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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
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Atlas of Genetics and Cytogenetics in Oncology and Haematology
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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
jlhuret@AtlasGeneticsOncology.org or Editorial@AtlasGeneticsOncology.org
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)
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http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
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(8)
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Volume 14, Number 8, August 2010
Table of contents
Gene Section
DIRAS3 (DIRAS family, GTP-binding RAS-like 3) 714 Yinhua Yu, Zhen Lu, Robert Z Luo, Robert C Bast Jr
JAK1 (Janus kinase 1) 717 Laurent Knoops, Tekla Hornakova, Jean-Christophe Renauld
PLAUR (plasminogen activator, urokinase receptor) 720 Benedikte Jacobsen, Martin Illemann, Michael Ploug
SHC4 (SHC (Src homology 2 domain containing) family, member 4) 732 Luigi Pasini, Luisa Lanfrancone
TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)) 735 Francesca Orso, Daniela Taverna
ATF4 (activating transcription factor 4 (tax-responsive enhancer element B67)) 739 Kurosh Ameri, Adrian L Harris
CLU (clusterin) 744 Hanna Rauhala, Tapio Visakorpi
ECM1 (Extracellular matrix protein 1) 749 Joseph Merregaert, Wim Van Hul
ESRRG (estrogen-related receptor gamma) 753 Rebecca B Riggins
GAS5 (growth arrest-specific 5 (non-protein coding)) 758 Mirna Mourtada-Maarabouni
GBP1 (guanylate binding protein 1, interferon-inducible, 67kDa) 761 Nathalie Britzen-Laurent, Michael Stürzl
GPNMB (glycoprotein (transmembrane) nmb) 765 Shyam A Patel, Philip K Lim, Pranela Rameshwar
MBD2 (methyl CpG binding domain protein 2) 768 Heather Owen
MEF2D (myocyte enhancer factor 2D) 772 Victor Prima, Lyudmyla G Glushakova, Stephen P Hunger
NDRG1 (N-myc downstream regulated 1) 776 Michel Wissing, Nadine Rosmus, Michael Carducci, Sushant Kachhap
SLC5A8 (solute carrier family 5 member 8) 781 Julie Di Bernardo, Kerry J Rhoden
TMPRSS4 (transmembrane protease, serine 4) 785 Youngwoo Park
TSPAN8 (tetraspanin 8) 788 Uwe Matthias Galli
t(11;14)(q13;q32) in multiple myeloma Huret JL, Laï JL
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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TXN (thioredoxin) 790 Zhe Chen, Eiji Yoshihara, Hajime Nakamura, Hiroshi Masutani, Junji Yodoi
Leukaemia Section
t(1;12)(q21;q24) 795 Sang-Guk Lee, Tae Sung Park, Jong Rak Choi
t(1;14)(q21;q32), t(1;22)(q21;q11) 797 Jean-Loup Huret
dic(9;20)(p11-13;q11) 800 Jon C Strefford
Solid Tumour Section
Ovary: inv(10)(q11q11) in ovarian germ cell tumors 804 Douglas S Richardson, Lois M Mulligan
Case Report Section
Dicentric dic(7;9)(p11;p11): a new case in childhood ALL 806 Elvira D Rodrigues Pereira Velloso, Carolina Kassab, Silvia Helena A Figueira, Denise Tiemi Noguchi,
Eliana Carla Armelin Benites, Cristóvão L P Mangueira, Fábio Morato de Oliveira
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 714
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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DIRAS3 (DIRAS family, GTP-binding RAS-like 3) Yinhua Yu, Zhen Lu, Robert Z Luo, Robert C Bast Jr
The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 354, Houston, TX
77030, USA (YY, ZL, RZL, RCBJr)
Published in Atlas Database: September 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/DIRAS3ID702ch1p31.html DOI: 10.4267/2042/44814
This article is an update of : Guénard F, Durocher F. DHX9 (DEAH (Asp-Glu-Ala-His) box polypeptide 9). Atlas Genet Cytogenet Oncol Haematol 2010;14(6):547-549 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: ARHI; NOEY2; RHOI
HGNC (Hugo): DIRAS3
Location: 1p31.3
Local order: Telomeric to GNG12, RMU7-80P and
centromeric to GPR177, RPS7P4.
Note: DIRAS3 is also known as NOEY2 and ARHI
(Ras homologue member I).
DNA/RNA
Description
DIRAS3 encompasses a 7.2-kb region and includes 2.0
kb of the 5'- flanking region, two exons, an intron, and
a 1.2-kb 3'-flanking region.
The first exon contains only the 5'-noncoding
region consisting of 81 nucleotides, whereas the second
exon contains the entire protein-coding region. The two
exons are separated by an intron of 3.2 kb. There are
three CpG island regions. CPG island I (nucleotide (nt)
-1232 to -914) is located about 1 kb upstream of the
transcription initiation site; CpG island II (nt -206 to
+79) is near the transcription initiation region and
adjacent exon 1; CpG island III (nt +3343 to +3691) is
located in the protein-encoding region of exon 2.
Transcription
The entire protein-coding region is located within exon
2 and encodes a 229-residue small GTP-binding
protein.
Pseudogene
No known pseudogenes.
The DIRAS3 gene contains two exons interrupted by a large intron. The red-blocked and opened boxes represent the coding and non-coding regions, respectively. There are three CpG island regions. Blue: CPG island I; green: CpG island II; grey: CpG island III.
DIRAS3 (DIRAS family, GTP-binding RAS-like 3) Yu Y, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 715
DIRAS3 protein.
Protein
Description
DIRAS3 encodes a 26-kDa GTPase. The DIRAS3 gene
ORF contains three motifs typical of Ras/Rap family
members: (1) a highly conserved GTP binding domain,
(2) a putative effector domain YLPTIENTY, and (3)
the membrane localizing CAAX motif at the COOH
terminus. DIRAS3 contains a unique 34 amino-acid
extension at the N-terminus and differs from other
members of Ras-superfamily.
Expression
DIRAS3 is expressed in brain, heart, liver, lung,
pancreas, breast and ovary.
Localisation
DIRAS is associated at the cell membrane through its
prenylation at the C-terminal cysteine residue.
Mutation of the conserved CAAX box at the C-
terminus led to a loss of its membrane association.
Function
DIRAS3 is a maternally imprinted tumor suppressor
gene that belongs to the Ras superfamily of small G
proteins. DIRAS3 regulates cell cycle, motility,
angiogenesis, autophagy and tumor dormancy.
Introduction of this gene into cancer cells that lack
DIRAS3 expression inhibits proliferation and motility
of cancer cells. DIRAS3 truncates signaling through the
Ras/MAP pathway, induces p21WAF1/CIP1
, down-
regulates cyclin D1, and triggers apoptosis. DIRAS3 is
required for autophagy and that re-expression of
DIRAS3 protein in ovarian cancer cells will induce
autophagic cell death in culture. In xenografts, re-
expression of DIRAS3 also induces autophagy, but can
also promote tumor dormancy in the presence of factors
that promote survival in the cancer microenvironment.
Homology
DIRAS3 shares 56% amino acid homology with
Rap1A, 56% with Rap1B, 58% with Rap 2A, 62% with
Rap2B, 59% with K-Ras, and 54% with H-Ras.
DIRAS3 shares about 40% homology with DIRAS1
and DIRAS2.
Mutations
Note
Mutations have not been detected.
Implicated in
Solid cancers
Disease
Ovarian cancer, breast cancer, pancreatic cancer,
hepatocellular carcinoma, oligodendroglial tumor,
follicular thyroid cancer.
Prognosis
Loss of DIRAS3 expression is associated with tumor
progression in breast cancer and decreased disease-free
survival in ovarian cancer.
Oncogenesis
DIRAS3 is monoallelically expressed and maternally
imprinted, expression from the paternal allele of
DIRAS3 can be lost through LOH, CpG methylation,
and transcriptional regulation. DIRAS3 is
downregulated in 60% of ovarian and breast cancers:
LOH was found in 40% of ovarian and breast cancers.
Mutations have not been detected, but the remaining
allele is silenced in ovarian cancer and breast cancer by
methylation in approximately 10-15% of cases. In the
remaining cancers, DIRAS3 is downregulated by
transcriptional mechanisms that involve E2F1 and
E2F4, as well as by the loss of RNA binding proteins
that decrease the half-life of DIRAS3 mRNA.
References Yu Y, Xu F, Peng H, Fang X, Zhao S, Li Y, Cuevas B, Kuo WL, Gray JW, Siciliano M, Mills GB, Bast RC Jr. NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas. Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):214-9
Peng H, Xu F, Pershad R, Hunt KK, Frazier ML, Berchuck A, Gray JW, Hogg D, Bast RC Jr, Yu Y. ARHI is the center of allelic deletion on chromosome 1p31 in ovarian and breast cancers. Int J Cancer. 2000 Jun 1;86(5):690-4
Xu F, Xia W, Luo RZ, Peng H, Zhao S, Dai J, Long Y, Zou L, Le W, Liu J, Parlow AF, Hung MC, Bast RC Jr, Yu Y. The human ARHI tumor suppressor gene inhibits lactation and growth in transgenic mice. Cancer Res. 2000 Sep 1;60(17):4913-20
Luo RZ, Peng H, Xu F, Bao J, Pang Y, Pershad R, Issa JP, Liao WS, Bast RC Jr, Yu Y. Genomic structure and promoter characterization of an imprinted tumor suppressor gene ARHI. Biochim Biophys Acta. 2001 Jun 28;1519(3):216-22
Bao JJ, Le XF, Wang RY, Yuan J, Wang L, Atkinson EN, LaPushin R, Andreeff M, Fang B, Yu Y, Bast RC Jr. Reexpression of the tumor suppressor gene ARHI induces apoptosis in ovarian and breast cancer cells through a caspase-independent calpain-dependent pathway. Cancer Res. 2002 Dec 15;62(24):7264-72
DIRAS3 (DIRAS family, GTP-binding RAS-like 3) Yu Y, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 716
Fujii S, Luo RZ, Yuan J, Kadota M, Oshimura M, Dent SR, Kondo Y, Issa JP, Bast RC Jr, Yu Y. Reactivation of the silenced and imprinted alleles of ARHI is associated with increased histone H3 acetylation and decreased histone H3 lysine 9 methylation. Hum Mol Genet. 2003 Aug 1;12(15):1791-800
Luo RZ, Fang X, Marquez R, Liu SY, Mills GB, Liao WS, Yu Y, Bast RC. ARHI is a Ras-related small G-protein with a novel N-terminal extension that inhibits growth of ovarian and breast cancers. Oncogene. 2003 May 15;22(19):2897-909
Wang L, Hoque A, Luo RZ, Yuan J, Lu Z, Nishimoto A, Liu J, Sahin AA, Lippman SM, Bast RC Jr, Yu Y. Loss of the expression of the tumor suppressor gene ARHI is associated with progression of breast cancer. Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3660-6
Yu Y, Fujii S, Yuan J, Luo RZ, Wang L, Bao J, Kadota M, Oshimura M, Dent SR, Issa JP, Bast RC Jr. Epigenetic regulation of ARHI in breast and ovarian cancer cells. Ann N Y Acad Sci. 2003 Mar;983:268-77
Yuan J, Luo RZ, Fujii S, Wang L, Hu W, Andreeff M, Pan Y, Kadota M, Oshimura M, Sahin AA, Issa JP, Bast RC Jr, Yu Y. Aberrant methylation and silencing of ARHI, an imprinted tumor suppressor gene in which the function is lost in breast cancers. Cancer Res. 2003 Jul 15;63(14):4174-80
Rosen DG, Wang L, Jain AN, Lu KH, Luo RZ, Yu Y, Liu J, Bast RC Jr. Expression of the tumor suppressor gene ARHI in epithelial ovarian cancer is associated with increased expression of p21WAF1/CIP1 and prolonged progression-free survival. Clin Cancer Res. 2004 Oct 1;10(19):6559-66
Nishimoto A, Yu Y, Lu Z, Mao X, Ren Z, Watowich SS, Mills GB, Liao WS, Chen X, Bast RC Jr, Luo RZ. A Ras homologue member I directly inhibits signal transducers and activators of transcription 3 translocation and activity in human breast and ovarian cancer cells. Cancer Res. 2005 Aug 1;65(15):6701-10
Weber F, Aldred MA, Morrison CD, Plass C, Frilling A, Broelsch CE, Waite KA, Eng C. Silencing of the maternally imprinted tumor suppressor ARHI contributes to follicular thyroid carcinogenesis. J Clin Endocrinol Metab. 2005 Feb;90(2):1149-55
Lu Z, Luo RZ, Peng H, Huang M, Nishmoto A, Hunt KK, Helin K, Liao WS, Yu Y. E2F-HDAC complexes negatively regulate
the tumor suppressor gene ARHI in breast cancer. Oncogene. 2006 Jan 12;25(2):230-9
Lu Z, Luo RZ, Peng H, Rosen DG, Atkinson EN, Warneke C, Huang M, Nishmoto A, Liu J, Liao WS, Yu Y, Bast RC Jr. Transcriptional and posttranscriptional down-regulation of the imprinted tumor suppressor gene ARHI (DRAS3) in ovarian cancer. Clin Cancer Res. 2006 Apr 15;12(8):2404-13
Yu Y, Luo R, Lu Z, Wei Feng W, Badgwell D, Issa JP, Rosen DG, Liu J, Bast RC Jr. Biochemistry and biology of ARHI (DIRAS3), an imprinted tumor suppressor gene whose expression is lost in ovarian and breast cancers. Methods Enzymol. 2006;407:455-68
Feng W, Lu Z, Luo RZ, Zhang X, Seto E, Liao WS, Yu Y. Multiple histone deacetylases repress tumor suppressor gene ARHI in breast cancer. Int J Cancer. 2007 Apr 15;120(8):1664-8
Lu Z, Luo RZ, Lu Y, Zhang X, Yu Q, Khare S, Kondo S, Kondo Y, Yu Y, Mills GB, Liao WS, Bast RC Jr. The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in human ovarian cancer cells. J Clin Invest. 2008 Dec;118(12):3917-29
Riemenschneider MJ, Reifenberger J, Reifenberger G. Frequent biallelic inactivation and transcriptional silencing of the DIRAS3 gene at 1p31 in oligodendroglial tumors with 1p loss. Int J Cancer. 2008 Jun 1;122(11):2503-10
Huang J, Lin Y, Li L, Qing D, Teng XM, Zhang YL, Hu X, Hu Y, Yang P, Han ZG. ARHI, as a novel suppressor of cell growth and downregulated in human hepatocellular carcinoma, could contribute to hepatocarcinogenesis. Mol Carcinog. 2009 Feb;48(2):130-40
Huang S, Chang IS, Lin W, Ye W, Luo RZ, Lu Z, Lu Y, Zhang K, Liao WS, Tao T, Bast RC Jr, Chen X, Yu Y. ARHI (DIRAS3), an imprinted tumour suppressor gene, binds to importins and blocks nuclear import of cargo proteins. Biosci Rep. 2009 Dec 15;30(3):159-68
This article should be referenced as such:
Yu Y, Lu Z, Luo RZ, Bast RC Jr. DIRAS3 (DIRAS family, GTP-binding RAS-like 3). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):714-716.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 717
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
JAK1 (Janus kinase 1) Laurent Knoops, Tekla Hornakova, Jean-Christophe Renauld
Hematology unit, Cliniques Universitaires Saint-Luc (LK); Ludwig Institute for Cancer Research de Duve
Institute, Université Catholique de Louvain, Avenue Hippocrate 74, B-1200 Brussels, Belgium (LK, TH,
JCR)
Published in Atlas Database: September 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/JAK1ID41031ch1p31.html DOI: 10.4267/2042/44815
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 2.7.10.2; JAK-1; JAK1A; JAK1B;
JTK3
HGNC (Hugo): JAK1
Location: 1p31.3
DNA/RNA
Description
25 exons spanning roughly 135 kb of genomic DNA.
