions in human breast tumor cells. Mol Carcinog. 1998 Apr;21(4):261-72
Castoria G, Barone MV, Di Domenico M, Bilancio A, Ametrano D, Migliaccio A, Auricchio F. Non-transcriptional action of oestradiol and progestin triggers DNA synthesis. EMBO J. 1999 May 4;18(9):2500-10
Irby RB, Mao W, Coppola D, Kang J, Loubeau JM, Trudeau W, Karl R, Fujita DJ, Jove R, Yeatman TJ. Activating SRC mutation in a subset of advanced human colon cancers. Nat Genet. 1999 Feb;21(2):187-90
Biscardi JS, Ishizawar RC, Silva CM, Parsons SJ. Tyrosine kinase signalling in breast cancer: epidermal growth factor receptor and c-Src interactions in breast cancer. Breast Cancer Res. 2000;2(3):203-10
Irby RB, Yeatman TJ. Role of Src expression and activation in human cancer. Oncogene. 2000 Nov 20;19(49):5636-42
Migliaccio A, Castoria G, Di Domenico M, de Falco A, Bilancio A, Lombardi M, Barone MV, Ametrano D, Zannini MS, Abbondanza C, Auricchio F. Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation. EMBO J. 2000 Oct 16;19(20):5406-17
Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem. 2001 Mar 30;276(13):9817-24
Castoria G, Migliaccio A, Bilancio A, Di Domenico M, de Falco A, Lombardi M, Fiorentino R, Varricchio L, Barone MV, Auricchio F. PI3-kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells. EMBO J. 2001 Nov 1;20(21):6050-9
Feng W, Webb P, Nguyen P, Liu X, Li J, Karin M, Kushner PJ. Potentiation of estrogen receptor activation function 1 (AF-1) by Src/JNK through a serine 118-independent pathway. Mol Endocrinol. 2001 Jan;15(1):32-45
Aligayer H, Boyd DD, Heiss MM, Abdalla EK, Curley SA, Gallick GE. Activation of Src kinase in primary colorectal carcinoma: an indicator of poor clinical prognosis. Cancer. 2002 Jan 15;94(2):344-51
Jones RJ, Avizienyte E, Wyke AW, Owens DW, Brunton VG, Frame MC. Elevated c-Src is linked to altered cell-matrix adhesion rather than proliferation in KM12C human colorectal cancer cells. Br J Cancer. 2002 Nov 4;87(10):1128-35
Summy JM, Gallick GE. Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev. 2003 Dec;22(4):337-58
Vadlamudi RK, Sahin AA, Adam L, Wang RA, Kumar R. Heregulin and HER2 signaling selectively activates c-Src phosphorylation at tyrosine 215. FEBS Lett. 2003 May 22;543(1-3):76-80
Silva CM. Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. Oncogene. 2004 Oct 18;23(48):8017-23
Shah YM, Rowan BG. The Src kinase pathway promotes tamoxifen agonist action in Ishikawa endometrial cells through phosphorylation-dependent stabilization of estrogen receptor (alpha) promoter interaction and elevated steroid receptor coactivator 1 activity. Mol Endocrinol. 2005 Mar;19(3):732-48
Tan M, Li P, Klos KS, Lu J, Lan KH, Nagata Y, Fang D, Jing T, Yu D. ErbB2 promotes Src synthesis and stability: novel mechanisms of Src activation that confer breast cancer metastasis. Cancer Res. 2005 Mar 1;65(5):1858-67
Galliher AJ, Schiemann WP. Beta3 integrin and Src facilitate transforming growth factor-beta mediated induction of epithelial-mesenchymal transition in mammary epithelial cells. Breast Cancer Res. 2006;8(4):R42
Hiscox S, Morgan L, Green T, Nicholson RI. Src as a therapeutic target in anti-hormone/anti-growth factor-resistant breast cancer. Endocr Relat Cancer. 2006 Dec;13 Suppl 1:S53-9
Massarweh S, Schiff R. Resistance to endocrine therapy in breast cancer: exploiting estrogen receptor/growth factor signaling crosstalk. Endocr Relat Cancer. 2006 Dec;13 Suppl 1:S15-24
Wessler S, Otto C, Wilck N, Stangl V, Fritzemeier KH. Identification of estrogen receptor ligands leading to activation of non-genomic signaling pathways while exhibiting only weak transcriptional activity. J Steroid Biochem Mol Biol. 2006 Jan;98(1):25-35
Huveneers S, van den Bout I, Sonneveld P, Sancho A, Sonnenberg A, Danen EH. Integrin alpha v beta 3 controls activity and oncogenic potential of primed c-Src. Cancer Res. 2007 Mar 15;67(6):2693-700
McGarrigle D, Huang XY. GPCRs signaling directly through Src-family kinases. Sci STKE. 2007 Jun 26;2007(392):pe35
Arpino G, Wiechmann L, Osborne CK, Schiff R. Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev. 2008 Apr;29(2):217-33
Brunton VG, Frame MC. Src and focal adhesion kinase as therapeutic targets in cancer. Curr Opin Pharmacol. 2008 Aug;8(4):427-32
Chang YM, Bai L, Liu S, Yang JC, Kung HJ, Evans CP. Src family kinase oncogenic potential and pathways in prostate cancer as revealed by AZD0530. Oncogene. 2008 Oct 23;27(49):6365-75
Giehl K, Menke A. Microenvironmental regulation of E-cadherin-mediated adherens junctions. Front Biosci. 2008 May 1;13:3975-85
Li S. Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia. Leuk Lymphoma. 2008 Jan;49(1):19-26
Weatherman RV. Sensing estrogen's many pathways. ACS Chem Biol. 2008 Jun 20;3(6):338-40
Hiscox S, Jordan NJ, Smith C, James M, Morgan L, Taylor KM, Green TP, Nicholson RI. Dual targeting of Src and ER prevents acquired antihormone resistance in breast cancer cells. Breast Cancer Res Treat. 2009 May;115(1):57-67
This article should be referenced as such:
Hiscox S. SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):301-304.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 305
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
TACC3 (transforming, acidic coiled-coil containing protein 3) Melissa R Eslinger, Brenda Lauffart, Ivan H Still
Department of Chemistry and Life Science Bartlett Hall, United States Military Academy, West Point, New
York 10996, USA (MRE), Department of Physical Sciences, Arkansas Tech University, 1701 N Boulder
Ave, Russellville, AR 72801, USA (BL), Department of Biological Sciences, Arkansas Tech University,
1701 N Boulder Ave, Russellville, AR 72801, USA (IHS)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/TACC3ID42458ch4p16.html DOI: 10.4267/2042/44716
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: ERIC1; MGC117382; MGC133242
HGNC (Hugo): TACC3
Location: 4p16.3
DNA/RNA
Description
The gene is composed of 16 verified exons spanning
23.6 kb.
Transcription
Encodes a single confirmed 2788 nt transcript
(NM_006342) (Still et al., 1999), although one
additional transcript with two additional small 5' coding
exons between exon 1 and the first coding exon (exon
2), based on NM_006342, is indicated based on several
cDNAs that may however be from suspect cDNA
libraries (see UCSC Genome Bioinformatics Site
(http://genome.ucsc.edu)). Four additional transcripts
variants are suggested based on singleton Expressed
sequence tags in tumor cell lines (AW516785,
BE552327, BX331864) and/or stem cell progenitors
(AV761182, CX872433).
Pseudogene
None.
TACC3 (transforming, acidic coiled-coil containing protein 3) Eslinger MR, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 306
Protein
Description
TACC3 encodes a single protein of 838 amino acids
with a molecular mass of 90 kDa (Still et al., 1999).
The protein is heavily phosphorylated based on direct
evidence and based on predictions from the Xenopus
and mouse orthologs (Beausoleil et al., 2004;
Beausoleil et al., 2008; Kinoshita et al., 2005; Yu et al.,
2007; Cantin et al., 2008; Dephoure et al., 2008). Thus,
human TACC3 migrates at approxi-mately 150 kDa in
SDS-PAGE. Additional variants are suggested based
on singleton cDNAs (see above) but their predicted
protein isoforms have not been confirmed.
Expression
High levels during early (mouse) embryogenesis, in
particular during early differentiation of specific tissues
(Sadek et al., 2003). In adult tissues, expression is
relatively limited, with high levels noted in
hematological tissues such as the thymus, spleen and
leukocytes, and reproductive tissues, especially meiotic
cells of the testes and ovary (Still et al., 1999; Sadek et
al., 2003).
TACC3 (transforming, acidic coiled-coil containing protein 3) Eslinger MR, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 307
Epithelial layers of the lung, mammary gland and ovary
express TACC3 and alterations in expression are noted
during tumorigenesis (see below). Expression in human
adult tissues is summarized in Lauffart et al. 2006.
Localisation
Human (and mouse) TACC3 is located in the
interphase nucleus and/or cytosol, depending on cell
type and cancer type (Gergely et al., 2000; Aitola et al.,
2003; Lauffart et al., 2005; Jung et al., 2006;
Vettaikkorumakankauv et al., 2008). TACC3 does not
however contain a classical nuclear localisation signal
(Still et al., 1999). TACC3 associates with the
centrosome in a cell cycle dependent manner (Gergely
et al., 2000). Phosphorylation of TACC3 by Aurora A
on key serine residues is required for this interaction
(Kinoshita et al., 2005; LeRoy et al., 2007).
Overexpression of TACC3 from artificial constructs
can result in accumulation in the cytosol of some cells
resulting in oligmerisation in punctate structures
(Gergely et al., 2000).
Function
Gene knockout and knockdown studies in mouse have
indicated that TACC3 is vital for embryonic
development. A functionally null TACC3 mutant dies
during mid to late gestation due to excessive apoptosis
affecting hematopoietic and other organ systems
(Piekorz et al., 2002). Hypomorphic alleles result in
defects in mitosis affecting mesenchymal sclerotome
and therefore the axial skeleton (Yao et al., 2007).
These mutational mouse models indicate that TACC3
has a role in chromosomal alignment, separation and
cytokinesis and that TACC3 can be associated with
p53-mediated apoptosis.