Transcription
5053 bp pre-mRNA; 1 transcript described.
Protein
Description
1154 amino acids; 133,3 kDa; JAK1 contains a N-
terminal FERM domain, responsible of the binding to
the receptor, a central Src homology 2 (SH2) domain,
and two C-terminal domains: a tyrosine kinase domain
JH1 and a pseudokinase domain JH2.
Expression
Ubiquitous.
Localisation
Intracellular, associated to cytokine receptors.
Function
JAK1 is a non-receptor tyrosine kinase that associates
to cytokine receptors without intrinsic kinase activity to
mediate cytokine-induced signal transduction; JAK1
associates with numerous cytokine receptors chains and
is involved in signaling by the majority of cytokines:
the gamma-C family (IL-2, IL-4, IL-7, IL-9, IL-15, IL-
21), the gp130 family (IL-6, OSM, LIF, ...), interferons,
...
Homology
JAK1 belongs to the janus kinase subfamily; four
mammalian JAKs have been identified (JAK1, JAK2,
JAK3 and TYK2); human JAK1 is > 90% identical to
the mouse and the rat JAK1 homologs.
Implicated in
Acute lymphoblastic leukemia T cell type (T-ALL) and Acute lymphoblastic leukemia B cell type (B-ALL)
Prognosis
JAK1 mutations are associated with advanced age, poor
response to therapy and overall prognosis (Flex et al.,
2008).
Oncogenesis
Somatic JAK1 mutations occur in T cell acute
lymphoblastic leukemia (ALL). These mutations seem
to be more frequent among adult T-ALL patients, but
the frequency varies between studies: 8/38 (21.0%;
adult; Flex et al., 2008), 1/49 (2.0%; children; Flex et
al., 2008), 2/11 (27.3%; adult; Jeong et al., 2008),
4/108 (3.7%; adult; Asnafi et al., 2009). These
mutations represent gain of function mutations that
participate in the leukemogenic process by inducing the
constitutive activation of the JAK-STAT pathway.
JAK1 (Janus kinase 1) Knoops L, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 718
Amino acid substitution Proof of hyperactivity domain reference
S512L
SH2 Flex et al., 2008
A634D Yes Pseudokinase Flex et al., 2008
Y652H
Pseudokinase Asnafi et al., 2009
V658F Yes Pseudokinase Jeong et al., 2008
R724H Yes Pseudokinase Flex et al., 2008
R724Q
Pseudokinase Asnafi et al., 2009
T782M
Pseudokinase Jeong et al., 2008
L783F
Pseudokinase Jeong et al., 2008
R879S
Kinase Flex et al., 2008
R879C Yes Kinase Flex et al., 2008
R879H
Kinasee Flex et al., 2008
Table 1: Somatic mutations in JAK1 found in T-ALL patients.
Amino acid substitution Proof of hyperactivity domain reference
K204M
FERM Flex et al., 2008
L624_R629>W Yes Pseudokinase Mullighan et al., 2009
A634D Yes Pseudokinase Flex et al., 2008
S646F Yes Pseudokinase Mullighan et al., 2009
L653F
Pseudokinase Flex et al., 2008
V658F Yes Pseudokinase Mullighan et al., 2009
R724H Yes Pseudokinase Flex et al., 2008
Table 2: Somatic mutations in JAK1 found in B-ALL patients.
Amino acid substitution Proof of hyperactivity domain reference
T478S
SH2 Xiang et al., 2008
V623A
Pseudokinase Xiang et al., 2008
V658F Yes Pseudokinase Jeong et al., 2008
Table 3: Somatic mutations in JAK1 found in AML samples.
Amino acid substitution Proof of hyperactivity domain reference
Q644H;V645F
Pseudokinase Xie et al., 2009
Table 4: Somatic mutations in JAK1 found in hepatocellular carcinomas.
Amino acid substitution Proof of hyperactivity domain reference
H647Y
Pseudokinase Jeong et al., 2008
Table 5: Somatic mutations in JAK1 found in breast cancer samples.
Amino acid substitution Proof of hyperactivity domain reference
P782M
Pseudokinase Jeong et al., 2008
Table 6: Somatic mutations in JAK1 found in non-small cell lung cancer samples.
JAK1 (Janus kinase 1) Knoops L, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 719
JAK1 mutations were found in 3 B-cell ALL samples
after the resequencing of 173 B-ALL (Flex et al., 2008)
and in 3 samples after the resequencing of 187 high risk
childhood B-ALL (Mullighan et al., 2009). No
mutations were found after the resequencing of 69 B-
ALL (Jeong et al., 2008).
JAK1 mutants induce the activation of different
cytokine-receptor complexes like the IL-9 receptor or
the IL-2 receptor, that will induce the constitutive
activation of the JAK-STAT pathway.
Acute myeloid leukemia (AML)
Oncogenesis
JAK1 mutaions were found in two AML samples after
the resequencing of 94 AML (Xiang et al., 2008) and in
one AML sample after the resequencing of 105 AML.
Hepatocellular carcinoma
Oncogenesis
JAK1 mutations were found in one hepatocellular
carcinoma sample after the screening of 84
hepatocellular carcinomas.
Breast cancer
Oncogenesis
JAK1 mutation was found in a breast cancer sample
after the resequencing of 90 breast cancers.
Non-small cell lung cancer
Oncogenesis
JAK1 mutation was found in a non-small cell lung
cancer sample after the resequencing of 47 non-small
cell lung cancer samples.
References Flex E, Petrangeli V, Stella L, Chiaretti S, Hornakova T, Knoops L, Ariola C, Fodale V, Clappier E, Paoloni F, Martinelli S, Fragale A, Sanchez M, Tavolaro S, Messina M, Cazzaniga G, Camera A, Pizzolo G, Tornesello A, Vignetti M, Battistini A, Cavé H, Gelb BD, Renauld JC, Biondi A, Constantinescu SN, Foà R, Tartaglia M. Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J Exp Med. 2008 Apr 14;205(4):751-8
Jeong EG, Kim MS, Nam HK, Min CK, Lee S, Chung YJ, Yoo NJ, Lee SH. Somatic mutations of JAK1 and JAK3 in acute leukemias and solid cancers. Clin Cancer Res. 2008 Jun 15;14(12):3716-21
Knoops L, Hornakova T, Royer Y, Constantinescu SN, Renauld JC. JAK kinases overexpression promotes in vitro cell transformation. Oncogene. 2008 Mar 6;27(11):1511-9
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This article should be referenced as such:
Knoops L, Hornakova T, Renauld JC. JAK1 (Janus kinase 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):717-719.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 720
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
PLAUR (plasminogen activator, urokinase receptor) Benedikte Jacobsen, Martin Illemann, Michael Ploug
Finsen Laboratory 3735, Rigshospitalet, Copenhagen Biocenter, 2200 Copenhagen N, Denmark (BJ, MI,
MP)
Published in Atlas Database: September 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/PLAURID41741ch19q13.html DOI: 10.4267/2042/44816
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: CD87; MO3; UPAR; URKR
HGNC (Hugo): PLAUR
Location: 19q13
DNA/RNA
Note
The gene for human urokinase-type plasminogen
activator receptor (uPAR) is located on chromosome
19q13 within a 2 Mb cluster harbouring all presently
known glycosylphosphatidylinositol (GPI)-anchored,
multi-domain proteins of the Ly6/uPAR/alpha-
neurotoxin (LU) domain family (Kjaergaard et al.,
2008).
Description
24254 bp; 7 exons (Figure 1).
Transcription
Transcription of the uPAR gene is regulated by a
TATA-less proximal promoter, partly through binding
to SP1 (Soravia et al., 1995).
Protein
Note
uPAR was originally identified on the monocyte-like
human cell line U937 as the membrane receptor for the
serine protease urokinase-type plasminogen activator
(uPA) (Vassalli et al., 1985). It has since been
implicated in a large number of
physiological and pathological conditions, including
cancer invasion and metastasis.
Description
uPAR is a multi-domain member of the
Ly6/uPAR/alpha-neurotoxin (LU) protein family
(Ploug, 2003), containing three of these LU domains
(DI, DII and DIII; Figure 2), each of ~ 90 amino acids,
adopting a "three-fingered" folding topology, and
encompassing 4 consensus disulfide bonds and an
invariant C-terminal asparagine (Figure 2B).
Intriguingly, one of the consensus disulfide bonds,
which is crucial to the proper folding of the single
domain LU proteins, is missing in the N-terminal LU
domain of uPAR. As evident from the crystal structures
solved for human uPAR, the three LU domains
cooperate in creating a deep and hydrophobic ligand-
binding cavity (Figure 2C), in which the growth factor-
like domain (GFD) of the cognate protease ligand uPA
(Huai et al., 2006; Barinka et al., 2006) or synthetic
peptide antagonists (Llinas et al., 2005) are buried
during formation of the corresponding high-affinity
receptor complexes.
The 335 amino acid residue long single polypeptide
chain of human uPAR is processed to a mature protein
of only 283 residues after post-translational excision of
signal peptides at the N- and C-termini, the latter event
being responsible for tethering uPAR to the cell
membrane via a GPI moiety (Figure 2A+C; Ploug et al
1991). Human uPAR contains 5 potential N-
glycosylation sites, of which only four are utilized
(Ploug et al., 1998; Gårdsvoll et al., 2004).
PLAUR (plasminogen activator, urokinase receptor) Jacobsen B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 721
Figure 1: Location of the uPAR gene in the uPAR-like gene cluster on chromosome 19q13. Each of the three LU domains of uPAR is encoded by separate exon sets, flanked by phase-1 introns (Casey et al., 1994). The introns dividing these 3 exon sets are also phase-1 and are located at a position corresponding to the surface-exposed tip of loop 2 in the three-finger fold of the LU domains (Ploug, 2003). The other known multi LU-domain members of this protein family, which are all present within this gene cluster, are: PRV1/CD177, TEX101, C4.4A, PRO4356 and GPQH2552.
Figure 2: Structure of the uPAR protein. Panel A - Schematic representation of the amino acid sequence of human uPAR showing its three homologous LU domains. Consensus disulfide bonds defining the LU domains are coloured black. The position of the C-terminal glycolipid anchor (GPI) is shown (modified from Ploug and Ellis, 1994, with permission). Insert: The archetypical three-finger fold is illustrated by a ribbon diagram for a single secreted LU-domain protein (snake venom toxin-a) using the PDB coordinates 1NEA and PyMOL
TM (DeLano Scientific).
PLAUR (plasminogen activator, urokinase receptor) Jacobsen B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 722
Panel B - LU domain signatures in the primary sequence of human uPAR. The three LU domains (DI, DII and DIII) of uPAR are aligned with the consensus structures being highlighted (disulfide bonds in yellow and the invariant asparagines in red). The number of residues between the individual cysteines is represented by dots or numbers in brackets (modified from Kjaergaard et al., 2008).
Panel C - The crystal structure solved for uPAR in complex with a peptide antagonist is shown as a ribbon diagram (Llinas et al., 2005). The individual LU domains are colour-coded (DI in yellow, DII in blue and DIII in red), and N-linked carbohydrates are shown as white sticks. The attachment to the cell surface by a glycolipid anchor is modelled in this cartoon. The insert shows uPAR in a surface representation, with the hydrophobic ligand-binding cavity marked with hatched lines; carbon, nitrogen and oxygen atoms are coloured white, blue and red, respectively. These structures are visualized by PyMOL
TM (DeLano Scientific), using the PDB coordinates 1YWH
(reproduced from Kjaergaard et al., 2008).
PLAUR (plasminogen activator, urokinase receptor) Jacobsen B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 723
Expression
Under normal homeostatic conditions, uPAR is
expressed by the following bone marrow-derived blood
cells: monocytes, neutrophils, eosinophils and
macrophages. In the bone marrow itself, uPAR has
been demonstrated in myelocytes, mature myeloid
elements and monocytes. Expression of the receptor is
significantly upregulated upon cytokine stimulation of
various monocyte-derived cell lines in vitro (Plesner et
al., 1994a). Consistent with these observations, uPAR
is classified as a differentiation antigen and is also
denoted CD87. The amount of uPAR in homeostatic
organs is in general low, and when present, usually
associated to quiescent endothelial cells, as
demonstrated in e.g. the lung, kidney, thymus, liver and
heart of normal mice (Solberg et al., 2001). Expression
of uPAR in kidney and thymus has also been
recapitulated in human samples (Wei et al., 2008;
Plesner et al., 1994a).
Whereas uPAR is scarce under normal conditions,
pronounced receptor expression has been observed in
various non-homeostatic tissue remodeling processes.
First, during wound healing, strong uPAR
immunoreactivity is found in migrating keratinocytes at
the leading re-epithelialization edge of the wound,
while non-migrating keratinocytes are negative (Rømer
et al., 1994). In addition, uPAR is located in infiltrating
granulocytes located underneath the wound crush, and
in endothelial cells in the wound area (Solberg et al.,
2001). In squamous cell carcinoma of the skin, uPAR
mRNA and protein is seen in well-differentiated cancer
cells at the invasive front of the tumour lesion (Rømer
et al., 2001; Ferrier et al., 2002).
In view of the localization of uPAR in the leading-edge
keratinocytes in regenerating epidermis during mouse
skin wound healing, it has been proposed that
similarities exist between the mechanisms of generation
and regulation of extracellular proteolysis during skin
re-epithelialization and squamous cell carcinoma
invasion (Rømer et al., 2001). As a second example of
tissue remodeling, late pregnancy in mouse shows
uPAR expression in spongiotrophoblasts and
endothelial cells in the placenta (Solberg et al., 2001).
In the human counterpart, uPAR was encountered in
endothelial cells and macrophages in association with
fibrinoid deposits, suggesting a participation of uPAR
in placental development and fibrin surveillance
(Pierleoni et al., 1998 and 2003). Third, uPAR is
present in the regression of mammary glands in post-
lactational involution in mice (Solberg et al., 2001).
These three processes mimic some of the
characteristics of cancer invasion and can accordingly
be used as model systems for the elucidation of the role
of uPAR in malignant transformation. Indeed, the
receptor is upregulated in several cancer types,
expression often being confined to stromal cells
associated with the
tumour, as detailed later for gastro-intestinal, breast and
squamous cell cancers (Figure 3). Other examples
conforming to this pattern include hepatocellular
carcinoma, where uPAR has been found in
macrophages and fibroblasts, as well as in a
subpopulation of rare CK7-positive tumoural
hepatocytes (Akahane et al., 1998; Dubuisson et al.,
2000). In invasive lesions of human prostate
adenocarcinoma, uPAR mRNA and protein is also
expressed by macrophages, located throughout the
interstitial tissue of tumours (Figure 3D), whereas in
benign lesions, it is confined to intraluminal
macrophages (Usher et al., 2005). A summary of uPAR
expression patterns in various cancer forms can be
found in Table below.
Cancer type Cancer
cells
Macrop
hages
Fibroblast-like
cells
Neutrop
hils
Endothelial
cells Nerves References
Breast + + + + Pyke et al., 1993; Nielsen et
al., 2007
Colon + + + + Pyke et al., 1994; Illemann et
al., 2009
Gastric + + + +
Migita et al., 1999; Zhang et
al., 2006; Alpízar-Alpízar et
al., 2009
Glioblastoma + + Yamamoto et al., 1994
Liver + + Dubuisson et al., 2000
Lung + + + Pappot et al., 1997; Morita et
al., 1998
Oral + + + + Lindberg et al., 2006
Prostate + + Usher et al., 2005
Skin + + Rømer et al., 2001; Ferrier et
al., 2002
PLAUR (plasminogen activator, urokinase receptor) Jacobsen B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 724
Figure 3: Expression of uPAR in cancer tissue. Peroxidase stainings with the same batch of a polyclonal antibody against uPAR produced at the Finsen Laboratory (Copenhagen, Denmark), showing reactivity in stromal cells associated with the tumour. Panel A - Primary colorectal adenocarcinoma (1) and a corresponding liver metastasis (2) (reproduced from Illemann et al., 2009). Panel B - Ductal carcinoma in situ lesion of the breast with microinvasion (1) and normal breast (2) (reproduced from Nielsen et al., 2007). Panel C - Gastric cancer, intestinal subtype (courtesy of W. Alpízar-Alpízar, Finsen Laboratory, Copenhagen, Denmark). Panel D - Prostate carcinoma (reproduced from Usher et al., 2005, Copyright (2004, Wiley-Liss, Inc.), with permission of John Wiley Sons, Inc.).
Localisation
The cell membrane attachment of uPAR via GPI
implicates a differential partitioning of the receptor into
detergent-resistant microdomain lipid rafts that are
enriched in cholesterol and sphingolipids. In complex
with uPA and the plasminogen activator inhibitor type
1, uPAR can also be internalized (Cubellis et al., 1990),
and later recycled back to the membrane (Nykjær et al.,
1997). Interestingly, upon stimulation of resting
neutrophils, uPAR is rapidly translocated from
secretory vesicles to the cell surface (Plesner et al.,
1994b). Proteolytic cleavage of the receptor either in
the linker region between DI and DII, e.g. by its own
ligand uPA (Høyer-Hansen et al., 1992), or between
domain III and the GPI-anchor, yield various soluble
uPAR fragments that are detectable in body fluids such
as plasma and urine, the levels of which have been
shown to correlate to overall survival in several human
cancers (Høyer-Hansen and Lund, 2007).
Function
Through its high-affinity interaction with the serine
protease urokinase-type plasminogen activator (uPA),
uPAR plays a central role in cell surface-associated
plasminogen activation, entailing proteolytic
degradation of the extracellular matrix surrounding the
cells (Ellis et al., 1989; Stephens et al., 1989). This
cascade, mediated by the broad-spectrum serine
protease plasmin, is involved in several tissue
remodeling processes such as wound healing and
mammary gland involution (Ploug,
2003; Danø et al., 2005). The proteolytic role of uPAR
in tumour invasion and metastasis is reflected by the
frequently encountered expression of uPAR at the
invasive front of cancer tissue, and by the impact of
uPAR status in malignant cells disseminated to the
bone marrow on the prognosis of gastric cancer patients
(Heiss et al., 2002).
Other ligands with which uPAR allegedly also interacts
include the matrix component vitronectin (Waltz and
Chapman, 1994; Wei et al., 1994; Gårdsvoll and Ploug,
2007; Huai et al., 2008), various integrins (Wei et al.,
1996; Aguirre Ghiso et al., 1999) and the G-protein
coupled receptor FPRL1 (Resnati et al., 1996),
affecting cell adhesion and migration, as well as signal
transduction (Figure 4; for reviews, see Ossowski and
Aguirre-Ghiso, 2000; Blasi and Carmeliet, 2002;
Kjøller, 2002; Kugler et al., 2003; Ragno, 2006; Tang
and Wei, 2008).
Homology
uPAR is homologous to the other multi-domain
proteins of the Ly6/uPAR/alpha-neurotoxin protein
domain family (C4.4A, PRV-1/CD177, TEX101,
PRO4356, GPQH2552), of which C4.4A is the best-
studied until now (Jacobsen and Ploug, 2008), and to a
vast number of single LU-domain proteins such as the
Ly-6 antigens, CD59, SLURP 1 and SLURP 2, the
extracellular ligand-binding domains of the TGF-
receptor family and the snake venom alpha-neurotoxins
(Ploug and Ellis, 1994; Ploug, 2003).
PLAUR (plasminogen activator, urokinase receptor) Jacobsen B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 725
Figure 4: uPAR ligands. Schematic representation of the functions of uPAR via its interaction with uPA, integrins, and vitronectin (modified from Kjaergaard et al., 2008).
Mutations
Note
An mRNA splice variant of uPAR, lacking exons 4 and
5, which encode domain II of the receptor, has recently
been shown to have prognostic relevance in breast
cancer (Kotzsch et al., 2008). Restriction fragment
length polymorphisms of the uPAR gene have been
identified by EcoRI and PstI (Børglum et al., 1991 and
1992), and a highly polymorphic CA/GT repeat is
present in intron 3 (Kohonen-Corish et al., 1996). In a
comparison of the latter in colon cancer patients and
controls, however, there were no significant differences
in the frequencies of alleles (Przybylowska et al., 2008;
Kohonen-Corish et al., 1998). Genetic linkage and
association analyses on 587 families with high
incidences of asthma have revealed a correlation
between asthma/lung function decline and certain SNP
in the uPAR gene (Barton et al., 2009).
Implicated in
Colon cancer
Note
The first study on uPAR expression was performed by
in situ hybridization on samples of human colon cancer
(Pyke et al., 1991), which revealed the presence of
uPAR mRNA both in stromal cells and some cancer
cells located at the invasive foci. Using
immunohistochemistry and antibodies raised against
recombinant human uPAR protein, this finding was
substantiated, and demonstrated that uPAR is expressed
primarily by macrophages, some a-smooth-muscle-
actin (a-SMA)-positive
myofibroblasts, a few endothelial cells located at the
front of the cancer, as well as by some so-called
budding cancer cells (Figure 3A1; Pyke et al., 1994;
Ohtani et al., 1995; Illemann et al., 2009). Interestingly,
these uPAR-positive budding cancer cells also produce
the 2-chain of laminin 5 (LN5.2), which has been
shown to correlate with poor prognosis in colon cancer,
in addition to being a marker of early invasion of cervix
cancers (Pyke et al., 1995; Lenander et al., 2001;
Skyldberg et al., 1999). Furthermore, by combining
immunohistochemistry and in situ hybridization, it
became clear that these uPAR- and LN5.2-positive
budding cancer cells produce uPA mRNA, thus linking
uPA and its receptor to cancer cells with high invasive
potential (Illemann et al., 2009). uPAR is also found in
neutrophils scattered throughout colon cancer tissue
and in nerve bundles located in muscularis propia
(Pyke et al., 1994; Illemann et al., 2009). In fact,
immunohistochemical staining in neutrophils represents
a valuable internal positive control, as uPAR is
synthesized in these cells during differentiation in the
bone marrow and is present in all circulating
neutrophils (Plesner et al., 1994a). In colon cancer liver
metastasis with encapsulation of the secondary tumour,
uPAR expression is in general very similar to that
found in the primary tumour (Figure 3A2; Illemann et
al., 2009).
Prognosis
The high expression of uPAR encountered in malignant
tissue can be furthered into its potential as a prognostic
marker in several cancer forms, including colon cancer.
Preoperative levels of soluble uPAR is an independent
predictor of survival in patients with colorectal cancer,
as observed in a study encompassing 591 patients
PLAUR (plasminogen activator, urokinase receptor) Jacobsen B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 726
(Stephens et al., 1999), with highest clinical utility in
early stage disease (Dukes' stage B).
Gastro-intestinal cancer
Note
In adenocarcinomas of the lower
esophagus/gastroesophageal junction, the pattern of
uPAR is reminiscent of that described in colon cancer
(Laerum et al., 2009), which is also the case for
adenocarcinomas of the lower stomach (Figure 3C;
Heiss et al., 1995; Migita et al., 1999; Alpízar-Alpízar
et al., 2009), i.e. expression by invasive cancer cells,
macrophages, a-SMA-positive myofibroblasts, and
some endothelial cells, as well as scattered neutrophils
and nerves bundles in the muscularis propia.
Interestingly, in these two cancer types, a much higher
number of invasive cancer cells are found to contain
uPAR as compared to colon cancer, which, in view of
the poorer prognosis of these patients, points to an
association of uPAR cancer cell expression with a
higher invasive potential (Alpízar-Alpízar et al., 2009).
In the lower esophagus and gastroesophageal junction,
uPAR expression is confined to invasive foci (Laerum
et al., 2009), whereas in the lower stomach, uPAR is
also present in benign lesions (Alpízar-Alpízar et al.,
2009). Cancer in the latter region is believed to be
caused by infection of Helicobacter pylori (Suzuki et
al., 2007). As non-neoplastic mucosa infected with H.
pylori has been shown to be positive for uPAR, in both
the epithelial cells and macrophages, the receptor
appears to be present in the tissue already at the onset
of tumourigenesis (Alpízar-Alpízar et al., 2009; Kenny
et al., 2008).
Prognosis
Importantly, in metastatic disease, uPAR positivity in
tumour cells that have disseminated to the bone marrow
is a strong negative prognostic indicator for disease-
free and overall survival in curatively resected gastric
cancer patients (Heiss et al., 2002).
Breast cancer
Note
In human ductal breast carcinomas, uPAR is primarily
expressed by tumour-associated macrophages and a-
SMA-positive myofibroblasts (Pyke et al., 1993;
Nielsen et al., 2007), whereas normal breast tissue is
devoid of reactivity (Figure 3B2). In some biopsies,
uPAR has in addition been found in invasive tumour
cells and a few endothelial cells. As for other solid
cancer forms, neutrophils also display uPAR
immunoreactivity in the breast. In early invasive ductal
carcinoma in situ (DCIS) lesions without
microinvasion, the receptor is confined to ductal
macrophages and few neoplastic cells within the
epithelial lesion. The advent of microinvasion is
accompanied by a strong uPAR signal in several layers
of tumour-associated macrophages and a-SMA-positive
myofibroblasts surrounding the DCIS lesions (Figure
3B1). These results indicate that restricted expression
of uPAR in myofibroblasts and macrophages is an early
event in breast carcinogenesis, which is strongly
amplified after transition to invasive ductal carcinoma.
Furthermore, uPAR and uPA co-localize in both
macrophages and myofibroblasts located at the front of
collapsed ducts in DCIS lesions with microinvasion
(Nielsen et al., 2007).
Prognosis
uPAR has shown potential as a prognostic marker in
breast cancer, with high levels of uPAR in cytosolic
extracts from primary breast tumours significantly
correlating with a shorter overall survival (Grøndahl-
Hansen et al., 1995). Similarly, there was a significant
association between age-adjusted levels of the receptor
in preoperative serum from breast cancer patients and
their relapse-free and overall survival, independent of
lymph node status, tumour size, and estrogen receptor
status (Riisbro et al., 2002).
Oral cancer
Note
In squamous cell carcinoma (SCC) of the oral cavity,
uPAR is strongly upregulated in areas with incipient
and invasive SCC compared to areas with dysplastic
and normal epithelium. The receptor is predominantly
observed in stromal cells, primarily macrophages, but
also in fibroblasts as well as neutrophils. uPAR-
positive neoplastic cells found in areas with incipient
and invasive SCC are also reported to express LN5.2
(Lindberg et al., 2006), which as mentioned above is a
marker for invasiveness.
Glioblastoma
Note
Presence of uPAR at the invasive edge of the cancer, as
seen in colon, breast and skin cancer, is recapitulated in
human glioblastomas, but with the notable difference
that the mRNA for uPAR in this particular case is
predominantly expressed by tumour cells, as well as in
some endothelial cells, indicating that uPAR is related
to tumour cell invasiveness and endothelial cell
migration (Yamamoto et al., 1994).
Lung cancer
Prognosis
The prognostic significance of uPAR in non-small cell
lung cancer is apparent for patients with the histologic
subtype of squamous cell carcinoma, where high levels
of uPAR is an independent marker of prognosis, as
evaluated in tumour extracts (Pedersen et al., 1994).
Measuring the levels of uPAR domain I alone in these
same extracts similarly predicted overall survival
(Almasi et al., 2005).
Ovarian cancer
Prognosis
Like in non-small cell lung cancer, uPAR domain I
present in high concentrations in preoperative plasma
PLAUR (plasminogen activator, urokinase receptor) Jacobsen B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 727
independently predicts poor survival of patients with
ovarian cancer. Furthermore, soluble full-length uPAR
+ the soluble fragment of uPAR domains II+III can,
together with CA125 in plasma collected
preoperatively, serve as a diagnostic tool,
discriminating between malignant and benign ovarian
tumours (Henic et al., 2008).
Prostate cancer
Prognosis
As described for breast, colon and lung cancer, uPAR
also correlates with shorter survival of patients with
prostate cancer, where serum levels of the receptor are
elevated as compared to healthy controls (Miyake et al.,
1999).
Haematological malignancies
Note
In line with its expression in normal hematopoietic
cells, uPAR is also observed in various hematopoietic
disorders, most importantly acute leukemia and
multiple myeloma, and its level could have diagnostic
and prognostic implications for these diseases (Béné et
al., 2004).
Paroxysmal nocturnal haemoglobinuria
Note
As a consequence of being a GPI-anchored protein,
membranous uPAR is absent from blood cells derived
from clonally expanded bone marrow cells affected by
point mutations causing the haematological disease
paroxysmal nocturnal haemoglobinuria, PNH (Ploug et
al., 1992).
Figure 5: Inhibition of the uPA-uPAR interaction. Two different peptide-based strategies for pharmacological inhibition of uPAR take advantage of either mimicking the binding of the GFD-portion of uPA (Panel A) or that of a peptide antagonist (Panel B), to the hydrophobic ligand-binding cavity in the receptor (made with PyMOL
TM (DeLano Scientific), using PDB coordinates 2FD6 and 1YWH, respectively) (reproduced from Jacobsen and Ploug, 2008, with
permission). Panel C - In vivo imaging showing uptake of the uPAR peptide antagonist AE105 coupled to
64Cu-DOTA in xenotransplanted uPAR-
positive human glioblastoma tumours (white arrow; reproduced from Li et al., 2008).