TACC3 has a well characterized function in
microtubule dynamics, particularly during mitosis,
based on mutational analysis (see above) and physical
interactions with Aurora A and Aurora B kinases,
CKAP5 (ch-TOG/XMAP215) and AKAP9 via the
TACC domain (see Peset and Vernos, 2008 for
review). Interaction with CEP120 is important in
interkinetic nuclear migration and maintenance of
neural progenitor self-renewal during the development
of the neocortex (Xie et al., 2007). Phosphorylation of
Ser34, Ser552 and Ser558 by Aurora A are required for
localization to centro-somes and is necessary for
recruitment of CKAP5 and nucleation of microtubules
(Kinoshita et al., 2005; LeRoy et al., 2007). Ser25,
Thr59, Ser71, Ser317, and Ser 434 are presumed
targets for cyclin dependent kinases in mitotic HeLa
cells (Yu et al., 2007; Cantin et al., 2008; Dephoure et
al., 2008). By homology, Ser558 phosphorylation by
TPX2 is required for nucleation of microtubules in
meiotic oocytes (Brunet et al., 2008).
TACC3 also has a defined role in interphase cells as a
transcriptional cofactor for the aryl-nuclear translocator
protein (Sadek, 2000), FOG1 (Garriga-Canut and
Orkin, 2004; Simpson et al., 2004) and is a possible
indirect activator of CREB via FHL family of
coactivator/corepressor proteins (Lauffart et al.,
2007b). Roles in transcriptional regulation
have also been proposed based on TACC3 binding to
GAS41 (YEATS4) via the SDP repeat, histone acetyl
transferases hGCN5L2 (KAT2A), pCAF (KAT2B),
and retinoid X-receptor beta via the TACC domain
(Gangisetty, 2004; Lauffart et al., 2002;
Vettaikkorumakankauv et al., 2008). TACC3
functionally interacts with MBD2 bound to methylated
promoters, promoting transcription by displacement of
HDAC2 and recruitment of KAT2B (Angrisano et al.,
2006). Human TACC3 may be involved in
transcriptional termination and/or pre-mRNA splicing
through TTF2 (Leonard et al., 2003). TACC3 can
interact with BARD1, BRCA1 and p53 and has been
shown to have some protective affects against
adriamycin-mediated DNA damage in ovarian cancer
cells (Lauffart et al., 2007a). Phosphorylation of the
last amino acid of the SDP repeat, Ser434, is noted in
nuclear extracts of HeLa (Beausoleil, 2004; Beausoleil,
2006), although its functional significance is unknown.
Homology
Member of the TACC family, based on the presence of
the evolutionarily conserved approxi-
mately 200 amino acid carboxy terminal coiled coil
domain (TACC domain) (Still et al., 1999; Still et al.,
2004). TACC3 orthologues are noted in all vertebrates
sequenced to date (Still et al., 2004 and Still
unpublished). However, the central region between the
conserved N-terminal region and the TACC domain is
highly variable in size and sequence. The SDP repeats
are noted within the central region in most vertebrates
except mouse and rat (Still et al., 2004).
Mutations
Note
Somatic mutations noted in ovarian cancer samples
(Lauffart et al., 2005; Eslinger, 2006).
TACC3 (transforming, acidic coiled-coil containing protein 3) Eslinger MR, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 308
See legend for normal protein.
Implicated in
Ovarian cancer
Prognosis
Overexpression of TACC3 is associated with
chemoresistance in ovarian tumors (L'Esperance et al.,
2006).
Oncogenesis
Total cellular expression or nuclear localization lost in
ovarian cancer (Lauffart et al., 2005).
Non-small cell lung cancer
Prognosis
High TACC3 expression is an independent prognostic
indicator associated with significantly shorter median
survival time. TACC3 expression was correlated with
p53 expression and poor prognosis (Jung et al., 2006).
Oncogenesis
A high level of TACC3 expression was observed in
14.8% of cases of non small cell lung cancer,
predominantly of the squamous cell carcinoma type
(Jung et al., 2006).
Breast cancer
Prognosis
Loss of TACC3 is observed as a predictor of poor
prognosis in breast cancer (Conte et al., 2002).
Oncogenesis
TACC3 protein downregulated in breast cancer (Conte
et al., 2002).
Multiple myeloma
Prognosis
TACC3 overexpression correlates with the t(4;14)
translocation that is associated with poor prognosis
(Stewart et al., 2004).
Oncogenesis
TACC3 is located close to the MMSET gene that is
rearranged in t(4;14) translocation (Still et al., 1999).
This rearrangement upregulates the TACC3 gene
(Stewart et al., 2004).
Thyroid cancer
Prognosis
Reduction of expression associated with increased
malignancy in cell line models (Ulisse et al., 2007).
Oncogenesis
Analysis of differentiated thyroid cancers indicates that
TACC3 mRNA levels were either upregulated (44%)
or downregulated (56%) in tumors, in some cases
correlation was observed between TACC3 and Aurora-
A kinase (Ulisse et al., 2007). However protein analysis
was not reported.
Breakpoints
Note
Rearrangements of the human TACC3 gene have not
been described. However, translocation breakpoints in
the WHSC1 gene, associated with multiple myeloma
upregulate the intact TACC3 promoter (Stewart et al.,
2004). Tacc3 in the mouse genome is a site of proviral
integration of MoMuLV transmitted via milk from
infected mothers. This leads to upregulation of the gene
and leads to the development of lymphomas
(Chakraborty et al., 2008).
References Still IH, Vince P, Cowell JK. The third member of the transforming acidic coiled coil-containing gene family, TACC3, maps in 4p16, close to translocation breakpoints in multiple myeloma, and is upregulated in various cancer cell lines. Genomics. 1999 Jun 1;58(2):165-70
TACC3 (transforming, acidic coiled-coil containing protein 3) Eslinger MR, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 309
Gergely F, Karlsson C, Still I, Cowell J, Kilmartin J, Raff JW. The TACC domain identifies a family of centrosomal proteins that can interact with microtubules. Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14352-7
Sadek CM, Jalaguier S, Feeney EP, Aitola M, Damdimopoulos AE, Pelto-Huikko M, Gustafsson JA. Isolation and characterization of AINT: a novel ARNT interacting protein expressed during murine embryonic development. Mech Dev. 2000 Oct;97(1-2):13-26
Lauffart B, Howell SJ, Tasch JE, Cowell JK, Still IH. Interaction of the transforming acidic coiled-coil 1 (TACC1) protein with ch-TOG and GAS41/NuBI1 suggests multiple TACC1-containing protein complexes in human cells. Biochem J. 2002 Apr 1;363(Pt 1):195-200
Piekorz RP, Hoffmeyer A, Duntsch CD, McKay C, Nakajima H, Sexl V, Snyder L, Rehg J, Ihle JN. The centrosomal protein TACC3 is essential for hematopoietic stem cell function and genetically interfaces with p53-regulated apoptosis. EMBO J. 2002 Feb 15;21(4):653-64
Aitola M, Sadek CM, Gustafsson JA, Pelto-Huikko M. Aint/Tacc3 is highly expressed in proliferating mouse tissues during development, spermatogenesis, and oogenesis. J Histochem Cytochem. 2003 Apr;51(4):455-69
Leonard D, Ajuh P, Lamond AI, Legerski RJ. hLodestar/HuF2 interacts with CDC5L and is involved in pre-mRNA splicing. Biochem Biophys Res Commun. 2003 Sep 5;308(4):793-801
Sadek CM, Pelto-Huikko M, Tujague M, Steffensen KR, Wennerholm M, Gustafsson JA. TACC3 expression is tightly regulated during early differentiation. Gene Expr Patterns. 2003 May;3(2):203-11
Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP. Large-scale characterization of HeLa cell nuclear phosphoproteins. Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12130-5
Gangisetty O, Lauffart B, Sondarva GV, Chelsea DM, Still IH. The transforming acidic coiled coil proteins interact with nuclear histone acetyltransferases. Oncogene. 2004 Apr 1;23(14):2559-63
Garriga-Canut M, Orkin SH. Transforming acidic coiled-coil protein 3 (TACC3) controls friend of GATA-1 (FOG-1) subcellular localization and regulates the association between GATA-1 and FOG-1 during hematopoiesis. J Biol Chem. 2004 May 28;279(22):23597-605
Simpson RJ, Yi Lee SH, Bartle N, Sum EY, Visvader JE, Matthews JM, Mackay JP, Crossley M. A classic zinc finger from friend of GATA mediates an interaction with the coiled-coil of transforming acidic coiled-coil 3. J Biol Chem. 2004 Sep 17;279(38):39789-97
Stewart JP, Thompson A, Santra M, Barlogie B, Lappin TR, Shaughnessy J Jr. Correlation of TACC3, FGFR3, MMSET and p21 expression with the t(4;14)(p16.3;q32) in multiple myeloma. Br J Haematol. 2004 Jul;126(1):72-6
Still IH, Vettaikkorumakankauv AK, DiMatteo A, Liang P. Structure-function evolution of the transforming acidic coiled coil genes revealed by analysis of phylogenetically diverse organisms. BMC Evol Biol. 2004 Jun 18;4:16
Jacquemier J, Ginestier C, Rougemont J, Bardou VJ, Charafe-Jauffret E, Geneix J, Adélaïde J, Koki A, Houvenaeghel G, Hassoun J, Maraninchi D, Viens P, Birnbaum D, Bertucci F. Protein expression profiling identifies subclasses of breast cancer and predicts prognosis. Cancer Res. 2005 Feb 1;65(3):767-79
Kinoshita K, Noetzel TL, Pelletier L, Mechtler K, Drechsel DN, Schwager A, Lee M, Raff JW, Hyman AA. Aurora A
phosphorylation of TACC3/maskin is required for centrosome-dependent microtubule assembly in mitosis. J Cell Biol. 2005 Sep 26;170(7):1047-55
Lauffart B, Vaughan MM, Eddy R, Chervinsky D, DiCioccio RA, Black JD, Still IH. Aberrations of TACC1 and TACC3 are associated with ovarian cancer. BMC Womens Health. 2005 May 26;5:8
Angrisano T, Lembo F, Pero R, Natale F, Fusco A, Avvedimento VE, Bruni CB, Chiariotti L. TACC3 mediates the association of MBD2 with histone acetyltransferases and relieves transcriptional repression of methylated promoters. Nucleic Acids Res. 2006;34(1):364-72
Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP. A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nat Biotechnol. 2006 Oct;24(10):1285-92
Eslinger MR.. Molecular Analysis of TACC3 in ovarian cancer. MS thesis, Department of Natural Science, Roswell Park Division, SUNY Buffalo 2006. 106p.