PLAUR (plasminogen activator, urokinase receptor) Jacobsen B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 728
Inflammatory conditions
Note
In inflammatory conditions such as Crohn's disease and
chronic ulcerative colitis, uPAR immunoreactivity is
seen in numerous macrophages, including granulomas
and granulocytes located throughout the whole
intestinal wall, as well as in nerve bundles (Laerum et
al., 2008), providing a possible link between uPAR and
inflammation.
To be noted
Note
As a result of the well-established correlation of uPAR
to tumour invasion and metastasis, several targeting
strategies with therapeutic potential have been devised
to interfere with the receptor (Mazar, 2008):
A series of small molecule antagonists of the uPA-
uPAR interaction have been identified by screening in
chemical libraries (Tyndall et al., 2008).
Synthetic peptide antagonists have also been
developed, either on the basis of the receptor-binding
region of human uPA (Figure 5A), or by combinatorial
chemistry of lead compounds selected by random
phage-display technology (Figure 5B) (Reuning et al.,
2003; Rømer et al., 2004; Jacobsen and Ploug, 2008).
The most potent of the latter group (the AE105 peptide)
has already shown its applicability in vivo. Conjugation
of modified versions of this peptide with the metal
chelator DOTA enabled its use in the non-invasive
molecular bioimaging of uPAR expression in
xenotransplanted human glioblastomas in nude mice by
PET scanning using the positron emitter 64
Cu (Figure
5C; Li et al., 2008). The biodistributions of 111
In- and 213
Bi-labelled peptide derivatives of AE105 were also
explored (Liu et al., 2009; Knör et al., 2008), the latter
with a view to subsequent studies on uPAR-targeted
radiotherapy.
Monoclonal antibodies are being developed aiming at
inhibiting the uPA-uPAR interaction and thereby
providing a means of cancer patient treatment (Bauer et
al., 2005; Jögi et al 2007; Pass et al., 2007).
Anti-tumour toxins targeting uPAR include engineered
anthrax toxins that rely on activation by receptor-bound
uPA to unleash their cytotoxicity (Liu et al., 2001), and
fusion proteins encompassing the uPAR-binding part of
uPA linked to e.g. diphtheria toxins (Rustamzadeh et
al., 2003).
In the field of gene therapy, downregulation of uPAR
gene expression has been done by anti-sense or siRNA
technology (Pillay et al., 2007).
New strategies are constantly unfolding regarding the
intervention of the uPA-uPAR interaction, as illustrated
by the recent reports of synthetic self-assembly
nanoparticles taken up by uPAR-expressing cells via
receptor-mediated endocytosis (Wang et al., 2009),
molecular imaging of pancreatic cancer using dual-
modality nanoparticles (Yang et al., 2009), and an
oncolytic measles virus retargeted against the receptor
with potent anti-tumour effect in a breast cancer
xenograft model (Jing et al., 2009).
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This article should be referenced as such:
Jacobsen B, Illemann M, Ploug M. PLAUR (plasminogen activator, urokinase receptor). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):720-731.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 732
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
SHC4 (SHC (Src homology 2 domain containing) family, member 4) Luigi Pasini, Luisa Lanfrancone
IEO, European Institute of Oncology, Department of Experimental Oncology, IFOM-IEO Campus, Via
Adamello 16, 20139 Milano, Italy (LP, LL)
Published in Atlas Database: September 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/SHC4ID44503ch15q21.html DOI: 10.4267/2042/44817
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: MGC34023; RaLP; SHCD; hShcD
HGNC (Hugo): SHC4
Location: 15q21.1
Note: The mammalian Src homology and collagen
(SHC) gene family comprises four distinct loci that
encode proteins sharing a unique structural
organization. SHC proteins function as
phosphotyrosine-binding docking molecule mediating
the signaling transduction of cell-membrane receptors,
including receptor tyrosine kinases (RTKs). SHC
proteins display mutually exclusive tissue localization.
SHC1 is ubiquitously expressed except than in the
nervous system, while SHC2 and SHC3 are specifically
found in the brain. SHC4 is the latest member being
identified and its expression is restricted to brain and
skeletal muscle
of adult mice, whereas in human it appears primarily
expressed in melanoma tissues and cell lines of
melanocytic origin.
DNA/RNA
Description
Human SHC4 locus spans 139,707 bases on
chromosome 15, starting at position 46,903,227 bp and
ending at position 47,042,933 from pter (according to
hg18-Mar-2006).
The same locus that codifies for SHC4 transcript also
produces the small and unrelated protein EP300
interacting inhibitor of differentiation 1 (EID1) that has
been found only in the mammalian genome.
Orthologs of SHC4 are present in other metazoan. The
corresponding mouse gene is located on chromosome
2F1.
Genomic position of the human SHC4 locus, situated on the long arm (q21.1-q21.2) of chromosome 15. The DNA sequence containing the SHC4 gene also codifies for the short unrelated transcript EID1.
SHC4 (SHC (Src homology 2 domain containing) family, member 4) Pasini L, Lanfrancone L
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 733
SHC4 shares the same genomic architecture and protein organization typical of the SHC family. Evolutionarily conserved phosphotyrosine sites in the collagen homology 1 (CH1) region are marked in blue. Green boxes identify exons; bent arrow highlights the first ATG codon.
Transcription
Both human and mouse SHC4 open reading frame
consist of twelve exons, producing nucleotide
sequences of 1893 nt and 1881 nt respectively that
encode for putative polypeptides of 630 amino acids in
human and 626 amino acids in mouse. No clear
evidence of alternative splicing isoforms of the main
mRNA transcript has been found so far.
Pseudogene
None identified.
Protein
Description
The amino-terminal positioning of the
phosphotyrosine-binding (PTB) domain and the
carbossi-terminal positioning of the Src homology 2
(SH2) domain is a hallmark of the SHC family. These
two domains are divided by the CH1 region, which
contains three highly conserved tyrosine residues. A
second collagen homology (CH2) region is present in
the longest isoforms of the Shc family members and in
SHC4. The human SHC4 protein consists of 630 amino
acids with a total estimated molecular weight of 69
kDa. Although no splicing isoform are known, it is
postulated that two other polypeptides may be
produced by the usage of alternate initiator codons,
corresponding to predicted products of 59 kDa and 49
kDa.
Expression
Human SHC4 shows a specific expression in advanced-
stage melanomas and in no other human normal and
tumoral adult tissues. SHC4 protein product is detected
in primary cultures and cell lines of metastatic
melanoma, while its expression decreases in non-
invasive melanoma cell lines and in primary
melanocytes. In adult mouse tissues
SHC4 is primarily detected in brain and skeletal
muscle.
Localisation
In humans, SHC4 protein is mostly localized in the
cytosol of melanocytes and melanoma cells and partly
to cell membranes. The murine SHC4 protein was
demonstrated to co-localize with muscle-specific
kinase (MuSK) at the postsynaptic neuromuscular
junction (NMJ).
Function
SHC4 is a substrate of several receptor tyrosine kinases
(RTK) and G protein-coupled receptors (GPCR). When
ectopically expressed in non-metastatic melanoma cell
lines SHC4 becomes phosphorylated upon growth
factor stimulation and associates with the growth factor
receptor-bound protein 2 (Grb2). Tyrosine-
phosphorylated SHC4 induces Ras GTPase and
mitogen activated protein kinase (MAPK) activation,
resulting in enhanced cell migration. Conversely,
silencing of SHC4 expression in metastatic melanoma
cells reduces migration without affecting MAPK
pathway, suggesting that SHC4 may participate in both
Ras - dependent and - independent pathways in human
melanoma. SHC4 appears to be important for the
regulation of postsynaptic signals of motoneurons
through association with MuSK and activation of
acetylcholine receptors (AChR), as indicated by
biochemical studies of the mouse protein.
Homology
Among all the human paralogous genes, SHC4 shares
an overall identity at protein level of 45%, 37% and
41% with SHC1, SHC2, and SHC3 respectively. The
highest conservation is detected in the PTB and SH2
regions. Human and murine SHC4 display 75%
sequence identity in both the PTB and SH2 domains.
SHC4 (SHC (Src homology 2 domain containing) family, member 4) Pasini L, Lanfrancone L
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 734
Phylogenetic relationship of SHC proteins based on the comparison of their aminoacidic sequences. SHC4 is most likely derived by gene duplication of the SHC1 locus.
Implicated in
Melanoma
Disease
Melanoma is an extremely aggressive cancer of the
skin and of the internal mucosa that is capable of
metastasizing in almost every site of the body. Patients
with an advanced-stage melanoma are at greater risk of
dying of their melanoma.
Prognosis
The more reliable prognostic parameters in melanoma
are the Breslow measurement and the Clark level. The
Breslow index measures the thickness of the
melanoma: the thinner the melanoma, the better the
prognosis. In general, melanomas less than 1 millimeter
(mm) in depth have a very small chance of spreading
and then invading. The Clark level describes how far a
melanoma has penetrated into the skin, using a scale of
I to V (with higher numbers indicating a deeper
melanoma). According to Clark's model, cutaneous
melanoma initially develops from an in situ growth to a
radial growth phase (RGP) and evolves into the vertical
growth phase (VGP), which is associated to an
increased risk of metastatization.
Oncogenesis
The RGP melanoma expands radially into the
epidermis and proceeds to the VGP phase invading the
dermis, before becoming metastatic. Analysis of a
cohort of human melanoma lesions at various stages of
the disease revealed that SHC4 expression is found in
around 50% of the VGP and metastatic melanomas and
not in nevi and RGP melanomas, thus suggesting a
putative role for SHC4 as a prognostic marker. When
SHC4 is ectopically overexpressed in RGP melanoma
cells it can stimulate migration in vitro, without
perturbing proliferation. Conversely, SHC4 silencing in
metastatic melanoma cell lines inhibits migration and
delays tumor formation in vivo, suggesting that SHC4
is important for the invasive potential of melanoma
cells.
References Fagiani E, Giardina G, Luzi L, Cesaroni M, Quarto M, Capra M, Germano G, Bono M, Capillo M, Pelicci P, Lanfrancone L. RaLP, a new member of the Src homology and collagen family, regulates cell migration and tumor growth of metastatic melanomas. Cancer Res. 2007 Apr 1;67(7):3064-73
Jones N, Hardy WR, Friese MB, Jorgensen C, Smith MJ, Woody NM, Burden SJ, Pawson T. Analysis of a Shc family adaptor protein, ShcD/Shc4, that associates with muscle-specific kinase. Mol Cell Biol. 2007 Jul;27(13):4759-73
Pasini L, Turco MY, Luzi L, Aladowicz E, Fagiani E, Lanfrancone L. Melanoma: targeting signaling pathways and RaLP. Expert Opin Ther Targets. 2009 Jan;13(1):93-104
This article should be referenced as such:
Pasini L, Lanfrancone L. SHC4 (SHC (Src homology 2 domain containing) family, member 4). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):732-734.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 735
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)) Francesca Orso, Daniela Taverna
Molecular Biotechnology Center (MBC) and Department of Oncological Sciences, University of Torino, Via
Nizza, 52, 10126 Torino, Italy (FO, DT); Center for Complex Systems in Molecular Biology and Medicine,
University of Torino, Via Acc Albertina, 13, 10023 Torino, Italy (FO, DT)
Published in Atlas Database: September 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/TFAP2AID42526ch6p24.html DOI: 10.4267/2042/44818
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: AP-2; AP-2alpha; AP2-alpha; AP2TF;
BOFS; FLJ51761; TFAP2
HGNC (Hugo): TFAP2A
Location: 6p24.3
DNA/RNA
Description
The gene encompasses 22.882 kb of DNA; 7 exons.
Transcription
mRNA, NM_001042425; NM_003220;
NM_001032280.
Figure 1 : TFAP2A human gene including promoter, 7 exons and 6 introns. Modified from Entrez Gene (Genomic DNA).
Figure 2 : Three main transcripts are shown. Exons: red and green. Red: protein-coding sequences; Green: 5' and 3' Untranslated (UTR) regions. Black lines: introns. Modified from Entrez Gene (Transcripts).
TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)) Orso F, Taverna D
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 736
Figure 3. Modified from Williams and Tjian, 1991.
Protein
Description
The main TFAP2A isoform consists of 437 amino acids
and has a molecular weight of 52 kDa. TFAP2A
proteins contain a unique, highly conserved helix-span-
helix dimerization motif at the C-terminal half of the
protein, a central basic region and a less conserved
proline- and glutamine-rich domain at the amino
terminus. The helix-span-helix motif and the basic
region mediate DNA binding and dimerization while
the proline- and glutamine-rich region is responsible
for transcriptional transactivation (see figure 3).
Expression
Ubiquitous. Abnormal expression is found in a variety
of human tumours.
Localisation
Located predominantly in the nucleus.
Function
The TFAP2A proteins are able to form hetero- as well
as homo-dimers and bind to GC-rich DNA sequences
within regulatory regions of their target genes,
mediating both activation and repression of gene
transcription. Functional TFAP2 binding sites, such as
5'-GCCN3GGC-3' or 5'-GCCN4GGC-3' or 5'-
GCCN3/4GGG-3' or 5'-CCCCAGGC-3' have been
identified and regulate genes involved in physiological
or pathological processes such as development, cell
growth, differentiation, apoptosis and tumorigenesis.
Examples of activated genes are CDKN1A, TGFA,
estrogen receptor, keratinocyte-specific genes, KIT,
ERBB2 and IGFBP5 while MCAM/MUC18, C/EBPA,
MYC and DCBLD2/ESDN/CLCP1 are repressed by
TFAP2A. TFAP2A protein expression is highly cell-
type specific, showing different spatial and temporal
expression during development and in various tissues.
The TFAP2A proteins are essential during
embryogenesis as demonstrated by mouse genetic
studies. Loss of TFAP2A impairs cranial closure and
leads to severe dismorphogenesis of different organs
and death at birth. Loss of TFAP2A activity in general
alters proliferation and induces premature
differentiation and/or apoptosis in various cell types as
demonstrated by in vivo and in vitro studies. Because
of their involvement in these fundamental cellular
processes TFAP2A proteins are essential for
maintaining cellular homeostasis. Deregulation of
TFAP2A protein
levels alter the cell functions in such a drastic way that
it can eventually lead to cancer formation and/or
progression. In fact, several studies have associated
aberrant TFAP2A activity with tumorigenesis (see
below).
Homology
With the other members of the TFAP2 family:
TFAP2B, TFAP2C, TFAP2D, TFAP2E.
Mutations
Note
Found in branchio-oculo-facial syndrome (BOFS).
A de novo 10529A-G transition in exon 4 of the
TFAP2A human gene was found in an 18-year-old man
with branchio-oculo-facial syndrome (BOFS), a rare
autosomal-dominant cleft palate-craniofacial disorder
with variable expressivity. The mutation leads to
arg255-to-gly (R255G) substitution in a highly
conserved residue in the basic region of the DNA-
binding domain, a change that replaces a charged polar
side chain with a nonpolar side chain with a predicted
conformational space change. Four additional BOFS
patients were found to have de novo missense
mutations in the highly conserved exons 4 and 5. No
mutations were found in more than 300 controls
(Milunsky et al., 2008).
A de novo deletion of 18 and insertion of 6 nucleotides,
resulting in LPGARR deletion and RI insertion
between amino acids 276 and 281, was found within
the basic DNA binding and dimerization domains of
TFAP2A in a 4-year-old girl with congenital
sensorineural deafness associated with inner ear
malformation. The girl also had pseudocleft lips, skin
defects, auricle abnormalities, and unilateral
multicystic dysplastic kidney, leading to the diagnosis
of branchio-oculo-facial (BOF) syndrome (Tekin et al.,
2009).
Implicated in
Various cancers
Note
TFAP2A has been implicated in various cancers, first
of all in melanoma and breast tumors. However several
evidences link deregulation of TFAP2A to prostate and
ovarian carcinomas as well as gliomas.
Melanoma
Note
Malignant melanoma follows the transformation
TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)) Orso F, Taverna D
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 737
and proliferation of melanocytes, normally present in
the basal cell layer of the epidermis. Tumor growth
consists of a horizontal or radial initial growth phase
(RGP) followed by a subsequent vertical growth phase
(VGP) corresponding to the infiltration of the dermis
and hypodermis (biphasic growth). Alternatively the
growth pattern can be only vertical (monophasic
growth). When the lesion enters the vertical growth
phase, the expression of adhesion molecules changes as
the tumor enters the dermis and acquires the capacity to
metastasize. Deregulated expression or activity of a
number of transcription factors and their downstream
target genes (including those involved in invasion and
motility) has been found and TFAP2A is one of them.
In fact, in cutaneous malignant melanoma, reduced
nuclear TFAP2A expression has been associated with
aggressive clinicopathological outcomes. Moreover
low TFAP2A levels predict shorter recurrence-free
survival. In melanoma cell lines, loss of TFAP2A
associates with enhanced invasion, metastasis
formation as well as angiogenesis as tested in mouse
models, due to events such as overexpression of the cell
adhesion molecule MCAM/MUC18, protease protease-
activated receptor 1 (F2R/PAR1), MMP2 as well as
downregulation of the tyrosine kinase receptor KIT. On
the other hand TFAP2A re-expression in melanoma
cells suppresses tumorigenicity and metastatic
potential.
Breast cancer
Note
TFAP2A nuclear or total expression is significantly
reduced in invasive carcinomas compared to benign
breast epithelium (BBE) or ductal carcinoma in situ
(DCIS) and associates with adverse clinicopathological
parameters suggesting a tumor suppressor function for
this transcription factor. However, there are reports
showing increased TFAP2A expression in breast
tumors. Discrepancies could be related to the low
specificity of the tools (mostly antibodies) used to
analyze TFAP2A expression. In fact, other TFAP2-
family members with biological or pathological
functions, could have been identified in those
experiments. One possible mechanism by which
TFAP2A could function as a tumor suppressor is by
inducing growth arrest and apoptosis via induction of
p21WAF1
expression, inhibition of MYC-related
transactivation and BCL2 expression. TFAP2A
expression in breast cancer has also been related to
high sensitiveness to chemotherapeutic drugs due to
massive induction of apoptosis in TFAP2A highly
expressing cells.
Prostate cancer
Note
TFAP2A expression is associated with luminal
differentiation of normal prostate tissues but its
expression is lost early when prostate adenocarcinomas
develop. Increase cell proliferation has been observed
in prostate tumors with low cytoplasmic TFAP2A
expression. In TFAP2A-negative prostate cancer cells,
TFAP2A expression inhibits tumorigenicity and leads
to deregulation of relevant genes such as VEGF.
Ovarian cancer
Note
Reduced cytoplasmic TFAP2A expression predicts
poor overall survival of epithelial ovarian tumors and in
ovarian cancer cells this transcription factor suppresses
cell proliferation and invasion parallel to decreased
phosphorylation of HER2, AKT and ERK pathways,
reduced pro-MMP2 levels and increased CDH1/ECAD
expression.
Gliomas
Note
High nuclear levels of TFAP2A associate with better
differentiation of human gliomas, absence of MMP2
and VEGF expression and offer some survival
advantage to the patients.
References Williams T, Tjian R. Characterization of a dimerization motif in AP-2 and its function in heterologous DNA-binding proteins. Science. 1991 Mar 1;251(4997):1067-71
Bosher JM, Williams T, Hurst HC. The developmentally regulated transcription factor AP-2 is involved in c-erbB-2 overexpression in human mammary carcinoma. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):744-7
Gaubatz S, Imhof A, Dosch R, Werner O, Mitchell P, Buettner R, Eilers M. Transcriptional activation by Myc is under negative control by the transcription factor AP-2. EMBO J. 1995 Apr 3;14(7):1508-19
Bosher JM, Totty NF, Hsuan JJ, Williams T, Hurst HC. A family of AP-2 proteins regulates c-erbB-2 expression in mammary carcinoma. Oncogene. 1996 Oct 17;13(8):1701-7
Schorle H, Meier P, Buchert M, Jaenisch R, Mitchell PJ. Transcription factor AP-2 essential for cranial closure and craniofacial development. Nature. 1996 May 16;381(6579):235-8
Wang D, Shin TH, Kudlow JE. Transcription factor AP-2 controls transcription of the human transforming growth factor-alpha gene. J Biol Chem. 1997 May 30;272(22):14244-50
Zeng YX, Somasundaram K, el-Deiry WS. AP2 inhibits cancer cell growth and activates p21WAF1/CIP1 expression. Nat Genet. 1997 Jan;15(1):78-82
Huang S, Jean D, Luca M, Tainsky MA, Bar-Eli M. Loss of AP-2 results in downregulation of c-KIT and enhancement of melanoma tumorigenicity and metastasis. EMBO J. 1998 Aug 3;17(15):4358-69
Karjalainen JM, Kellokoski JK, Eskelinen MJ, Alhava EM, Kosma VM. Downregulation of transcription factor AP-2 predicts poor survival in stage I cutaneous malignant melanoma. J Clin Oncol. 1998 Nov;16(11):3584-91
Gee JM, Robertson JF, Ellis IO, Nicholson RI, Hurst HC. Immunohistochemical analysis reveals a tumour suppressor-like role for the transcription factor AP-2 in invasive breast cancer. J Pathol. 1999 Dec;189(4):514-20
Hilger-Eversheim K, Moser M, Schorle H, Buettner R. Regulatory roles of AP-2 transcription factors in vertebrate
TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)) Orso F, Taverna D
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 738
development, apoptosis and cell-cycle control. Gene. 2000 Dec 30;260(1-2):1-12
Perissi V, Menini N, Cottone E, Capello D, Sacco M, Montaldo F, De Bortoli M. AP-2 transcription factors in the regulation of ERBB2 gene transcription by oestrogen. Oncogene. 2000 Jan 13;19(2):280-8
Pellikainen J, Kataja V, Ropponen K, Kellokoski J, Pietiläinen T, Böhm J, Eskelinen M, Kosma VM. Reduced nuclear expression of transcription factor AP-2 associates with aggressive breast cancer. Clin Cancer Res. 2002 Nov;8(11):3487-95
Nyormoi O, Bar-Eli M. Transcriptional regulation of metastasis-related genes in human melanoma. Clin Exp Metastasis. 2003;20(3):251-63
Eckert D, Buhl S, Weber S, Jäger R, Schorle H. The AP-2 family of transcription factors. Genome Biol. 2005;6(13):246
Wajapeyee N, Raut CG, Somasundaram K. Activator protein 2alpha status determines the chemosensitivity of cancer cells: implications in cancer chemotherapy. Cancer Res. 2005 Oct 1;65(19):8628-34
Wajapeyee N, Britto R, Ravishankar HM, Somasundaram K. Apoptosis induction by activator protein 2alpha involves transcriptional repression of Bcl-2. J Biol Chem. 2006 Jun 16;281(24):16207-19
Pellikainen JM, Kosma VM. Activator protein-2 in carcinogenesis with a special reference to breast cancer--a mini review. Int J Cancer. 2007 May 15;120(10):2061-7
Juriloff DM, Harris MJ. Mouse genetic models of cleft lip with or without cleft palate. Birth Defects Res A Clin Mol Teratol. 2008 Feb;82(2):63-77
Melnikova VO, Bar-Eli M. Transcriptional control of the melanoma malignant phenotype. Cancer Biol Ther. 2008 Jul;7(7):997-1003
Milunsky JM, Maher TA, Zhao G, Roberts AE, Stalker HJ, Zori RT, Burch MN, Clemens M, Mulliken JB, Smith R, Lin AE. TFAP2A mutations result in branchio-oculo-facial syndrome. Am J Hum Genet. 2008 May;82(5):1171-7
Orso F, Penna E, Cimino D, Astanina E, Maione F, Valdembri D, Giraudo E, Serini G, Sismondi P, De Bortoli M, Taverna D. AP-2alpha and AP-2gamma regulate tumor progression via specific genetic programs. FASEB J. 2008 Aug;22(8):2702-14
Tekin M, Sirmaci A, Yüksel-Konuk B, Fitoz S, Sennaroğlu L. A complex TFAP2A allele is associated with branchio-oculo-facial syndrome and inner ear malformation in a deaf child. Am J Med Genet A. 2009 Mar;149A(3):427-30
This article should be referenced as such:
Orso F, Taverna D. TFAP2A (transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):735-738.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 739
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
ATF4 (activating transcription factor 4 (tax-responsive enhancer element B67)) Kurosh Ameri, Adrian L Harris
Stanford University School of Medicine, Department of Surgery, Medical School Lab Surge Building 1201
Welch Road, Stanford, CA 94305, USA (KA); University of Oxford, Cancer Research UK, Weatherall
Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK (ALH)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/ATF4ID44413ch22q13.html DOI: 10.4267/2042/44819
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: CREB-2; CREB2; TAXREB67;
TXREB
HGNC (Hugo): ATF4
Location: 22q13.1
Note: ATF4 has a genomic size of 2122 bp.
The mouse ATFx has been classified as a member of
the ATF4 subgroup due to 55% identity to mATF4.
DNA/RNA
Note
ATF4 gene is transcribed at very high levels (according
to ACEview). Several stress conditions such as
hypoxia, anoxia, and glucose deprivation result in
endoplasmic reticulum stress (ER stress), initiating the
unfolded protein response pathway (UPR pathway) that
increases the synthesis (increased mRNA translation)
of ATF4.
Description
The mouse ATF4 mRNA contains two upstream
open reading frames, uORF1 and uORF2, and the
human ATF4 contains three open reading frames,
uORF1 (uO1), uORF2 (uO2), and uORF3 (uO3) that
are located 5' to the ATF4 coding sequence. These
uORFs are translated in non-stressed conditions, which
result in exclusion of ATF4 translation. In mouse,
uORF2, or in humans, uORF3 overlap ATF4 ORF in
an out of frame manner. After translation of uORF1,
sufficient eIF2-GTP makes it possible to reinitiate
translation from the uORF2 in mouse, and uORF3 in
human, and therefore ATF4 synthesis is minimized.
During ER stress, PERK phosphorylates eIF2alpha
resulting in a decrease of functional eIF2 complex.
Stress-induced p-elF2alpha leads to limited eIF2-GTP
and prolongs the duration for the scanning ribosome to
reinitiate following uORF1, 2, and 3. Consequently
ribosome scanning bypasses the mouse uORF2 or
human uORF3, and translation re-initiation occurs at
the ATF4 ORF (initiation at the ATF4 coding region is
increased). Therefore, translation of ATF4 is increased
in response to stress including hypoxia, anoxia,
nutrition deprivation, including amino acid limitation
and glucose deprivation.
ATF4 (activating transcription factor 4 (tax-responsive enhancer element B67)) Ameri K, Harris AL
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 740
Protein
Note
ATF4 protein consists of 351 amino acids and is 38,590
Da. The protein is structured into several
domains/motifs.
Description
ATF4 protein consists of 351 amino acids. The protein
is unstable and structured into several domains/motifs
that are essential for ATF4 homo/heterodimerization,
DNA binding, and the regulation of ATF4 at the
protein stability level. The organization of the motifs
modulating ATF4 protein stability is potentially
essential for the regulation of ATF4 stability in
response to stress, including hypoxic and anoxic insult.
ATF4 has an oxygen dependent degradation domain
(ODDD) motif which is recognized by the orthologs of
C. elegans Egl-9, designated as PH (prolyl
hydroxylase) domain containing enzymes (PHD) [also
called HIF Prolyl Hydroxylase, HPH], specifically
PHD3. The betaTrCP recognition motif is another
degradation motif, which when phosphorylated, is
recognized by betaTrCP and targeted for proteasomal
degradation.
Expression
ATF4 mRNA is transcribed ubiquitously, but protein
expression and level is increased in cells that are
exposed to various stress factors such as hypoxia,
anoxia, lack of nutrition, as well as during
development.
Localisation
ATF4 protein is targeted to the nucleus. Single point
mutations of basic amino acids within the basic region
of ATF4 identified the sequence KKLKK (amino acids
280 to 284) as important for nuclear targeting.
Function
ATF4 protein can function as a transcriptional
activator, as well as a repressor. It is also a protective
gene regulating the adaptation of cells to stress factors
such as anoxic insult, endoplasmic
reticulum stress and oxidative stress. ATF4 plays an
essential role in development, and is particularly
required for proper skeletal and eye development as
well as haematopoiesis. ATF4 is also involved in
proper function of memory. Furthermore, ATF4 is also
a major factor in nutrition sensing, and has also been
recently implicated in extreme hypoxia/anoxia
mediated metastasis.
Metabolism: ATF4 is a conserved regulator of
metabolism and carbohydrate homeostasis, and
provides a mechanistic link between nutrients, insulin
resistance, and diabetes, and has been described as a
major mediator of nutrition-sensing response pathway,
regulating the expression of asparagine synthetase
(ASNS). In addition to regulating the expression of
ASNS during lack of nutrition, ATF4 also regulates
several aspects of mammalian metabolism, such as fat
storage, energy expenditure, and glycemic control. The
TOR pathway regulates invertebrate and vertebrate
metabolism, and ATF4 mutant mice have reduced TOR
signaling, and consequently reduced expression of
genes important in the intracellular concentration of
amino acids. Therefore, lack of ATF4 results in
reduced concentration of amino acids, attributed to
reduced TOR input. Thus, there is a close relationship
between ATF4 function, the TOR pathway, and
metabolism. This function of ATF4 also explains why
type I collagen synthesis is specifically reduced in
primary osteoblast cultures lacking ATF4, which can
be rescued by adding nonessential amino acids to the
culture. Thus, ATF4 is required for efficient amino acid
import into osteoblasts.
Bone metabolism: ATF4 is being considered as a
global regulator of osteoblast biology and bone
metabolism and formation. ATF4 supports bone
formation through two mechanisms, which depend on
its phosphorylation by RSK2. ATF4 regulates
osteoblast-specific gene transcription and the synthesis
of type I collagen, the main component of the bone
ATF4 (activating transcription factor 4 (tax-responsive enhancer element B67)) Ameri K, Harris AL
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 741
extracellular matrix (ECM). ATF4 does this by
favoring amino acid import, and therefore is a critical
determinant of the synthesis of proteins in osteoblasts.
Type I collagen is the most abundant protein of the
bone ECM, and therefore, ATF4 is a major regulator of
bone formation and of bone ECM mineralization.