Jung CK, Jung JH, Park GS, Lee A, Kang CS, Lee KY. Expression of transforming acidic coiled-coil containing protein 3 is a novel independent prognostic marker in non-small cell lung cancer. Pathol Int. 2006 Sep;56(9):503-9
Lauffart B, Dimatteo A, Vaughan MM, Cincotta MA, Black JD, Still IH. Temporal and spatial expression of TACC1 in the mouse and human. Dev Dyn. 2006 Jun;235(6):1638-47
L'Espérance S, Popa I, Bachvarova M, Plante M, Patten N, Wu L, Têtu B, Bachvarov D. Gene expression profiling of paired ovarian tumors obtained prior to and following adjuvant chemotherapy: molecular signatures of chemoresistant tumors. Int J Oncol. 2006 Jul;29(1):5-24
Lauffart B, Gangisetty O, Still IH.. Evolutionary conserved interaction of TACC2/TACC3 with BARD1 and BRCA1: potential implications for DNA damage response in breast and ovarian cancer. Cancer Therapy. 2007a Dec;5(2):409-416.
Lauffart B, Sondarva GV, Gangisetty O, Cincotta M, Still IH. Interaction of TACC proteins with the FHL family: implications for ERK signaling. J Cell Commun Signal. 2007 Jun;1(1):5-15
LeRoy PJ, Hunter JJ, Hoar KM, Burke KE, Shinde V, Ruan J, Bowman D, Galvin K, Ecsedy JA. Localization of human TACC3 to mitotic spindles is mediated by phosphorylation on Ser558 by Aurora A: a novel pharmacodynamic method for measuring Aurora A activity. Cancer Res. 2007 Jun 1;67(11):5362-70
Ulisse S, Baldini E, Toller M, Delcros JG, Guého A, Curcio F, De Antoni E, Giacomelli L, Ambesi-Impiombato FS, Bocchini S, D'Armiento M, Arlot-Bonnemains Y. Transforming acidic coiled-coil 3 and Aurora-A interact in human thyrocytes and their expression is deregulated in thyroid cancer tissues. Endocr Relat Cancer. 2007 Sep;14(3):827-37
Xie Z, Moy LY, Sanada K, Zhou Y, Buchman JJ, Tsai LH. Cep120 and TACCs control interkinetic nuclear migration and the neural progenitor pool. Neuron. 2007 Oct 4;56(1):79-93
Yao R, Natsume Y, Noda T. TACC3 is required for the proper mitosis of sclerotome mesenchymal cells during formation of the axial skeleton. Cancer Sci. 2007 Apr;98(4):555-62
Yu LR, Zhu Z, Chan KC, Issaq HJ, Dimitrov DS, Veenstra TD. Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra. J Proteome Res. 2007 Nov;6(11):4150-62
Brunet S, Dumont J, Lee KW, Kinoshita K, Hikal P, Gruss OJ, Maro B, Verlhac MH. Meiotic regulation of TPX2 protein levels
TACC3 (transforming, acidic coiled-coil containing protein 3) Eslinger MR, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 310
governs cell cycle progression in mouse oocytes. PLoS One. 2008 Oct 3;3(10):e3338
Cantin GT, Yi W, Lu B, Park SK, Xu T, Lee JD, Yates JR 3rd. Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis. J Proteome Res. 2008 Mar;7(3):1346-51
Chakraborty J, Okonta H, Bagalb H, Lee SJ, Fink B, Changanamkandat R, Duggan J. Retroviral gene insertion in breast milk mediated lymphomagenesis. Virology. 2008 Jul 20;377(1):100-9
Dephoure N, Zhou C, Villén J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP. A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7
Peset I, Vernos I. The TACC proteins: TACC-ling microtubule dynamics and centrosome function. Trends Cell Biol. 2008 Aug;18(8):379-88
Vettaikkorumakankauv AK, Lauffart B, Gangisetty O, Cincotta MA, Hawthorne LA, Cowell JK, Still IH.. The TACC proteins are coregulators of the Retinoid-X Receptor Beta. Cancer Therapy. 2008 Dec;6(2):805-816.
This article should be referenced as such:
Eslinger MR, Lauffart B, Still IH. TACC3 (transforming, acidic coiled-coil containing protein 3). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):305-310.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 311
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
TP53INP1 (tumor protein p53 inducible nuclear protein 1) Mylène Seux, Alice Carrier, Juan Iovanna, Nelson Dusetti
INSERM U.624, Parc Scientifique de Luminy, Case 915, 13288 Marseille Cedex 9, France (MS, AC, JI,
ND)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Genes/TP53INP1ID42672ch8q22.html DOI: 10.4267/2042/44717
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity Other names: SIP; TEAP; p53DINP1; TP53INP1A;
TP53INP1B; TP53DINP1
HGNC (Hugo): TP53INP1
Location: 8q22.1
DNA/RNA
Description
Gene is ~24 kb, with 5 exons.
Transcription
Alternative splicing: 2 transcripts: TP53INP1alpha
(exons 1, 2, 3, 4 and 5 with a stop codon in the fourth
exon) and TP53INP1beta (exons 1, 2, 3 and 5 with a
stop codon in the fifth exon).
Protein
Description
2 isoforms: TP53INP1alpha, 18 kDa (164 amino acids)
and TP53INP1beta, 27 kDa (240 amino acids). Both
isoforms contain a PEST domain (sequence rich in
proline, glutamic acid, serine and threonine between
amino acids 26 and 62 found in proteins with half-lives
of less than 2 h).
Expression
In mouse: TP53INP1 is expressed in thymus, spleen
and bone marrow. It is also expressed at low levels in
heart, stomach, liver, intestine, testis, kidney and
pancreas. TP53INP1 expression is highly induced
during the acute phase of mouse experimental
pancreatitis (caerulein induced).
In cells lines: TP53INP1 is transcriptionally induced in
response to stress in a p53-dependent and independent
manner. Examples: in mouse fibroblast, it is induced
upon adriamycin, methyl-methane sulfonate, ethanol,
H2O2, UV exposure and heat shock treatment; in
neuronal cells by copper treatment; in pancreatic cancer
cell lines by gemcitabine; in pro-B cells by IL-3
deprivation or treatement with staurosporine, cisplatin,
campto-thecin, methotrexate and paclitaxel; in mouse
embryonic fibroblast (MEF), human fibroblasts and
MCF7 by gamma irradiation; in melanoma cells by UV
mimetic compound (4NQ).
TP53INP1 expression is regulated by different
transcriptional regulators: p53, E2F1, p73 (in p53-/-
cells), myc (in neuroblastoma cell lines) and PLZF (in
hematopoietic cell lines).
Localisation
Nuclear when over-expressed and in PML-bodies
(Promyelocytic leukemia protein) upon PML-IV over-
expression.
TP53INP1 (tumor protein p53 inducible nuclear protein 1) Seux M, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 312
Green boxes: exons, black lines: introns, alternative splicing for TP53INP1beta in black and TP53INP1alpha in red.
Function
TP53INP1 is a tumor suppressor gene induced with
different stress conditions. TP53INP1 overexpres-sion
leads to cell cycle arrest (G1 phase) and p53-dependent
or independent apoptosis. TP53INP1 interacts with p53
and two kinases (HIPK2, and PKCd). These kinases
phosphorylate p53 on serine 46 modifying the p53
activity. TP53INP1 can modulate the p53 and p73
transcriptional activity to potentiate pro-apoptotic
pathways. Colitis and colitis-associated cancer are
exacerbated in mice deficient for TP53INP1.
Homology
TP53INP1 is conserved between species (from fly to
human). In vertebrates, one paralog has been identified,
TP53INP2 localized on chromosome 20q11.2.
TP53INP2 is involved in autophagy.
Mutations
Note
No mutation identified.
Implicated in
Pancreatic Adenocarcinoma
Note
TP53INP1 is lost early during pancreatic cancer
progression (from the neoplasia stages PanIN2). This
downregulation seems to be important for tumour
development. TP53INP1 expression is down regulated
by the oncogenic micro-RNA miR-155 during
pancreatic cancer progression.
Disease
Sporadic cancer, very aggressive, epigenetic disease
with known mutations/deletions of p53, K-Ras,
SMAD4, p16, BRCA2, EGFR and HER2.
Prognosis
Very bad, with only 20% of patients reaching two years
of survival, and 3% after 5 years.
Breast cancer
Note
TP53INP1 expression is lost during breast cancer
development.
Disease
Mainly in female (only 1% in male). Genetic disorders
known: loss of HER2 and ER expression, mutations in
p53 and BRCA1.
Prognosis
Mortality rate: 25%.
Gastric cancer
Note
TP53INP1 expression is lost during cancer
development. The decreased expression of TP53INP1
protein may reflect the malignant grade of gastric
cancer.
Disease
10% are familial. Mutations in APC, p53, Bcl-2.
Prognosis
The 5-year survival after surgical resection is 30-50%
for patients with stage II and 10-25% for patients with
stage III.
Anaplastic carcinoma of the thyroid (ATC)
Note
TP53INP1 is overexpressed in anaplastic thyroid
carcinoma.
Disease
ATC is less than 2% of total thyroid cancer but
represents 40% of death by thyroid cancer. It is a very
aggressive cancer with early dissemination.
Prognosis
5-year survival rate is less than 10%.