Consequently, ATF4-deficient mice are runted and
harbor low bone mass, reduced osteoblast activity,
decreased type I collagen synthesis, and inhibited
osteocalcin and bone sialoprotein gene transcription.
Skeletogenesis: ATF4 plays an important role in
assuring that osteoblasts fulfill their function. Rsk2-
deficient mice display decreased bone mass due to
impaired bone formation. ATF4 is more strongly
phosphorylated by Rsk2 than any other proposed
substrate. ATF4-deficient mice have revealed that this
transcription factor plays several crucial roles in
osteoblast differentiation and function. ATF4-deficient
mice display a delayed skeletal development and result
in a severe low-bone-mass phenotype caused by
decreased bone formation.
Osteoclast differentiation: ATF4 regulates osteoclast
differentiation and ultimately bone resorption through
its expression in osteoblasts. ATF4 binds to the
promoter of the receptor activator of nuclear factor-
KappaB ligand (RankL) gene, which encodes a factor
secreted by osteoblasts that promotes osteoclast
differentiation. Accordingly, ATF4-deficient mice have
decreased osteoclast numbers owing to reduced RankL
expression.
Fetal liver hematopoiesis: A knockout mutation of
ATF4 has demonstrated severe fetal anemia in mice.
ATF4-/-
Fetal livers are pale and hypoplastic, and the
number of hematopoietic progenitors of multiple
lineages is decreased more than 2 fold. Therefore,
ATF4 is essential for the normal, high-level
proliferation required for fetal-liver hematopoiesis.
Memory: ATF4 is a memory repressor that blocks the
new expression of genes needed for memories, which
appears to be a conserved mechanism. Decreasing the
activity of ATF4 in mice or ApCREB2 (the ortholog of
ATF4) in the sea slug Aplysia lowers the threshold for
long-lasting changes and memory.
Homology
Drosophila: Cryptocephal (CRC) gene.
C. elegans: According to WormBase, the C. elegans
homologue of the human ATF4 gene is atf-5
(T04C10.4). The binding site of C. elegans ATF-5 is
uncharacterized.
Mutations
Note
A frameshift mutation is present in one allele of the
ATF4 gene in F9 embryonal carcinoma stem cells. The
mutation gives rise to the fusion of a short 5' open
reading frame to the coding sequence of ATF4.
Overexpression of mutant ATF4 suppresses ras-
induced transformation.
Implicated in
Note
Implication of ATF4 in disease comes mainly from
transgenic and in vitro studies. Studies in transgenic
animals have indicated that ATF4 is required for
skeletal and eye development, cellular proliferation,
hematopoiesis, and neurological disorders, including
memory. ATF4 has also been observed in greater levels
in tumors than in normal tissue, suggesting that ATF4
signaling in hypoxic and anoxic areas of tumors might
regulate processes relevant to cancer progression.
Various cancers
Note
ATF4 is a major factor induced by tumor hypoxia and
anoxia, as well as lack of nutrition including low
glucose levels. The expression of ATF4 has been noted
to be greater in patient cancer compared to paired
normal tissue. ATF4 is important for cellular survival
under conditions of extreme hypoxia, including anoxia.
Recently it has been shown that antiangiogenic
treatment with avastin results in induction of ATF4 in
vivo.
ATF4 renders cells resistant to multiple anti-cancer
drugs and it has been implicated to be a multidrug
resistant gene in cancer, and is involved in metastasis,
by regulating the expression of the metastasis
associated gene LAMP3.
Oncogenesis
ATF4 is a major factor in regulating the expression of
asparagine synthetase (ASNS) during hypoxia and
nutritional deprivation (lack of amino acids and
glucose). ASNS is associated with drug resistance in
leukemia and oncogenesis triggered by mutated p53.
Skeletal abnormalities of neurofibromatosis
Note
There has been a link between increased Rsk2-
dependent phosphorylation of ATF4 and the
development of the skeletal abnormalities in human
patients suffering from neurofibromatosis. This disease
of tumor development in the nervous system, is caused
by inactivating mutations of the neurofibromatosis 1
(NF 1), which plays a major physiological role in bone
remodeling. The Nf1ob-/-
(NF knockout specifically in
osteoblasts) mice display a high bone mass phenotype.
NF1 induces an increased production of type I
collagen, attributed to Rsk2-dependent activation of
ATF4. Thus, transgenic mice overexpressing ATF4 in
osteoblasts display a phenotype similar to the Nf1ob-/-
mice.
ATF4 (activating transcription factor 4 (tax-responsive enhancer element B67)) Ameri K, Harris AL
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 742
Alzheimer's
Note
In human brains, ATF4 and phospho-eIF2alpha levels
are tightly correlated and up-regulated in Alzheimer
disease, most probably representing an adaptive
response against disease-related cellular stress rather
than a correlate of neurodegeneration.
Coffin-lowry syndrome
Note
Coffin-Lowry Syndrome (CLS) is an X-linked mental
retardation condition associated with skeletal
abnormalities. ATF4 has been identified as a critical
regulator of osteoblast differentiation and function, and
lack of ATF4 phosphorylation by RSK2 may contribute
to the skeletal phenotype of CLS.
Vascular disease
Note
ATF4 can be induced by both vascular injury and
fibroblast growth factor-2 (FGF-2) and can serves as a
conduit for the inducible expression of one growth
factor by another during the process of intimal
thickening.
Joubert syndrome
Note
The centrosomal protein, nephrocystin-6 (NPHP6), is
disrupted in Joubert syndrome. NPHP6 interacts
physically with and activates ATF4 as a signaling
component on the level of transcriptional regulation in
this disease group.
Microphthalmia
Note
Lack of ATF4 results in severe microphthalmia due to
complete aphakia (absence of the eye lens). The affects
of lack of ATF4 is attributed to p53 mediated apoptosis
of anterior lens epithelial cells.
References Bartsch D, Ghirardi M, Skehel PA, Karl KA, Herder SP, Chen M, Bailey CH, Kandel ER. Aplysia CREB2 represses long-term facilitation: relief of repression converts transient facilitation into long-term functional and structural change. Cell. 1995 Dec 15;83(6):979-92
Mielnicki LM, Hughes RG, Chevray PM, Pruitt SC. Mutated Atf4 suppresses c-Ha-ras oncogene transcript levels and cellular transformation in NIH3T3 fibroblasts. Biochem Biophys Res Commun. 1996 Nov 12;228(2):586-95
Cibelli G, Schoch S, Thiel G. Nuclear targeting of cAMP response element binding protein 2 (CREB2). Eur J Cell Biol. 1999 Sep;78(9):642-9
Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000 Nov;6(5):1099-108
Hettmann T, Barton K, Leiden JM. Microphthalmia due to p53-mediated apoptosis of anterior lens epithelial cells in mice
lacking the CREB-2 transcription factor. Dev Biol. 2000 Jun 1;222(1):110-23
Hewes RS, Schaefer AM, Taghert PH. The cryptocephal gene (ATF4) encodes multiple basic-leucine zipper proteins controlling molting and metamorphosis in Drosophila. Genetics. 2000 Aug;155(4):1711-23
Lassot I, Ségéral E, Berlioz-Torrent C, Durand H, Groussin L, Hai T, Benarous R, Margottin-Goguet F. ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase. Mol Cell Biol. 2001 Mar;21(6):2192-202
Masuoka HC, Townes TM. Targeted disruption of the activating transcription factor 4 gene results in severe fetal anemia in mice. Blood. 2002 Feb 1;99(3):736-45
Siu F, Bain PJ, LeBlanc-Chaffin R, Chen H, Kilberg MS. ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. J Biol Chem. 2002 Jul 5;277(27):24120-7
Chen A, Muzzio IA, Malleret G, Bartsch D, Verbitsky M, Pavlidis P, Yonan AL, Vronskaya S, Grody MB, Cepeda I, Gilliam TC, Kandel ER. Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins. Neuron. 2003 Aug 14;39(4):655-69
Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003 Mar;11(3):619-33
Ameri K, Lewis CE, Raida M, Sowter H, Hai T, Harris AL. Anoxic induction of ATF-4 through HIF-1-independent pathways of protein stabilization in human cancer cells. Blood. 2004 Mar 1;103(5):1876-82
Scian MJ, Stagliano KE, Deb D, Ellis MA, Carchman EH, Das A, Valerie K, Deb SP, Deb S. Tumor-derived p53 mutants induce oncogenesis by transactivating growth-promoting genes. Oncogene. 2004 May 27;23(25):4430-43
Vattem KM, Wek RC. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11269-74
Yang X, Matsuda K, Bialek P, Jacquot S, Masuoka HC, Schinke T, Li L, Brancorsini S, Sassone-Corsi P, Townes TM, Hanauer A, Karsenty G. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell. 2004 Apr 30;117(3):387-98
Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N, Harding H, Novoa I, Varia M, Raleigh J, Scheuner D, Kaufman RJ, Bell J, Ron D, Wouters BG, Koumenis C. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 2005 Oct 5;24(19):3470-81
Lassot I, Estrabaud E, Emiliani S, Benkirane M, Benarous R, Margottin-Goguet F. p300 modulates ATF4 stability and transcriptional activity independently of its acetyltransferase domain. J Biol Chem. 2005 Dec 16;280(50):41537-45
Elefteriou F, Benson MD, Sowa H, Starbuck M, Liu X, Ron D, Parada LF, Karsenty G. ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab. 2006 Dec;4(6):441-51
Sayer JA, Otto EA, O'Toole JF, Nurnberg G, Kennedy MA, Becker C, Hennies HC, Helou J, Attanasio M, Fausett BV, Utsch B, Khanna H, Liu Y, Drummond I, Kawakami I, Kusakabe T, Tsuda M, Ma L, Lee H, Larson RG, Allen SJ, Wilkinson CJ, Nigg EA, Shou C, Lillo C, Williams DS, Hoppe B, Kemper MJ, Neuhaus T, Parisi MA, Glass IA, Petry M, Kispert
ATF4 (activating transcription factor 4 (tax-responsive enhancer element B67)) Ameri K, Harris AL
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 743
A, Gloy J, Ganner A, Walz G, Zhu X, Goldman D, Nurnberg P, Swaroop A, Leroux MR, Hildebrandt F. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet. 2006 Jun;38(6):674-81
Igarashi T, Izumi H, Uchiumi T, Nishio K, Arao T, Tanabe M, Uramoto H, Sugio K, Yasumoto K, Sasaguri Y, Wang KY, Otsuji Y, Kohno K. Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines. Oncogene. 2007 Jul 19;26(33):4749-60
Köditz J, Nesper J, Wottawa M, Stiehl DP, Camenisch G, Franke C, Myllyharju J, Wenger RH, Katschinski DM. Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor. Blood. 2007 Nov 15;110(10):3610-7
Ameri K, Harris AL. Activating transcription factor 4. Int J Biochem Cell Biol. 2008;40(1):14-21
Deng ZL, Sharff KA, Tang N, Song WX, Luo J, Luo X, Chen J, Bennett E, Reid R, Manning D, Xue A, Montag AG, Luu HH, Haydon RC, He TC. Regulation of osteogenic differentiation during skeletal development. Front Biosci. 2008 Jan 1;13:2001-21
Malabanan KP, Kanellakis P, Bobik A, Khachigian LM. Activation transcription factor-4 induced by fibroblast growth factor-2 regulates vascular endothelial growth factor-A transcription in vascular smooth muscle cells and mediates
intimal thickening in rat arteries following balloon injury. Circ Res. 2008 Aug 15;103(4):378-87
Lewerenz J, Maher P. Basal levels of eIF2alpha phosphorylation determine cellular antioxidant status by regulating ATF4 and xCT expression. J Biol Chem. 2009 Jan 9;284(2):1106-15
Milani M, Rzymski T, Mellor HR, Pike L, Bottini A, Generali D, Harris AL. The role of ATF4 stabilization and autophagy in resistance of breast cancer cells treated with Bortezomib. Cancer Res. 2009 May 15;69(10):4415-23
Mujcic H, Rzymski T, Rouschop KM, Koritzinsky M, Milani M, Harris AL, Wouters BG. Hypoxic activation of the unfolded protein response (UPR) induces expression of the metastasis-associated gene LAMP3. Radiother Oncol. 2009 Sep;92(3):450-9
Seo J, Fortuno ES 3rd, Suh JM, Stenesen D, Tang W, Parks EJ, Adams CM, Townes T, Graff JM. Atf4 regulates obesity, glucose homeostasis, and energy expenditure. Diabetes. 2009 Nov;58(11):2565-73
This article should be referenced as such:
Ameri K, Harris AL. ATF4 (activating transcription factor 4 (tax-responsive enhancer element B67)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):739-743.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 744
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
CLU (clusterin) Hanna Rauhala, Tapio Visakorpi
Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland
(HR, TV)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/CLUID40107ch8p21.html DOI: 10.4267/2042/44820
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: AAG4; APOJ; Apo-J; CLI; KUB1;
MGC24903; NA1/NA2; SGP-2; SGP2; SP-40; TRPM-
2; TRPM2
HGNC (Hugo): CLU
Location: 8p21.1
DNA/RNA
Description
Clusterin gene is 17876 bp long and contains 10 exons
in total. First two exons are alternative (designated 1
and 1') used by two different transcript isoforms.
A) Clusterin gene genomic location at chromosome 8p21-p12 (minus strand) and annotated transcripts. B) Exons are numbered and presented by boxes. Shaded areas represent untranslated regions (UTR). Endoplastic reticulum (ER)-targeting signal in exon 2 and nuclear localization signal (NLS) in exon 3 are marked. Three in-frame translation start sites in exons 1, 2 and 3 are marked (ATG).
CLU (clusterin) Rauhala H, Visakorpi T
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 745
Other exons (2-9) are shared with both isoforms. CLU
gene resides in minus strand and is transcribed in
reverse orientation (from centromere to p-telomere).
Transcription
Clusterin gene is transcribed into 2 mRNA isoforms
(NM-001831, 2859 bp; and NM-203339, 2979 bp).
They result from the use of alternative first exons (1
and 1') and shared exons 2 to 9.
Protein
Description
Secreted clusterin is produced from the transcript
isoform 2. The initial protein precursor, presecretory
psCLU (~60 kDa), becomes heavily glycosylated and
cleaved in the ER, and the resulting alpha and beta
peptide chains are held together by 5 disulfide bonds in
the mature secreted heterodimer protein form, sCLU
(~75-80 kDa).
Also the nuclear clusterin is first translated as a non-
glycosylated protein precursor, pnCLU (~49 kDa), that
is then translocated into nucleus. There is evidence of
two distinct sized nuclear clusterin proteins (~50 kDa
and ~60 kDa, Pajak et al., 2007), that could results
from translation started either at ATG present in exon 3
or in exon 1, respectively.
Clusterin proteins have never been crystallized, so
the suggested protein structures are based on
computational modeling.
Expression
Ubiquitous expression in various tissue types.
Localisation
The different clusterin protein isoforms localize to
different cellular compartments. The nuclear clusterin
translocated to nucleus after translation and
glycosylation. The secreted clusterin is initially
targeted to ER, and the glycosylated protein is
eventually secreted. There is also evidence of stress-
caused retention of sCLU in the cytosol instead of
secretion (Nizard et al., 2007).
Function
The functions of clusterin in cells are not fully known.