References Okamura S, Arakawa H, Tanaka T, Nakanishi H, Ng CC, Taya Y, Monden M, Nakamura Y. p53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis. Mol Cell. 2001 Jul;8(1):85-94
Nowak J, Tomasini R, Mattei MG, Azizi Samir LA, Dagorn JC, Dusetti N, Iovanna JL, Pébusque MJ. Assignment of tumor protein p53 induced nuclear protein 1 (TP53INP1) gene to human chromosome band 8q22 by in situ hybridization. Cytogenet Genome Res. 2002;97(1-2):140E
Tomasini R, Samir AA, Pebusque MJ, Calvo EL, Totaro S, Dagorn JC, Dusetti NJ, Iovanna JL. P53-dependent expression
TP53INP1 (tumor protein p53 inducible nuclear protein 1) Seux M, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 313
of the stress-induced protein (SIP). Eur J Cell Biol. 2002 May;81(5):294-301
Tomasini R, Samir AA, Carrier A, Isnardon D, Cecchinelli B, Soddu S, Malissen B, Dagorn JC, Iovanna JL, Dusetti NJ. TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity. J Biol Chem. 2003 Sep 26;278(39):37722-9
Hershko T, Chaussepied M, Oren M, Ginsberg D. Novel link between E2F and p53: proapoptotic cofactors of p53 are transcriptionally upregulated by E2F. Cell Death Differ. 2005 Apr;12(4):377-83
Tomasini R, Seux M, Nowak J, Bontemps C, Carrier A, Dagorn JC, Pébusque MJ, Iovanna JL, Dusetti NJ. TP53INP1 is a novel p73 target gene that induces cell cycle arrest and cell death by modulating p73 transcriptional activity. Oncogene. 2005 Dec 8;24(55):8093-104
Vanlandingham JW, Tassabehji NM, Somers RC, Levenson CW. Expression profiling of p53-target genes in copper-mediated neuronal apoptosis. Neuromolecular Med. 2005;7(4):311-24
Ito Y, Motoo Y, Yoshida H, Iovanna JL, Nakamura Y, Kuma K, Miyauchi A. High level of tumour protein p53-induced nuclear protein 1 (TP53INP1) expression in anaplastic carcinoma of the thyroid. Pathology. 2006 Dec;38(6):545-7
Ito Y, Motoo Y, Yoshida H, Iovanna JL, Takamura Y, Miya A, Kuma K, Miyauchi A. Decreased expression of tumor protein p53-induced nuclear protein 1 (TP53INP1) in breast carcinoma. Anticancer Res. 2006 Nov-Dec;26(6B):4391-5
Jiang PH, Motoo Y, Garcia S, Iovanna JL, Pébusque MJ, Sawabu N. Down-expression of tumor protein p53-induced nuclear protein 1 in human gastric cancer. World J Gastroenterol. 2006 Feb 7;12(5):691-6
Jiang PH, Motoo Y, Sawabu N, Minamoto T. Effect of gemcitabine on the expression of apoptosis-related genes in human pancreatic cancer cells. World J Gastroenterol. 2006 Mar 14;12(10):1597-602
Kis E, Szatmári T, Keszei M, Farkas R, Esik O, Lumniczky K, Falus A, Sáfrány G. Microarray analysis of radiation response
genes in primary human fibroblasts. Int J Radiat Oncol Biol Phys. 2006 Dec 1;66(5):1506-14
Bell E, Lunec J, Tweddle DA. Cell cycle regulation targets of MYCN identified by gene expression microarrays. Cell Cycle. 2007 May 15;6(10):1249-56
Bernardo MV, Yelo E, Gimeno L, Campillo JA, Parrado A. Identification of apoptosis-related PLZF target genes. Biochem Biophys Res Commun. 2007 Jul 27;359(2):317-22
Gironella M, Seux M, Xie MJ, Cano C, Tomasini R, Gommeaux J, Garcia S, Nowak J, Yeung ML, Jeang KT, Chaix A, Fazli L, Motoo Y, Wang Q, Rocchi P, Russo A, Gleave M, Dagorn JC, Iovanna JL, Carrier A, Pébusque MJ, Dusetti NJ. Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16170-5
Gommeaux J, Cano C, Garcia S, Gironella M, Pietri S, Culcasi M, Pébusque MJ, Malissen B, Dusetti N, Iovanna J, Carrier A. Colitis and colitis-associated cancer are exacerbated in mice deficient for tumor protein 53-induced nuclear protein 1. Mol Cell Biol. 2007 Mar;27(6):2215-28
Cano CE, Gommeaux J, Pietri S, Culcasi M, Garcia S, Seux M, Barelier S, Vasseur S, Spoto RP, Pébusque MJ, Dusetti NJ, Iovanna JL, Carrier A. Tumor protein 53-induced nuclear protein 1 is a major mediator of p53 antioxidant function. Cancer Res. 2009 Jan 1;69(1):219-26
Nowak J, Archange C, Tardivel-Lacombe J, Pontarotti P, Pébusque MJ, Vaccaro MI, Velasco G, Dagorn JC, Iovanna JL. The TP53INP2 protein is required for autophagy in mammalian cells. Mol Biol Cell. 2009 Feb;20(3):870-81
Nowak J, Iovanna JL. TP53INP2 is the new guest at the table of self-eating. Autophagy. 2009 Apr;5(3):383-4
This article should be referenced as such:
Seux M, Carrier A, Iovanna J, Dusetti N. TP53INP1 (tumor protein p53 inducible nuclear protein 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):311-313.
Leukaemia Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 314
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
del(5q) in myeloid neoplasms Kazunori Kanehira, Rhett P Ketterling, Daniel L Van Dyke
FACMG, Cytogenetics Laboratory, Mayo Clinic, Rochester, Minnesota, USA (KK, RPK, DLV)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/del5qID1092.html DOI: 10.4267/2042/44718
This article is an update of: Charrin C. del(5q) in myeloid malignancies. Atlas Genet Cytogenet Oncol Haematol 1998;2(3):88-90 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Note
Interstitial del(5q) was first reported as a type of refractory anemia with characteristic clinical features; female
predominance (unlike other MDS), macrocytosis, erythroid hypoplasia, frequent thrombocytosis and
dysmegakaryopoiesis. It is one of the most common structural rearrangements in MDS (10%), seen as an isolated
abnormality or with additional karyotypic anomalies. It is also observed in AML, with important prognostic
significance.
del(5q) G-banding (top) - Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap Cytogenetics at theWaisman Center (1 and 5 from the left), Kazunori Kanehira, Rhett P. Ketterling, Daniel L. Van Dyke (2, 4, 6, and 7), and Jean-Luc Lai (3); R-banding (bottom), Courtesy Christiane Charrin (1 and 3), Editor (2).
Clinics and pathology
Disease
5q- syndrome
Note
The World Health Organization (WHO) defined the 5q-
syndrome as a specific type of MDS, restricting
diagnosis to the cases with isolated interstitial del(5q),
without excess blasts in the bone marrow (<5%). It also
defined a new category, therapy-related MDS/AML,
excluding cases with a history of previous
chemotherapy from 5q- syndrome MDS.
del(5q) in myeloid neoplasms Kanehira K, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 315
Clinics
As described above, cases of MDS with isolated
del(5q) show female predominance (M:F=1:1.5-4),
anemia, macrocytosis, normal or moderately decreased
WBC, normal or moderately decreased platelet count,
and dysmegakaryopoiesis.
Treatment
Supportive care including RBC transfusion for anemia
is the mainstay of treatment. It is not infrequent that
transfusions are needed for years, causing iron
overload, and increasing the risk of blood-borne
infections. Anemia of 5q- syndrome does not respond
well to erythropoietin. Leanalidomide, a Thalidomide
derivative, has been investigated for treatment of MDS
with 5q-. Lenalidomide has immunomodulatory
properties, including the suppression of pro-
inflammatory cytokine production by monocytes,
enhancement of T-cell and NK-cell activation, and
inhibition of angiogenesis. In Phase II trials in
transfusion-dependent MDS with 5q-, 168 patients
were enrolled, of whom 76% had isolated 5q- and 29%
had the 5q- syndrome. Transfusion independence was
obtained in 67%. A complete cytogenetic response was
achieved in 45% of patients. Cytogenetic response rate
was not significantly different in isolated del(5q),
del(5q) + 1 and del(5q) + >1 additional chromosome
abnormalities. Although the results of lenalidomide
treatment seem promising, it is not yet clear if the
treatment will affect the natural disease course and
prolongs survival.
Prognosis
The impact of lenalidomide on the prognosis of MDS
patients with 5q- is unknown at this point. Progression
to AML is rare (10%). With the supportive therapy, the
prognosis of 5q- syndrome is favorable, with reported
median survival ranging from 53 to 146 months. MDS
patients with 5q- plus one additional chromosome
abnormality seem to have significantly shorter survival
(with exception of loss of the Y chromosome). MDS
with 5q- as part of a complex karyotype (3 or more
abnormalities) have an unfavorable prognosis.
Disease
AML (Acute Myeloid Leukemia).
Clinics
Deletion of 5q can be observed in both de novo and
therapy related AML. It is also seen as monosomy 5. In
AML, 5q deletion is usually associated with a complex
karyotype.
Prognosis
Prognosis of AML with 5q-/-5 is generally unfavorable,
associated with rapid disease progression and poor
outcome and survival, especially when it is seen as a
part of complex karyotype.
Cytogenetics
Cytogenetics morphological
The most commonly observed interstitial deletions are
del(5)(q13q31), del(5)(q13q33), and del(5)(q22q33),
forming a commonly deleted region (CDR) at 5q31-
q32.
Cytogenetics molecular
The CDR is the approximately 1.5 Mb interval between
D5S413 and GLRA1 gene, containing around 40 genes.
No cases of 5q- syndrome have been reported to have
biallelic deletion within the CDR, and no point
mutations have been found in the genes in the region.
Recently, it is suggested that haploinsufficienty (a gene
dosage effect) of one or more of the genes mapping to
the CDR is the pathogenetic basis of the 5q- syndrome.
Ebert et al. demonstrated that impaired function of the
ribosomal subunit protein RPS14 recapitulated the
characteristic phenotype of the 5q- syndrome, a severe
decrease in the production of erythroid cells with
relative preservation of megakaryocytic cells, in normal
CD34+ human hematopoietic progenitor cells. In
addition, forced expression of RPS14 rescued the
disease phenotype in patient-derived bone marrow
cells.
Germline heterozygous mutations for two other
ribosomal proteins, RPS19 and RPS24, have recently
been described in the congenital disorder known as
Diamond-Blackfan anemia. The conge-nital anemia is
characterized by sever anemia, macrocytosis, relative
preservation of the platelet and neutrophil count,
erythroid hypoplasia in the bone marrow and an
increased risk of leukemia. The erythroid specificity of
5q- syndrome and Diamond-Blackfan anemia in
ribosomal expression is noteworthy.
Additional anomalies
By definition, an interstitial deletion of 5q must be the
sole abnormality for 5q- syndrome. However, 5q
deletion can be seen with other accompanying
abnormalities. Review of the recent Mayo Clinic cases
shows that major abnormalities include -7, +8, -20,
20q-, -13/13q-, and abnormalities in 12p, in the
descending order.
References Van den Berghe H, Cassiman JJ, David G, Fryns JP, Michaux JL, Sokal G. Distinct haematological disorder with deletion of long arm of no. 5 chromosome. Nature. 1974 Oct 4;251(5474):437-8
Pedersen B, Jensen IM. Clinical and prognostic implications of chromosome 5q deletions: 96 high resolution studied patients. Leukemia. 1991 Jul;5(7):566-73
Rubin CM, Arthur DC, Woods WG, Lange BJ, Nowell PC, Rowley JD, Nachman J, Bostrom B, Baum ES, Suarez CR. Therapy-related myelodysplastic syndrome and acute myeloid leukemia in children: correlation between chromosomal abnormalities and prior therapy. Blood. 1991 Dec 1;78(11):2982-8
del(5q) in myeloid neoplasms Kanehira K, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 316
Neuman WL, Rubin CM, Rios RB, Larson RA, Le Beau MM, Rowley JD, Vardiman JW, Schwartz JL, Farber RA. Chromosomal loss and deletion are the most common mechanisms for loss of heterozygosity from chromosomes 5 and 7 in malignant myeloid disorders. Blood. 1992 Mar 15;79(6):1501-10
Baranger L, Szapiro N, Gardais J, Hillion J, Derre J, Francois S, Blanchet O, Boasson M, Berger R. Translocation t(5;12)(q31-q33;p12-p13): a non-random translocation associated with a myeloid disorder with eosinophilia. Br J Haematol. 1994 Oct;88(2):343-7
Boultwood J, Lewis S, Wainscoat JS. The 5q-syndrome. Blood. 1994 Nov 15;84(10):3253-60
Boultwood J, Fidler C. Chromosomal deletions in myelodysplasia. Leuk Lymphoma. 1995 Mar;17(1-2):71-8
Fenaux P. Syndromes myelodysplasiques et deletion 5q. Hematologie. 1995; 1: 35-43.
Van den Berghe H, Michaux L. 5q-, twenty-five years later: a synopsis. Cancer Genet Cytogenet. 1997 Mar;94(1):1-7
Giagounidis AA, Germing U, Wainscoat JS, Boultwood J, Aul C. The 5q- syndrome. Hematology. 2004 Aug;9(4):271-7
Nishino HT, Chang CC. Myelodysplastic syndromes: clinicopathologic features, pathobiology, and molecular pathogenesis. Arch Pathol Lab Med. 2005 Oct;129(10):1299-310
Bernasconi P, Boni M, Cavigliano PM, Calatroni S, Giardini I, Rocca B, Zappatore R, Dambruoso I, Caresana M. Clinical relevance of cytogenetics in myelodysplastic syndromes. Ann N Y Acad Sci. 2006 Nov;1089:395-410
Cherian S, Bagg A. The genetics of the myelodysplastic syndromes: classical cytogenetics and recent molecular insights. Hematology. 2006 Feb;11(1):1-13
Armand P, Kim HT, DeAngelo DJ, Ho VT, Cutler CS, Stone RM, Ritz J, Alyea EP, Antin JH, Soiffer RJ. Impact of cytogenetics on outcome of de novo and therapy-related AML and MDS after allogeneic transplantation. Biol Blood Marrow Transplant. 2007 Jun;13(6):655-64
Haase D. Cytogenetic features in myelodysplastic syndromes. Ann Hematol. 2008 Jul;87(7):515-26
Kelaidi C, Eclache V, Fenaux P. The role of lenalidomide in the management of myelodysplasia with del 5q. Br J Haematol. 2008 Feb;140(3):267-78
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW.. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition; 2008;102.
This article should be referenced as such:
Kanehira K, Ketterling RP, Van Dyke DL. del(5q) in myeloid neoplasms. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):314-316.
Leukaemia Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 317
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
t(11;11)(q13;q23) Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t1111q13q23ID1541.html DOI: 10.4267/2042/44719
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Epidemiology
The involvement of MLL in 11q23 and ARHGEF17 in
11q13 was ascertained in only 1 case (Teuffel et al.,
2005). It was an unusual case of treatment-related MLL
rearrangement in the absence of leukemia.
Clinics
The case reported by Teuffel et al. (2005), was a five-
year-old girl, who experienced an acute myeloid
leukemia (AML) with a variant t(8;21) and achieved
remission under treatment. Four years later, a follow-up
control of her karyotype revealed a t(11;11)(q13;q23),
in the absence of any sign of leukemia in the bone
marrow, over a period of 30 months following the
discover of the t(11;11).
Other cases of t(11;11)(q13;q23) were:
A 13-year-old girl, who have had a M4eo AML with
inv(16)(p13q22). Eleven month later, a
t(11;11)(q13;q23) was found, but bone marrow
remained normal; however, an overt M5b AML was
diagnosed 6 months later (Leblanc et al., 1994). This
case resembles the case of Teuffel.
There was also the case of a 69-year-old male patient
with a primary M4 AML, who died 5 months after
diagnosis, and an AML (not classified) female patient
(Testa et al., 1985; Mackinnon and Campbell, 2007).
Cytology
In the case reported by Teuffel, the MLL-ARHGEF17
was only seen in the myeloid lineage. The myeloid
differentiation was not perturbed by the presence of the
chimeric protein, and normal mature myeloid cells
carrying the chimeric protein were found in normal
amounts.
Cytogenetics
Cytogenetics morphological
The t(11;11) was apparently the sole anomaly in 3 of
the 4 cases; a complex karyotype with del(5q), a
marker chromosome, and other anomalies was found in
the case reported by Mackinnon and Campbell, 2007.
Genes involved and proteins
ARHGEF17
Location
11q13
Protein
Guanine nucleotide exchange factor (GEF) for RhoA
GTPases. Involved in transduction of various signals
into downstream signaling cascades.
MLL
Location
11q23
DNA/RNA
36 exons, multiple transcripts 13-15 kb.
Protein
3969 amino acids; 431 kDa; contains two DNA binding
motifs (a AT hook and a CXXC domain), a DNA
methyl transferase motif, a bromodomain. MLL is
cleaved by taspase 1 into 2 proteins before entering the
nucleus, called MLL-N and MLL-C.
The FYRN and FRYC domains of native MLL
associate MLL-N and MLL-C in a stable complex; they
form a multiprotein complex with transcription factor
TFIID. MLL is a transcriptional regulatory factor. MLL
can be associated with more than 30 proteins, including
t(11;11)(q13;q23) Huret JL
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 318
the core components of the SWI/SNF chromatin
remodeling complex and the transcription complex
TFIID. MLL binds pro-motors of HOX genes through
acetylation and methylation of histones. MLL is a
major regulator of hematopoesis and embryonic
development.
Result of the chromosomal anomaly
Hybrid gene
Description
The fusion between MLL and ARHGEF17 occurred in
introns 12 and 1 respectively.
References Testa JR, Misawa S, Oguma N, Van Sloten K, Wiernik PH. Chromosomal alterations in acute leukemia patients studied with improved culture methods. Cancer Res. 1985 Jan;45(1):430-4
Leblanc T, Hillion J, Derré J, Le Coniat M, Baruchel A, Daniel MT, Berger R. Translocation t(11;11)(q13;q23) and HRX gene rearrangement associated with therapy-related leukemia in a child previously treated with VP16. Leukemia. 1994 Oct;8(10):1646-8
Teuffel O, Betts DR, Thali M, Eberle D, Meyer C, Schneider B, Marschalek R, Trakhtenbrot L, Amariglio N, Niggli FK, Schäfer BW. Clonal expansion of a new MLL rearrangement in the absence of leukemia. Blood. 2005 May 15;105(10):4151-2
Mackinnon RN, Campbell LJ. Dicentric chromosomes and 20q11.2 amplification in MDS/AML with apparent monosomy 20. Cytogenet Genome Res. 2007;119(3-4):211-20
This article should be referenced as such:
Huret JL. t(11;11)(q13;q23). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):317-318.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 319
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
t(11;19)(q23;p13.3) MLL/ACER1 Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t1119q23p13ID1540.html DOI: 10.4267/2042/44720
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Disease
Acute lymphocytic leukemia (ALL)
Epidemiology
Only one case to date, a case of congenital leukemia
(Lo Nigro et al., 2002).
Genes involved and proteins
MLL
Location
11q23
DNA/RNA
36 exons, multiple transcripts 13-15 kb.
Protein
3969 amino acids; 431 kDa; contains two DNA binding
motifs (a AT hook and a CXXC domain), a DNA
methyl transferase motif, a bromodomain. MLL is
cleaved by taspase 1 into 2 proteins before entering the
nucleus, called MLL-N and MLL-C. The FYRN and
FRYC domains of native MLL associate MLL-N and
MLL-C in a stable complex; they form a multiprotein
complex with transcription factor TFIID. MLL is a
transcriptional regulatory factor. MLL can be
associated with more than 30 proteins, including the
core components of the SWI/SNF chromatin
remodeling complex and the transcription complex
TFIID. MLL binds pro-motors of HOX genes through
acetylation and methylation of histones. MLL is a
major regulator of hematopoesis and embryonic
development.
ACER1
Location
19p13.3
Protein
ACER1 is the alkaline ceramidase 1. Ceramidases
catalyze hydrolysis of ceramide to generate sphingosine
(SPH), which is phosphorylated to form sphingosine-1-
phosphate (S1P). Ceramide, SPH, and S1P are
bioactive lipids that mediate cell proliferation,
differentiation, apoptosis, adhesion and migration (Mao
and Obeid, 2008).
Result of the chromosomal anomaly
Hybrid gene
Description
5' MLL - 3' ACER1; fusion of MLL intron 8 to
ACER1.
References Lo Nigro L, Slater DJ, Rappaport EF, Biondi A, Maude S, Megnigal MD, Bungaro S, Schiliro G, Felix CA.. Two partner genes of MLL and additional heterogeneity in t(11;19)(q23;p13) translocations. Blood 2002; 2080 p531a.
Mao C, Obeid LM. Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate. Biochim Biophys Acta. 2008 Sep;1781(9):424-34
This article should be referenced as such:
Huret JL. t(11;19)(q23;p13.3) MLL/ACER1. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):319.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 320
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
t(2;5)(p21;q33) Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0205p21q33ID1511.html DOI: 10.4267/2042/44721
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Clinics and pathology
Disease Atypical myeloproliferative disease with eosino-philia
Epidemiology One case to date, a 73-year-old female patient
(Gallagher et al., 2008).
Prognosis The patient was alive and well after 3 years of therapy
with imatinib.
Cytogenetics Cytogenetics morphological The t(2;5) was the sole anomaly.