The controversiality of clusterin functions mainly
results from the not well-established role of the two
different protein isoforms with distinct subcellular
localization and somewhat opposing functionalities.
Some known functions include involvement in
apoptosis through complexing with Ku70 autoantigen
(nCLU, proapoptotic) or interfering with Bax-
activation (sCLU, antiapoptotic) (Yang et al., 2000;
Leskov et al., 2003; Zhang et al., 2005; Zhang et al.,
2006).
Clusterin transcripts contain 3 different translation start sites (ATG), all in-frame. The best characterized protein isoform is produced from transcript isoform 2, where translation starts at the second ATG present in exon 2, right before ER-targeting signal. This protein (NP-976084) consists of 449 amino acids. The mechanism by which the protein products are translated from isoform 1 is not as well understood. There is evidence suggesting that two nuclear protein isoforms can be produced from this transcript isoform, one in which translation starts at ATG in exon 3 (417 aa), and another with translation starting from ATG in exon 1 (459 aa).
CLU (clusterin) Rauhala H, Visakorpi T
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 746
Clusterin has also been linked to spermatogenesis
(Roberts et al., 1991), lipid transport (Jenne et al.,
1991; Calero et al., 1994; Gelissen et al., 1998),
epithelial cell differentiation (French et al., 1993;
Schedin et al., 2000; Kim et al., 2007), TGF-beta
signaling through Smad2/Smad3 (Lee et al., 2008),
complement activation (Kirszbaum et al., 1992) and
tumorigenesis (see below).
Homology
Homolog to murine Clu (75%),
Homolog to rat Clu (77%),
Low level homology to human clusterin-like 1 (retinal)
(25%).
Mutations
Somatic
6316delT, an insertion (I)/deletion (D) polymorphism,
has been studied in Japanese population (Miwa et al.,
2005). D/D genotype was shown to associate with
significantly higher total cholesterol levels and low-
density lipoprotein (LDL) levels in hypertensive
females, and the D allele was an independent predictor
of plaque prevalence.
Several SNPs have also been found in CLU-gene, both
at coding regions and at UTRs and introns. See SNP
database at NCBI.
Implicated in
Prostate cancer
Note
Several studies have shown decreased clusterin levels
in prostate cancer (Bettuzzi et al., 2000; Scaltriti et al.,
2004; Rauhala et al., 2008). On the other hand, there
are also reports on increased expression of clusterin in
prostate cancer, specifically after androgen ablation
therapy (July et al., 2002). These opposing results have
been explained by the different isoforms of clusterin,
i.e. proapoptotic nCLU being decreased, while
antiapoptotic, pro-survival sCLU could be increased.
Antisense oligonucleotide (ASO) therapy against
clusterin is currently tested in clinical trials to evaluate
its efficacy in improving androgen deprivation therapy,
as well as to prevent chemoresistance (reviewed in
Gleave and Miyake, 2005; Sowery et al., 2008). Data
supporting the tumor suppressive role for clusterin
include reports on epigenetic regulation of clusterin
expression in prostate cancer cell lines (Rauhala et al.,
2008) and a recently developed TRAMP/cluKO mouse
clusterin knock-out model that develops more poorly
differentiated and metastatic tumors (Bettuzzi et al.,
2008).
Breast cancer
Note
Clusterin expression has been shown to increase in
breast cancer (Redondo et al., 2000; Kruger et al.,
2007). Similarly to prostate cancer, clusterin ASO
therapy is being tested also for breast cancer. Recent
results from phase II trial did not support show
significant increase in treatment response when
docetaxel was combined with anti-clusterin therapy
(Chia et al., 2009).
Ovarian cancer
Note
Cytoplasmic clusterin expression has been shown to
increase in ovarian cancer in stage-specific manner and
in response to chemotherapy as a cell-survival
promoter (Xie et al., 2007; Wei et al., 2009).
Colorectal cancer
Note
Increased cytoplasmic clusterin expression has also
been found in colorectal cancers (Xie et al., 2005), and
the increased clusterin levels were shown to associate
with poor prognosis of stage II colon cancers (Kevans
et al., 2009). Clusterin has also been suggested to be a
potential stool biomarker for colon cancer screening
(Pucci et al., 2009).
Pancreatic cancer
Note
In pancreatic cancer the reports of clusterin expression
are controversial, with both high and low expression
reported for cancers (Xie et al., 2002; Jhala et al.,
2006). Lack of clusterin expression was also suggested
as a potential discriminator factor for distinguishing
pancreatic adenocarcinomas from pancreatic patients
from fine-needle aspirations (Jhala et al., 2006). In
pancreatic cancers, clusterin expression was associated
with longer survival, supporting the idea of clusterin
down-regulation in tumor progression (Xie et al.,
2002).
Alzheimer's disease
Note
Increased clusterin levels are shown in Alzheimer's
disease, mostly in astrocytes. Clusterin can bind to
amyloid-beta peptides stabilizing them leading to their
clearance from the brain. Fibrillized amyloid deposits
can be masked by clusterin so that they are not
recognized by the host defense system, thus preventing
excessive inflammation reaction. Additional protection
of neural cells is achieved by inhibiting the
complement activation. Furthermore, clusterin can
CLU (clusterin) Rauhala H, Visakorpi T
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 747
function antiapoptotically through Bax-interference and
potentiate survival mediated through TGF-beta
signalling (reviewed in Nuutinen et al., 2009).
Nephrotic syndrome
Note
Clusterin expression is decreased in glomerular
diseases causing nephrotic syndrome, with
hypercholesterolemia appearing as the unifying feature
(Ghiggeri et al., 2002).
References Jenne DE, Lowin B, Peitsch MC, Böttcher A, Schmitz G, Tschopp J. Clusterin (complement lysis inhibitor) forms a high density lipoprotein complex with apolipoprotein A-I in human plasma. J Biol Chem. 1991 Jun 15;266(17):11030-6
Roberts KP, Awoniyi CA, Santulli R, Zirkin BR. Regulation of Sertoli cell transferrin and sulfated glycoprotein-2 messenger ribonucleic acid levels during the restoration of spermatogenesis in the adult hypophysectomized rat. Endocrinology. 1991 Dec;129(6):3417-23
Kirszbaum L, Bozas SE, Walker ID. SP-40,40, a protein involved in the control of the complement pathway, possesses a unique array of disulphide bridges. FEBS Lett. 1992 Feb 3;297(1-2):70-6
French LE, Chonn A, Ducrest D, Baumann B, Belin D, Wohlwend A, Kiss JZ, Sappino AP, Tschopp J, Schifferli JA. Murine clusterin: molecular cloning and mRNA localization of a gene associated with epithelial differentiation processes during embryogenesis. J Cell Biol. 1993 Sep;122(5):1119-30
Gelissen IC, Hochgrebe T, Wilson MR, Easterbrook-Smith SB, Jessup W, Dean RT, Brown AJ. Apolipoprotein J (clusterin) induces cholesterol export from macrophage-foam cells: a potential anti-atherogenic function? Biochem J. 1998 Apr 1;331 ( Pt 1):231-7
Calero M, Tokuda T, Rostagno A, Kumar A, Zlokovic B, Frangione B, Ghiso J. Functional and structural properties of lipid-associated apolipoprotein J (clusterin). Biochem J. 1999 Dec 1;344 Pt 2:375-83
Bettuzzi S, Davalli P, Astancolle S, Carani C, Madeo B, Tampieri A, Corti A. Tumor progression is accompanied by significant changes in the levels of expression of polyamine metabolism regulatory genes and clusterin (sulfated glycoprotein 2) in human prostate cancer specimens. Cancer Res. 2000 Jan 1;60(1):28-34
Redondo M, Villar E, Torres-Muñoz J, Tellez T, Morell M, Petito CK. Overexpression of clusterin in human breast carcinoma. Am J Pathol. 2000 Aug;157(2):393-9
Schedin P, Mitrenga T, Kaeck M. Estrous cycle regulation of mammary epithelial cell proliferation, differentiation, and death in the Sprague-Dawley rat: a model for investigating the role of estrous cycling in mammary carcinogenesis. J Mammary Gland Biol Neoplasia. 2000 Apr;5(2):211-25
Ghiggeri GM, Bruschi M, Candiano G, Rastaldi MP, Scolari F, Passerini P, Musante L, Pertica N, Caridi G, Ferrario F, Perfumo F, Ponticelli C. Depletion of clusterin in renal diseases causing nephrotic syndrome. Kidney Int. 2002 Dec;62(6):2184-94
July LV, Akbari M, Zellweger T, Jones EC, Goldenberg SL, Gleave ME. Clusterin expression is significantly enhanced in prostate cancer cells following androgen withdrawal therapy. Prostate. 2002 Feb 15;50(3):179-88
Xie MJ, Motoo Y, Su SB, Mouri H, Ohtsubo K, Matsubara F, Sawabu N. Expression of clusterin in human pancreatic cancer. Pancreas. 2002 Oct;25(3):234-8
Scaltriti M, Brausi M, Amorosi A, Caporali A, D'Arca D, Astancolle S, Corti A, Bettuzzi S. Clusterin (SGP-2, ApoJ) expression is downregulated in low- and high-grade human prostate cancer. Int J Cancer. 2004 Jan 1;108(1):23-30
Gleave M, Miyake H. Use of antisense oligonucleotides targeting the cytoprotective gene, clusterin, to enhance androgen- and chemo-sensitivity in prostate cancer. World J Urol. 2005 Feb;23(1):38-46
Miwa Y, Takiuchi S, Kamide K, Yoshii M, Horio T, Tanaka C, Banno M, Miyata T, Sasaguri T, Kawano Y. Insertion/deletion polymorphism in clusterin gene influences serum lipid levels and carotid intima-media thickness in hypertensive Japanese females. Biochem Biophys Res Commun. 2005 Jun 17;331(4):1587-93
Xie D, Lau SH, Sham JS, Wu QL, Fang Y, Liang LZ, Che LH, Zeng YX, Guan XY. Up-regulated expression of cytoplasmic clusterin in human ovarian carcinoma. Cancer. 2005 Jan 15;103(2):277-83
Xie D, Sham JS, Zeng WF, Che LH, Zhang M, Wu HX, Lin HL, Wen JM, Lau SH, Hu L, Guan XY. Oncogenic role of clusterin overexpression in multistage colorectal tumorigenesis and progression. World J Gastroenterol. 2005 Jun 7;11(21):3285-9
Jhala N, Jhala D, Vickers SM, Eltoum I, Batra SK, Manne U, Eloubeidi M, Jones JJ, Grizzle WE. Biomarkers in Diagnosis of pancreatic carcinoma in fine-needle aspirates. Am J Clin Pathol. 2006 Oct;126(4):572-9
Kim SY, Lee S, Min BH, Park IS. Functional association of the morphogenic factors with the clusterin for the pancreatic beta-cell differentiation. Diabetes Res Clin Pract. 2007 Sep;77 Suppl 1:S122-6
Krüger S, Ola V, Fischer D, Feller AC, Friedrich M. Prognostic significance of clusterin immunoreactivity in breast cancer. Neoplasma. 2007;54(1):46-50
Bettuzzi S, Davalli P, Davoli S, Rizzi F, Belloni L, Pellacani D, Astancolle S, Corti A.. The tumor-suppressor activity of Clusterin (CLU) is fully displayed in a novel transgenic model of prostate cancer: the TRAMP/CluKO mice model. 18th Meeting of the European Society for Urological Research (ESUR) 2008.
Lee KB, Jeon JH, Choi I, Kwon OY, Yu K, You KH. Clusterin, a novel modulator of TGF-beta signaling, is involved in Smad2/3 stability. Biochem Biophys Res Commun. 2008 Feb 22;366(4):905-9
Rauhala HE, Porkka KP, Saramäki OR, Tammela TL, Visakorpi T. Clusterin is epigenetically regulated in prostate cancer. Int J Cancer. 2008 Oct 1;123(7):1601-9
Sowery RD, Hadaschik BA, So AI, Zoubeidi A, Fazli L, Hurtado-Coll A, Gleave ME. Clusterin knockdown using the antisense oligonucleotide OGX-011 re-sensitizes docetaxel-refractory prostate cancer PC-3 cells to chemotherapy. BJU Int. 2008 Aug;102(3):389-97
Chia S, Dent S, Ellard S, Ellis PM, Vandenberg T, Gelmon K, Powers J, Walsh W, Seymour L, Eisenhauer EA. Phase II trial of OGX-011 in combination with docetaxel in metastatic breast cancer. Clin Cancer Res. 2009 Jan 15;15(2):708-13
Kevans D, Foley J, Tenniswood M, Sheahan K, Hyland J, O'Donoghue D, Mulcahy H, O'Sullivan J. High clusterin expression correlates with a poor outcome in stage II colorectal cancers. Cancer Epidemiol Biomarkers Prev. 2009 Feb;18(2):393-9
CLU (clusterin) Rauhala H, Visakorpi T
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 748
Nuutinen T, Suuronen T, Kauppinen A, Salminen A. Clusterin: a forgotten player in Alzheimer's disease. Brain Res Rev. 2009 Oct;61(2):89-104
Pucci S, Bonanno E, Sesti F, Mazzarelli P, Mauriello A, Ricci F, Zoccai GB, Rulli F, Galatà G, Spagnoli LG. Clusterin in stool: a new biomarker for colon cancer screening? Am J Gastroenterol. 2009 Nov;104(11):2807-15
Wei L, Xue T, Wang J, Chen B, Lei Y, Huang Y, Wang H, Xin X. Roles of clusterin in progression, chemoresistance and metastasis of human ovarian cancer. Int J Cancer. 2009 Aug 15;125(4):791-806
This article should be referenced as such:
Rauhala H, Visakorpi T. CLU (clusterin). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):744-748.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 749
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
ECM1 (Extracellular matrix protein 1) Joseph Merregaert, Wim Van Hul
Laboratory of Molecular Biotechnology, Department of Biomedical Sciences, University of Antwerp,
Universiteitsplein 1, 2610 Wilrijk/Antwerp, Belgium (JM, WVH)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/ECM1ID40398ch1q21.html DOI: 10.4267/2042/44821
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: p85 protein
HGNC (Hugo): ECM1
Location: 1q21.2
DNA/RNA
Description
The gene was initially described as having 10 exons.
Afterwards an alternative spliced exon 5a was detected.
Transcription
Four transcripts are described of which three transcripts
have been identified by Northern blot analysis and 1 by
PCR.
ECM1a (lacks exon 5a, 1.8 kb);
ECM1b (exon 5a and exon 7 are missing, 1.4 kb);
ECM1c (contains exon 5a, 1.85 kb);
ECM1d (splice variant in which 71 bp of the 3' end of
intron 1 are transcribed, resulting in a truncated 57 aa
protein, only dedected by PCR, DQ010946).
A. ECM1 DNA. B. ECM1 transcripts.
ECM1 (Extracellular matrix protein 1) Merregaert J, Van Hul W
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 750
Protein
Expression
ECM1a is widely expressed in liver, small testines,
lung, ovary, prostate, testis, skeletal muscle, pancreas,
kidney, placenta, heart, basal keratinocytes, dermal
blood vessels, and adnexal epithelia including hair
follicles and sweat glands.