Genes involved and proteins SPTBN1
Location
2p16.2 is the exact location
Protein
SPTBN1 (spectrin beta1 non erythrocytic), also called
beta-fodrin, is a cytoskeleton protein. Forms dimers
with alpha-fodrin (SPTAN1, 9q34), which self-
associates head-to-head into tetramers. Mem-brane
skeleton protein associated with ion channels and
pumps (Winkelmann and Forget, 1993); Stabilizes cell
surface membranes; role in mitotic spindles assembly
(Bennett and Baines, 2001).
PDGFRB
Location
5q33
Protein
Comprises an extracellular part with 5 Ig-like C2 type
domains, a transmembrane domain, and an intracellular
part with a tyrosine kinase domain (made of two
tyrosine kinase subdomains) for transduction of the
signal. Receptor tyrosine kinase; receptor for PDGFB
and PDGFD (Bergsten et al., 2001); forms
homodimers, or heterodimer with PDGFRA; upon
dimerization, subsequent activa-tion by
autophosphorylation of the tyrosine kinase intracellular
domains occurs.
Result of the chromosomal anomaly Fusion protein
Description
Constitutive activation of the PDGFRB tyrosine kinase
domain.
References Winkelmann JC, Forget BG. Erythroid and nonerythroid spectrins. Blood. 1993 Jun 15;81(12):3173-85
Bennett V, Baines AJ. Spectrin and ankyrin-based pathways: metazoan inventions for integrating cells into tissues. Physiol Rev. 2001 Jul;81(3):1353-92
Bergsten E, Uutela M, Li X, Pietras K, Ostman A, Heldin CH, Alitalo K, Eriksson U. PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor. Nat Cell Biol. 2001 May;3(5):512-6
Gallagher G, Horsman DE, Tsang P, Forrest DL. Fusion of PRKG2 and SPTBN1 to the platelet-derived growth factor receptor beta gene (PDGFRB) in imatinib-responsive atypical myeloproliferative disorders. Cancer Genet Cytogenet. 2008 Feb;181(1):46-51
This article should be referenced as such:
Huret JL. t(2;5)(p21;q33). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):320.
Solid Tumour Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 321
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Head and Neck: Ear: Endolymphatic Sac Tumor (ELST) Rodney C Diaz
Department of Otolaryngology-Head and Neck Surgery, University of California Davis Medical Center,
Sacramento, California 95817, USA (RCD)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Tumors/EndolymphaticSacTumID5096.html DOI: 10.4267/2042/44722
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Alias
Low Grade Papillary Adenocarcinoma of the
Endolymphatic Sac, Papillary Adenoma of the
Endolymphatic Sac.
Note
Endolymphatic sac tumors (ELSTs) are rare tumors of
the petrous temporal bone. Classified as mastoid
papillary tumors of unknown origin, these tumors were
synthesized into a new, distinct clinico-pathological
entity by Heffner in 1989. Initially described as a low
grade papillary adenocarcinoma, their histologic
appearance and apparent lack of metastatic potential
has since persuaded most practitioners to reclassify
them as papillary adenomas. ELSTs can arise
sporadically or in association with von Hippel-Lindau
(VHL) disease.
Classification
Note
The differential diagnosis for ELSTs includes all
intrinsic temporal bone neoplasms (most commonly
paraganglioma) as well as metastatic papillary thyroid
carcinoma, metastatic renal cell carcinoma, and choroid
plexus papilloma, the latter three of which are similar
in appearance to ELSTs histologically.
Clinics and pathology
Disease
Endolymphatic sac tumors are rare. As a recognized,
distinct entity, ELSTs are relatively new.
The first reported case of a tumor arising from the
endolymphatic sac was discovered during
decompression of the endolymphatic sac for presumed
unilateral Ménière's Disease in 1984.
Although benign, ELSTs can be locally destructive.
They present with hearing loss, tinnitus, facial nerve
weakness or paralysis, vertigo, and can be lethal. CT
imaging demonstrates erosion of the posterior petrous
temporal bone with occasional intratumoral
calcification. MRI tumor signal is isointense to brain
and demonstrates gadolinium enhancement and
heterogeneous signal intensity from intratumoral
calcification and vascularity.
Etiology
The synthesis of sporadic temporal bone papillary
tumors into a distinct clinicopathological entity was
proposed in 1989 by Heffner, with the anatomic origin
of these tumors being the endolymphatic sac.
Knowledge of this tumor has grown, expedited in part
by its association with VHL disease, yet many aspects
are still poorly understood.
Head and Neck: Ear: Endolymphatic Sac Tumor (ELST) Diaz RC
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 322
MRI T1 weighted axial images of the brain at the level of the endolymphatic sac and internal auditory canal. The top view without gadolinium contrast shows moderate expansion of the endolymphatic sac and duct on the right. The bottom view with gadolinium contrast shows contrast enhancement of the endolymphatic sac on the right.
CT axial image of the temporal bones at the level of the endolymphatic sac and internal auditory canals. The vestibular aqueduct on the right is markedly widened directly behind the internal auditory canal and vestibule, in contrast to the appearance of the vestibular aqueduct on the left, which is thin and nondescript. The bony erosion and widening of the vestibular aqueduct on the right is highly suggestive of a neoplastic or otherwise destructive process within the endolymphatic sac, consistent with an ELST.
Head and Neck: Ear: Endolymphatic Sac Tumor (ELST) Diaz RC
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 323
Initially described as a low grade papillary
adenocarcinoma, the histologic appearance and
apparent lack of metastatic potential of these tumors
has convinced some to reclassify them as benign
papillary adenomatous tumors. The high overall
survival following surgical resection, despite locally
aggressive behavior, is likely due to the underlying
benign histology of the tumor.
Epidemiology
Over 175 case reports of ELSTs have now been
reported in the literature. The majority of these are
single case reports of a practice group or university.
As the majority of these case reports do not disclose the
population size of their patient base, it is difficult to
assess the true incidence of these tumors. ELSTs tend
to afflict women more than men with an overall female
to male ratio of 2:1 in a review of the literature.
Clinics
The most common presenting complaints were aural,
with hearing loss occurring in neary every reported
patient, followed by tinnitus, aural fullness, and
imbalance. The symptoms of pulsatile tinnitus, otalgia,
otorrhea, vertigo, and facial paresis were also present in
some patients. Cranial neuropathies were also
diagnosed either at the time of presentation or
following treatment. The most commonly involved
nerve was the facial nerve, with preoperative facial
paresis or paralysis in 43% of patients. In patients with
larger tumors or in those who delayed presentation for
decades after onset of initial symptoms, multiple
cranial neuropathies were present including trigeminal,
glossopharyngeal, and vagal nerves.
From a statistical standpoint, a vascular tumor eroding
the temporal bone and cranial base is likely to be a
paraganglioma, and likely a glomus jugulare
tumor. Large glomus tumors as well as large ELSTs
can both present as pink or purple masses encroaching
on the middle ear and external auditory canal. Glomus
tumors exhibit a characteristic "salt and pepper" tumor
appearance on MRI, but this heterogeneity in signal
reflects the vascularity of such tumors and is not
pathognomonic. The heterogeneity in signal seen in
large ELSTs - arising from hypervascularity as well as
intra-tumoral hemorrhage and/or calcification - can
often mimic glomus tumors in this respect. This is not
necessarily problematic, as management would proceed
similarly for either histologic type of tumor: pre-
operative embolization followed by total tumor
resection via the appropriate lateral skull base
approach.
Pathology
ELSTs are highly vascular and are comprised of
papillary cystic structures lined with a simple cuboidal
or columnar epithelium. Siderophages and cholesterol
clefts are seen, as are clear, vacuolated cells. Nuclear
pleomorphism is not pronounced, and mitoses are rare.
Immunohistochemistry and special staining may aid in
differentiation of papillary tumors of question-able
origin. ELSTs usually stain positive for cytokeratin,
vimentin, and epithelial membrane antigen, as well as
stain on Periodic acid-Schiff (diastase sensitive). Some
papers have also reported sensitivity to glial fibrillary
acid protein; however, most authors have had poor
tumor reactivity to glial fibrillary acid protein. Papillary
thyroid metastasis to the temporal bone may be
differentiated by positive reaction to thyroglobulin
immunohisto-chemistry.
Transthyretin has been shown to exhibit differential
expression in choroid plexus papillomas with little to
no expression in ELSTs.
MRI T1 weighted images of the brain, showing a very large ELST of the left temporal bone, in axial view on the left and coronal view on the right. There has been complete erosion of the petrous temporal bone by the tumor, with significant brainstem and cerebellar compression.
Head and Neck: Ear: Endolymphatic Sac Tumor (ELST) Diaz RC
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 324
Histological appearance of ELST. HE stain, low power magnification, demonstrating the characteristic papillary cystic architecture of these tumors.
Treatment
Surgical resection is the primary modality of treatement
for ELSTs. Despite the benign histologic nature of
these tumors, complete resection appears crucial for
ensuring success. Total tumor resection is clearly the
treatment of choice, as only one patient with reported
complete resection had subsequent recurrence.
Although the most common presenting symptom was
sensorineural hearing loss, many patients, particularly
those with VHL disease, present with small ELSTs and
consequently present with serviceable hearing. VHL
patients are unique in that all undergo active
surveillance and cranial imaging for hemangioblastoma
as part of their VHL disease management.
Subsequently, ELSTs in these patients are frequently
diagnosed early, with relatively little delay between
onset of audio-vestibular symptoms and identification
of tumor. This significantly affected surgical decision
making, as 32% of patients underwent hearing
conservation procedures while 68% underwent hearing
ablative procedures. In patients with excellent
preoperative hearing and a small ELST, such a hearing
conservation approach may be warranted. However, the
completeness of tumor resection should not be
compromised for the sake of hearing conservation. Half
of patients undergoing hearing conservation approaches
with subtotal resection followed by adjuvant radiation
therapy had regrowth of tumor.
In some tumors, total resection cannot be achieved
without risk of catastrophic loss of function or death,
and in these patients subtotal resection may be
warranted. Patients who have subtotal resection may
benefit from postoperative radiotherapy, but there still
remains a roughly 50% risk of tumor regrowth and
therefore close surveillance is warranted as re-resection
may be necessary. Stereotactic radiotherapy has shown
no increased benefit above standard fractionated
radiotherapy in survival or recurrence rates, and
Head and Neck: Ear: Endolymphatic Sac Tumor (ELST) Diaz RC
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 325
subtotal resection followed by stereotactic radiotherapy
has uniformly resulted in tumor regrowth. There are no
reported cases of radiation therapy and/or stereotactic
radiotherapy used as the primary modality of treatment
for ELSTs.
Evolution
There are currently no reported cases of spontaneous
metastatic dissemination of ELSTs in the literature.
Recently however, two reports have surfaced
describing metastatic disease following subtotal
resection. The first was a reported case of ELST drop
metastasis with dissemination onto the ipsilateral
cerebellar convexity beyond the original tumor site in a
patient who had undergone previous subtotal resection
and radiotherapy. A second case of drop metastasis of
ELST involved the spine, manifesting after multiple
subtotal resections and three courses of stereotactic
radiosurgery.
These seminal reports serve to illustrate the importance
of complete tumor removal on initial resection in order
to minimize both recurrence and metastatic seeding.
The oncologic principle of complete tumor extirpation
on primary resection is certainly applicable to ELSTs,
despite their benign histology and absence of
spontaneous metastasis.
Prognosis
Overall survival characteristics for all reported cases of
ELSTs are: 74% no evidence of disease, 20% alive
with disease, and 4% died of disease, for the reporting
periods.
ELSTs are histologically benign yet sometimes
destructive, highly aggressive lesions. They show
excellent response to primary surgical resection, with
or without adjuvant radiotherapy. Complete tumor
removal on initial resection is crucial. Hearing
preservation should not take precedence over complete
tumor removal, as adjuvant radiotherapy does not
ensure against tumor recurrence, which can be
devastating and lethal. In addition, drop metastases
following subtotal tumor resection have now been
reported. In patients with VHL disease, regularly
scheduled audiometry and surveillance MRI are vital to
early detection of ELSTs, which can optimize the
opportunity for hearing preservation without
compromising tumor control.
Genetics
Note
The current literature suggests that approximately one
third of all ELSTs are associated with VHL disease.
VHL disease is an autosomal dominant familial cancer
syndrome. VHL disease affects approximately 1 in
39,000 people. It encompasses a variety of neoplasia
both benign and malignant including renal cell
carcinomas, central nervous system
hemangioblastomas, retinal hemangioblas-tomas,
pheochromocytomas, and cysts of the kidneys,
pancreas, and epididymis.
The gene responsible for VHL disease is a tumor
suppressor and it has been mapped to chromosome
3p25. The VHL gene product pVHL forms a multi-
protein complex that contains elongin B, elongin C,
Cul-2, and Rbx1.
The pVHL complex has a role in oxygen sensing. The
VHL gene regulates vascular endothelial growth factor
VEGF, and inactivation of the gene promotes VEGF
overexpression and angiogenesis. In addition, its loss of
function mutation can increase expression of hypoxia-
inducible factor HIF1, stimulating angiogenesis and
tumorigenesis. In VHL disease, it is believed that
tumors arise when both an inherited germline mutation
and a loss-of-function mutation of the wild-type VHL
gene are present.
In addition, it has been shown that somatic mutations to
the VHL gene locus at 3p25/26 are detected even in
cases of sporadic ELSTs, that is, in non-VHL patients.
Genetic sequencing analysis of the 3p25 VHL gene
locus in both sporadic and VHL-associated ELSTs
demonstrates nucleotide substitution as well as
deletion/frameshift errors.
Even though temporal bone lesions were described in
patients by Lindau in 1926, the association of these
tumors with VHL disease was not made until recently.
This clinical association has been confirmed at the
molecular level with mutations in the VHL gene
identified in endolymphatic sac tumors in VHL
patients. Approximately 10% of patients with VHL
disease have ELSTs, and approximately 30% of VHL
patients with ELSTs have bilateral tumors. This
variable phenotypic expression may be a reflection of
VHL gene function secondary to the type of mutation
present.
Indeed, VHL disease has been found to have
phenotypic expression consistent within members of a
family, thus implying a singular, conserved mutation
within affected families. VHL disease is categorized
into two familial types, with type 1 being without
pheochromocytomas and type 2 being with
pheochromocytomas. There is further subclassification
of type 2 into type 2a, low risk for developing renal cell
carcinoma, and type 2b, high risk for developing renal
cell carcinoma. Clinical presentation type correlates
with genetic mutation type: type 1 families usually
have deletion or truncation mutations, whereas type 2
families usually have missense mutations.
If a family history of VHL disease exists, or if the
diagnosis of VHL disease is made in the absence of an
ELST, then early routine audiologic screening can
allow for early tumor detection and the possibility of
hearing preservation surgery should ELST develop.
Positive identification of tumor on MRI with
gadolinium is necessary prior to surgery: to date,
Head and Neck: Ear: Endolymphatic Sac Tumor (ELST) Diaz RC
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 326
surgical exploration in VHL patients with
audiovestibular symptoms but without MRI abnor-
mallities has not been documented and is not
recommended.
Genes involved and proteins
VHL
Location
3p25.3
DNA / RNA
The VHL gene is a tumor suppressor gene mapped to
chromosome 3p25/26.
Protein
The VHL gene product, pVHL, forms a multi-protein
complex that contains elongin B, elongin C, Cul-2, and
Rbx1.
References Schindler RA. Histopathology of the human endolymphatic sac. Am J Otol. 1981 Oct;3(2):139-43
Hassard AD, Boudreau SF, Cron CC. Adenoma of the endolymphatic sac. J Otolaryngol. 1984 Aug;13(4):213-6
Heffner DK. Low-grade adenocarcinoma of probable endolymphatic sac origin A clinicopathologic study of 20 cases. Cancer. 1989 Dec 1;64(11):2292-302
Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993 May 28;260(5112):1317-20
Lo WW, Applegate LJ, Carberry JN, Solti-Bohman LG, House JW, Brackmann DE, Waluch V, Li JC. Endolymphatic sac tumors: radiologic appearance. Radiology. 1993 Oct;189(1):199-204
Chen F, Kishida T, Yao M, Hustad T, Glavac D, Dean M, Gnarra JR, Orcutt ML, Duh FM, Glenn G. Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat. 1995;5(1):66-75
Megerian CA, McKenna MJ, Nuss RC, Maniglia AJ, Ojemann RG, Pilch BZ, Nadol JB Jr. Endolymphatic sac tumors: histopathologic confirmation, clinical characterization, and implication in von Hippel-Lindau disease. Laryngoscope. 1995 Aug;105(8 Pt 1):801-8
Manski TJ, Heffner DK, Glenn GM, Patronas NJ, Pikus AT, Katz D, Lebovics R, Sledjeski K, Choyke PL, Zbar B, Linehan WM, Oldfield EH. Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease. JAMA. 1997 May 14;277(18):1461-6
Vortmeyer AO, Choo D, Pack SD, Oldfield E, Zhuang Z. von Hippel-Lindau disease gene alterations associated with
endolymphatic sac tumor. J Natl Cancer Inst. 1997 Jul 2;89(13):970-2
Noujaim SE, Pattekar MA, Cacciarelli A, Sanders WP, Wang AM. Paraganglioma of the temporal bone: role of magnetic resonance imaging versus computed tomography. Top Magn Reson Imaging. 2000 Apr;11(2):108-22
Vortmeyer AO, Huang SC, Koch CA, Governale L, Dickerman RD, McKeever PE, Oldfield EH, Zhuang Z. Somatic von Hippel-Lindau gene mutations detected in sporadic endolymphatic sac tumors. Cancer Res. 2000 Nov 1;60(21):5963-5
Hamazaki S, Yoshida M, Yao M, Nagashima Y, Taguchi K, Nakashima H, Okada S. Mutation of von Hippel-Lindau tumor suppressor gene in a sporadic endolymphatic sac tumor. Hum Pathol. 2001 Nov;32(11):1272-6
Ferreira MA, Feiz-Erfan I, Zabramski JM, Spetzler RF, Coons SW, Preul MC. Endolymphatic sac tumor: unique features of two cases and review of the literature. Acta Neurochir (Wien). 2002 Oct;144(10):1047-53
Megerian CA, Haynes DS, Poe DS, Choo DI, Keriakas TJ, Glasscock ME 3rd. Hearing preservation surgery for small endolymphatic sac tumors in patients with von Hippel-Lindau syndrome. Otol Neurotol. 2002 May;23(3):378-87
Bambakidis NC, Megerian CA, Ratcheson RA. Differential grading of endolymphatic sac tumor extension by virtue of von Hippel-Lindau disease status. Otol Neurotol. 2004 Sep;25(5):773-81
Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol. 2004 Dec 15;22(24):4991-5004
Lonser RR, Kim HJ, Butman JA, Vortmeyer AO, Choo DI, Oldfield EH. Tumors of the endolymphatic sac in von Hippel-Lindau disease. N Engl J Med. 2004 Jun 10;350(24):2481-6
Kim HJ, Butman JA, Brewer C, Zalewski C, Vortmeyer AO, Glenn G, Oldfield EH, Lonser RR. Tumors of the endolymphatic sac in patients with von Hippel-Lindau disease: implications for their natural history, diagnosis, and treatment. J Neurosurg. 2005 Mar;102(3):503-12
Patel NP, Wiggins RH 3rd, Shelton C. The radiologic diagnosis of endolymphatic sac tumors. Laryngoscope. 2006 Jan;116(1):40-6
Santarpia L, Lapa D, Benvenga S. Germline mutation of von Hippel-Lindau (VHL) gene 695 G>A (R161Q) in a patient with a peculiar phenotype with type 2C VHL syndrome. Ann N Y Acad Sci. 2006 Aug;1073:198-202
Skalova A, Síma R, Bohus P, Curík R, Lukás J, Michal M. Endolymphatic sac tumor (aggressive papillary tumor of middle ear and temporal bone): report of two cases with analysis of the VHL gene. Pathol Res Pract. 2008;204(8):599-606
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Diaz RC. Head and Neck: Ear: Endolymphatic Sac Tumor (ELST). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):321-326.
Solid Tumour Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 327
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Lymphangioleiomyoma Connie G Glasgow, Angelo M Taveira-DaSilva, Joel Moss
Translational Medicine Branch, NHLBI, NIH, Building 10, Room 6D05, MSC 1590, Bethesda, Maryland
20892-1590, USA (CGG, AMTD, JM)
Published in Atlas Database: April 2009
Online updated version: http://AtlasGeneticsOncology.org/Tumors/LymphangioleiomyomaID5868.html DOI: 10.4267/2042/44723
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Classification
Note
Lymphangioleiomyoma is a benign neoplasm of
lymphatic vessels characterized as a PEComa
(perivascular epithelioid cell tumour), involving the
proliferation of epithelioid cells, with mutations in the
tuberous sclerosis complex (TSC) genes TSC1 and
TSC2.
Clinics and pathology
Note
Lymphangioleiomyomas are commonly associated with
lymphangioleiomyomatosis (LAM), a multi-system
disorder primarily affecting women of child-bearing
age. Initial presentation of LAM may
result from pulmonary or extrapulmonary lesions.
Pulmonary LAM is characterized by thin-walled cysts,
which are diffused throughout the lungs. Patients with
these lesions experience deterioration of lung function
that can lead to oxygen depen-dency, lung
transplantation or death. Extrapul-monary LAM
involves the axial lymphatics of the abdomen and
thorax (lymphangioleiomyomas, adenopathy), and
abdominal organs, especially the kidneys
(angiomyolipomas).
Abdomino-pelvic lymphangioleiomyomas may present
with abdominal pain as an acute abdomen, with a
neuropathy or with abdominal bloating. Thoraco-
abdominal lymphadenopathy and lymph-
angioleiomyomas, along with chylothorax (Figure 1) or
ascites may suggest the presence of a malignant
lymphoproliferative disease.
Figure 1: Large left chylous pleural effusion (white arrow) in a patient with LAM.
Lymphangioleiomyoma Glasgow CG, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 328
Figure 2 A, B, C, D, and E. Histological characterization of extrapulmonary LAM. LAM cells form fascicles separated by lymphatic channels (A). (HE, original magnification x 100) An example of LAM cells arranged in trabecular bundles and irregular papillary patterns (B). (H&E, original magnification x 250) Image representing morphological heterogeneity of LAM cells; large epithelioid LAM cells (asterik) and smaller, round to oval cells (arrows) (C). (H&E, original magnification x 1,000) Positive reactivity of LAM cells to HMB-45 (D). (immunoperoxidase with hematoxylin counterstain, original magnification x 400) Positive reactivity of LAM cells to SMMHC (E). (original magnification x 400). (from Matsui et al., Hum Pathol. 2000 October;31(10):1242-1248).
Lymphangioleiomyoma Glasgow CG, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 329
Etiology
LAM results from proliferation of an abnormal cell,
termed the LAM cell. LAM occurs in 30-40% of
patients with tuberous sclerosis complex, an autosomal
dominant disorder associated with mutations in the
TSC1 or TSC2 genes. Sporadic LAM is caused
presumably by cells with mutations of the TSC2 gene.
Lymphatic involvement (including
lymphangioleiomyomas) occurs less frequently in
patients with LAM/TSC, than in patients with sporadic
LAM.
Epidemiology
Lymphangioleiomyomas are present in about 16-21%
of patients with LAM.
Pathology
Histological examination of the cells lining the walls of
the extrapulmonary lesions reveal common
characteristics with pulmonary LAM cells, abnormal
smooth muscle-like cells with a mixture of epithelioid
and splindle-shaped morphologies. Cells react with
HMB-45, a monoclonal antibody against gp100 (a
premelanosomal marker), and with antibodies against
SMMHC, a smooth muscle-cell marker. Unlike the
nodular collections of the pulmonary LAM cells, the
extrapulmonary cells usually form fascicles or papillary
patterns. Both types of lesions contain slit-like
lymphatic channels (Figure 2A, B, C, D, and E).
Radiologic Imaging: Retroperitoneal lymphangio-
leiomyomas have a distinctive radiologic appearance
(Figures 3-7), and diurnal variation in size of the tumor
masses can be demonstrated by ultrasonography or
computed tomography scans (Figure 8).
Lymphangioleiomyomas are well characterized by
either ultrasonography or computed tomography
scanning, appearing as well-circumscribed lobular, thin
or thick-walled masses without evidence of necrosis or
hemorrhage. Masses greater than 3 cm in diameter are
usually cystic in appearance and many contain fluid,
presumably chyle. Lesions as large as 20 cm in
diameter have been observed. In patients with LAM,
the lesions most often occur in the retroperitoneal
region.
Treatment
There is no effective treatment for lymphangio-
leiomyomas. The lesions are usually asymptomatic,
however, ascites, peripheral edema, and compres-sion
of the bladder, bowel, pelvic veins and other viscera by
large lymphangioleiomyomata may cause severe
symptomatology, including pain, obstipation, urinary
frequency, and peripheral edema. Although surgery is
sometimes contemplated to ameliorate symptoms
caused by visceral compression, it is contraindicated,
as, in our experience; it may lead to persistent
lymphatic
leakage and intractable chylothorax and ascites.
Chylous effusions including pleural effusions are
particularly difficult to treat. Repeated thora-centeses
lead to malnutrition and may result in infectious
complications. Low fat diet with medium-chain
triglycerides and therapeutic thora-centesis should be
attempted initially. However, most patients require
pleurodesis, which may be effective if the rate of chyle
generation can be reduced. Patients should be placed on
a fat-free parenteral nutrition regimen prior to, during,
and after surgery. It is essential that good lung
expansion be obtained to ensure complete apposition of
the visceral and parietal pleura to avoid residual pleural
pockets. After a successful pleurodesis, a low fat diet
with mid-chain trigly-cerides is recommended. A
peritoneal-venous shunt may be considered for most
severe cases when the ascites is disabling and is
causing mechanical/ nutritional problems, but little
experience with this therapeutic modality in LAM is
reported. Treatment with octreotide may be considered
for those patients with disabling ascites and large
lymph-angioleiomyomata. Previous studies with
somato-statin and octreotide in other clinical settings
(e.g., traumatic damage to the lymphatics, yellow nail
syndrome) have shown a successful reduction in
chylous effusions, chyluria, ascites, and peripheral
lymphedema.
Sirolimus: The TSC1 and TSC2 genes encode
respectively, hamartin and tuberin. Although Hamartin
and tuberin may have individual functions, they are
also known to interact in a cytosolic complex.
Hamartin may play a role in the reorganization of the
actin cytoskeleton. Tuberin has roles in pathways
controlling cell growth and proliferation. It is a
negative regulator of cell cycle progression, and loss of
tuberin function shortens the G1 phase of the cell cycle.
Tuberin binds p27KIP1, a cyclin-dependent kinase
inhibitor, thereby preventing its degradation and
leading to inhibition of the cell cycle. Tuberin also
integrates signals from growth factors and energy
stores through its interaction with mTOR (mammalian
target of rapamycin). Tuberin has Rheb GAP (Ras
homolog enriched in brain GTPase-activating protein)
activity, which converts active Rheb-GTP to inactive
Rheb-GDP. Rheb regulates mTOR, a serine/threonine
kinase that phosphorylates at least two substrates: 4E-
BP1, allowing cap-dependent translation, and S6K1,
leading to translation of 5' TOP (terminal
oligopyrimidine tract)-containing RNAs.
Phosphorylation of tuberin by Akt, which is activated
by growth factors, leads to inhibition of tuberin,
resulting in cell growth and proliferation.
Phosphorylation of tuberin by AMPK (AMP-activated
kinase) activates tuberin and further promotes
inhibition of cell growth in conditions of energy
deprivation.
Lymphangioleiomyoma Glasgow CG, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 330
Figure 3. Mediastinal lymphangioleiomyoma (white arrow), located posteriorly to the descending thoracic aorta. A: aorta. Figure 4. Mediastinal lymphangioleiomyomas (white arrow), located posteriorly to the trachea. Figure 5. Large retroperitoneal lymphangioleiomyoma (white arrow) surrounding the aorta and inferior vena cava. A: aorta; IVC: inferior vena cava. Figure 6A and B. Black arrows point to large pelvic lymphangioleiomyoma (A). A complex lymphangioleiomyoma is shown marked by circle on panel B. Figure 7A, B and C. Evidence of bladder and bowel compression caused by the tumors. B: bladder.
Lymphangioleiomyoma Glasgow CG, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 331
Figure 8A, B, C and D. Diurnal variation of lymphangioleiomyomas. Abdominal ultrasound shows that the size of a lymphangioleiomyoma is greater in the evening (panel B) that in the morning (panel A). Abdominal CT scan showing also diurnal variation in tumor size from morning (panel C) to evening (panel D).
Sirolimus, an inmmunosuppressive agent, inacti-vates
mTOR. Sirolimus has been shown to induce apoptosis
of tumors in rodents and decrease the size of renal
angiomyolipomas in patients with lymph-
angioleiomyomatosis or TSC. Further, sirolimus was
effective in decreasing the size of chylous effusions and
lymphangioleiomyomas in one patient with LAM and
improved chylous effusions in another patient who
underwent lung trans-plantation.
Evolution
Lymphangioleiomyomas are thought to occur due to
the proliferation of LAM cells in lymphatic vessels,
causing obstruction and dilatation of the vessels leading
to collection of chylous material in cyst-like structures.
The cysts, when overdistended, may rupture resulting
in chylous ascites. Lymphangioleiomyomas can exhibit
diurnal variation, (visualized by CT or sonography)
with lesions increasing in size during the day. This
phenomenon can be an aid in a differential diagnosis of
a probable lymphangioleiomyoma with thick walls and
no fluid, from other mass lesions such as a lymphoma
or a sarcoma.
Prognosis
Lymphatic involvement (defined by the presence of
adenopathy and/or lymphangioleiomyomas) in patients
with LAM, is correlated with more severe lung disease
assessed by computed tomography scans.
Genes involved and proteins
Note
Serum levels of VEGF-D, a lymphangiogenic growth
factor, are higher in patients with LAM than those in
healthy volunteers. In addition, serum levels of VEGF-
D in patients with LAM who have
lymphangioleiomyomas and adenopathy are higher
than in patients without lymphangioleiomyomas. LAM
lung nodules demonstrate immunoreactivity for VEGF-
D. Because of these findings and reported observations
of LAM cell clusters in lymphatic channels, it has been
hypothesized that LAM-associated lymphangiogenesis,
driven by VEGF-D, may account for the dissemination
of LAM cells through the shedding of LAM cell
clusters into the lymphatic system.
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lymphangioleiomyomatosis (LAM) reflect lymphatic involvement. Accepted by Chest for publication October 8, 2008. in press.
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Lymphangioleiomyoma Glasgow CG, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 335
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