ECM1b is dedectable in tonsils and the spinous and
granular layers of the epidermis.
ECM1c is expressed in the basal layer of the epidermis.
Important remark: ECM1 antibodies available to detect
ECM1 protein are not able to discriminate between
ECM1a and ECM1c.
ECM1d: expression pattern is not known yet.
Localisation
Ultrastructurally, ECM1a/c is a basement membrane
protein in human skin and is part of network-like
suprastructures containing perlecan, collagen type IV
and laminin 332 as constituents.
Function
The exact biological function of ECM1 is not
elucidated yet, but evidence for its involvement in
important biophysiological processes, like skin
differentiation, endochondral bone formation and
angiogenesis have now emerged. In the broader context
of skin biology, ECM1 appears to have many functions
and particular a 'biological super-glue' action has been
hypothesized.
Homology
A computationally predicted three-dimensional
structure of ECM1a is depicted below. Based on the
third serum albumin domain ECM1a protein can be
divided into four domains. The first domain containing
alpha-helices (alphaD1) and three serum albumin
subdomain-like domains (SASDL 2-4), each of three
sequences comparable with a complete subdomain of
the third serum albumin domain. AlphaD1 exits only of
Alpha-helices, whereas SASDL2 and -3 are capable of
binding most of the extracellular matrix proteins
identified so far (collagen type IV, laminin 332,
fibronectin, perlecan, fibulin 1C/D, fibulin-3 and MPP-
9).
Schematic representation of ECM1 and its four splice variants: ECM1 protein is divided in a signal sequence (19 aa) (black box) and four different domains based on the presence or absence of cysteines: an N-terminal cysteine-free domain (white box), two tandem repeats (green and gray box), and a C-terminal region (blue box). ECM1c differs from ECM1a containing 19 aa encoded by exon 5a, ECM1b results from an alternative trancript caused by splicing out exon 7(shaded black). ECM1d encodes a truncated protein composed of 57 aa containing exon 1, exon 2 and a part of exon 3.
Computationally predicted three-dimensional structure of ECM1a.
ECM1 (Extracellular matrix protein 1) Merregaert J, Van Hul W
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 751
Mutation in ECM1. The homozygous mutations in LiP patients are indicated with double arrows. Missense or nonsense mutations are indicated in red and frameshift mutations in black.
Mutations
Note
Mutations were described in lipoid proteinosis (LiP;
OMIN#247100), also known as hyalinosis cutis et
mucosae or Urbach-Wiethe disease. This is a rare,
autosomal recessive disorder characterized by
generalized thickening of skin, mucosae, and certain
viscera. Histologically, there is widespread deposition
of hyaline (glycoprotein) material and
disruption/reduplication of basement membrane.
Classic features include beaded eyelid papules and
laryngeal infiltration leading to hoarseness. More than
40 distinct missenses, nonsenses, splice sites, small and
large deletions and insertions have been reported.
Approximately 50% of the mutations cluster to exon 6
and 7 of the gene.
Implicated in
Lipoid proteinosis
Disease
Lipoid proteinosis, also known as hyalinosis cutis et
mucosae or Urbach-Wiethe disease.
Lipoid proteinosis is a rare autosomal recessive
genodermatosis characterized by the deposition of an
amorphous hyaline material in the skin, mucosa, and
viscera. Papular infiltration of the margin of the lids
producing 'itchy eyes', and infiltration in the tongue and
its frenulum, in the larynx leading to hoarseness, and in
the skin (e.g., elbows and axilla) are characteristic.
Lichen sclerosus et atrophicus
Disease
Lichen sclerosus (LS) is a chronic inflammatory skin
disorder of unknown aethiology that results in white
plaques with epidermal atrophy. It has both genital and
extragenital presentations. HLA-subtype susceptibility
and high rates of other autoimmune disorders suggest
that autoantibodies to specific mucocutaneous antigens
may be involved in the aetiology of lichen sclerosus.
The similarities with lipoid proteinosis, which results
from mutations in the ECM1 gene, suggested that this
protein may be an autoantigen in lichen sclerosus.
Indeed, circulating auto-antibodies to ECM1 were
found in the sera of 67% of lichen sclerosus patients.
In conclusion lipoid proteinosis and lichen sclerosus
are immunogenetic counterparts targeting ECM1.
Ulcerative colitis
Note
A nonsynonymous SNP (rs11205387) has been
associated with ulcerative colitis. ECM1 variation was
not associated with Crohn's disease.
Cancer
Note
A survey of ECM1 expression in different tumors
indicated that ECM1, although not tumor specific, is
significantly elevated in many malignant epithelial
tumors that gave rise to metastases. Together with the
observation that human recombinant ECM1 stimulates
proliferation of cultured endothelial cells and promotes
blood vessel formation in the chorioallantoic membrane
of chicken embryos suggest that ECM1 is a possible
trigger for angiogenesis, tumor progression and
malignancies.
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Smits P, Poumay Y, Karperien M, Tylzanowski P, Wauters J, Huylebroeck D, Ponec M, Merregaert J. Differentiation-dependent alternative splicing and expression of the extracellular matrix protein 1 gene in human keratinocytes. J Invest Dermatol. 2000 Apr;114(4):718-24
Han Z, Ni J, Smits P, Underhill CB, Xie B, Chen Y, Liu N, Tylzanowski P, Parmelee D, Feng P, Ding I, Gao F, Gentz R, Huylebroeck D, Merregaert J, Zhang L. Extracellular matrix protein 1 (ECM1) has angiogenic properties and is expressed by breast tumor cells. FASEB J. 2001 Apr;15(6):988-94
Hamada T, McLean WH, Ramsay M, Ashton GH, Nanda A, Jenkins T, Edelstein I, South AP, Bleck O, Wessagowit V,
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Mallipeddi R, Orchard GE, Wan H, Dopping-Hepenstal PJ, Mellerio JE, Whittock NV, Munro CS, van Steensel MA, Steijlen PM, Ni J, Zhang L, Hashimoto T, Eady RA, McGrath JA. Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1). Hum Mol Genet. 2002 Apr 1;11(7):833-40
Hamada T, Wessagowit V, South AP, Ashton GH, Chan I, Oyama N, Siriwattana A, Jewhasuchin P, Charuwichitratana S, Thappa DM, Jeevankumar B, Lenane P, Krafchik B, Kulthanan K, Shimizu H, Kaya TI, Erdal ME, Paradisi M, Paller AS, Seishima M, Hashimoto T, McGrath JA. Extracellular matrix protein 1 gene (ECM1) mutations in lipoid proteinosis and genotype-phenotype correlation. J Invest Dermatol. 2003 Mar;120(3):345-50
Mongiat M, Fu J, Oldershaw R, Greenhalgh R, Gown AM, Iozzo RV. Perlecan protein core interacts with extracellular matrix protein 1 (ECM1), a glycoprotein involved in bone formation and angiogenesis. J Biol Chem. 2003 May 9;278(19):17491-9
Oyama N, Chan I, Neill SM, Hamada T, South AP, Wessagowit V, Wojnarowska F, D'Cruz D, Hughes GJ, Black MM, McGrath JA. Autoantibodies to extracellular matrix protein 1 in lichen sclerosus. Lancet. 2003 Jul 12;362(9378):118-23
Wang L, Yu J, Ni J, Xu XM, Wang J, Ning H, Pei XF, Chen J, Yang S, Underhill CB, Liu L, Liekens J, Merregaert J, Zhang L. Extracellular matrix protein 1 (ECM1) is over-expressed in malignant epithelial tumors. Cancer Lett. 2003 Oct 8;200(1):57-67
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Horev L, Potikha T, Ayalon S, Molho-Pessach V, Ingber A, Gany MA, Edin BS, Glaser B, Zlotogorski A. A novel splice-site mutation in ECM-1 gene in a consanguineous family with lipoid proteinosis. Exp Dermatol. 2005 Dec;14(12):891-7
Kebebew E, Peng M, Reiff E, Duh QY, Clark OH, McMillan A. ECM1 and TMPRSS4 are diagnostic markers of malignant thyroid neoplasms and improve the accuracy of fine needle aspiration biopsy. Ann Surg. 2005 Sep;242(3):353-61; discussion 361-3
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Fisher SA, Tremelling M, Anderson CA, Gwilliam R, Bumpstead S, Prescott NJ, Nimmo ER, Massey D, Berzuini C, Johnson C, Barrett JC, Cummings FR, Drummond H, Lees CW, Onnie CM, Hanson CE, Blaszczyk K, Inouye M, Ewels P, Ravindrarajah R, Keniry A, Hunt S, Carter M, Watkins N, Ouwehand W, Lewis CM, Cardon L, Lobo A, Forbes A, Sanderson J, Jewell DP, Mansfield JC, Deloukas P, Mathew CG, Parkes M, Satsangi J. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat Genet. 2008 Jun;40(6):710-2
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Sercu S, Zhang M, Oyama N, Hansen U, Ghalbzouri AE, Jun G, Geentjens K, Zhang L, Merregaert JH. Interaction of extracellular matrix protein 1 with extracellular matrix components: ECM1 is a basement membrane protein of the skin. J Invest Dermatol. 2008 Jun;128(6):1397-408
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Sercu S, Lambeir AM, Steenackers E, El Ghalbzouri A, Geentjens K, Sasaki T, Oyama N, Merregaert J. ECM1 interacts with fibulin-3 and the beta 3 chain of laminin 332 through its serum albumin subdomain-like 2 domain. Matrix Biol. 2009 Apr;28(3):160-9
Sercu S, Oyama N, Merregaert J. Importance of extracellular matrix protein 1 (ECM1) in maintaining the functional integrity of the human skin. The Open Dermatology. 2009, 3, 44-51. (REVIEW)
This article should be referenced as such:
Merregaert J, Van Hul W. ECM1 (Extracellular matrix protein 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):749-752.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 753
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
ESRRG (estrogen-related receptor gamma) Rebecca B Riggins
Department of Oncology, Georgetown University, 3970 Reservoir Road NW, E407 Research Bldg,
Washington, DC 20057, USA (RBR)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/ESRRGID45840ch1q41.html DOI: 10.4267/2042/44822
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: ERR3; ERRG2; FLJ16023; KIAA0832;
NR3B3; DKFZp781L1617
HGNC (Hugo): ESRRG
Location: 1q41
DNA/RNA
Description
The ESRRG gene encompasses 587 kb of sequence on
the minus strand. ERRgamma transcript variant 1
contains 7 exons, while variants 2, 3, and 4 contain 6
exons.
Transcription
ERRgamma has 4 coding and 1 (presumed) non-coding
transcript variants. ERRgamma transcript variant 1
(NCBI, NM_001438) is the longest isoform, while
ERRgamma transcript variant 2 (NM_206594) utilizes
an alternate 5' UTR and lacks the first 23 amino acids
of the coding sequence of variant 1 (Heard et al., 2000).
In 2006, a third splice variant (ERRgamma3,
NM_206595) was identified (Kojo et al., 2006). This
isoform has 3 novel amino-terminal exons and lacks
Exon F, which contains the second zinc-finger binding
motif within the DNA binding domain of the receptor.
Consequently ERRgamma3 cannot stimulate
transcription from an estrogen response element (ERE)-
driven reporter construct, although it can modulate the
activity of other nuclear receptors, such as estrogen
receptors alpha and beta (ERalpha, ERbeta), thyroid
hormone receptor (TR), and glucocorticoid receptor
(GR) (Kojo et al., 2006). ERRgamma4
(NM_001134285), similar to variant 2, uses an
alternate 5' UTR and also encodes a shorter protein
isoform than variant 1. ERRgamma5 (NR_024099) is
transcribed but presumed to be non-coding.
Protein
Note
The domain structure of ERRgamma is typical for a
member of the nuclear receptor superfamily.
ERRgamma and its family members (ERRalpha and
ERRbeta) are most similar to the classical estrogen
receptors alpha and beta (ERalpha, ERbeta).
Description
AF1: Like most nuclear receptors, the activation
function -1 (AF1) domain of ERRgamma participates
in the regulation of transcription by the receptor. It is
the region to which several coactivators can bind (see
below), as well as the site of post-translational
modification.
Schematic of ERRgamma domain structure. aa = amino acid, and numbers correspond to the ERRgamma1 isoform; AF1 = activation function-1 ; DBD = DNA binding domain ; LBD = ligand binding domain; (%) denotes amino acid identity to estrogen receptor alpha (ERalpha).
ESRRG (estrogen-related receptor gamma) Riggins RB
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 754
Phosphorylation of the family member ERRalpha at
serine 19 has recently been shown to direct subsequent
SUMOylation at a nearby lysine (residue 14), and that
this series of post-translational modifications is in fact
inhibitory for receptor transcriptional activity (Vu et
al., 2007). While ERRgamma lacks a serine residue in
this position, in March of 2008 Tremblay et al.
confirmed ERRalpha phosphorylation at serine 19 and
reported that ERRgamma transcriptional activity can
also be inhibited by SUMOylation of lysine 40 that is
directed by phosphorylation of serine 45 (Tremblay et
al., 2008). The authors went on to identify protein
inhibitor of activated signal transducer and activator of
transcription gamma (PIAS4) as a functional E3 ligase
for the family member ERRalpha, and hypothesized
that PIAS4 and the SUMO-conjugating enzyme Ubc9
are responsible for the modification of ERRgamma as
well.
DBD: The greater than 60% identity between the DNA
binding domains (DBDs) of ERRgamma and ERalpha
(see figure) results in ERRgamma being able to bind
the estrogen response element (ERE:
AGGTCA...TGACCT). However, ERRgamma also
binds to what was originally identified as the consensus
sequence for steroidogenic factor 1 (SF1, SFRE:
TCAAGGTCA) (Horard and Vanacker, 2003).
LBD: A key difference between ERRgamma and most
members of the nuclear receptor superfamily is the
regulation of its transcriptional activity. There is only
about 23% sequence identity between classical
ERalpha and ERRgamma in the ligand binding domain
(LBD) (see figure). Therefore, while ERalpha (like
most nuclear receptors) is dependent upon ligand for
full activation, ERRgamma and the other members of
the ERR family exhibit constitutive transcriptional
activity. None of the ERR family members are affected
by estradiol (E2) stimulation because their LBDs
cannot accommodate E2 binding (discussed in Ariazi
and Jordan, 2006). However, ERRgamma
transcriptional activity at EREs and SFREs can be
inhibited by 4-hydroxytamoxifen (4HT) and the
synthetic estrogen diethylstilbestrol (Greschik et al.,
2002; Greschik et al., 2004; Yu and Forman, 2005). In
contrast, 4HT-bound ERRgamma acquires the ability to
positively regulate transcription at activator protein-1
(AP1) sites (Huppunen et al., 2004), but the mechanism
by which this occurs is not clear. ERRgamma
constitutive activity can be enhanced or stabilized by
the synthetic agonist GSK4716 (Yu and Forman, 2005;
Zuercher et al., 2005), the endocrine disruptor
Bisphenol A (BPA) (Matsushima et al., 2007;
Takayanagi et al., 2006), and a variant of this
compound (4-alpha-cumylphenol) (Matsushima et al.,
2008). ERRgamma constitutive activity has also
recently been shown to be inhibited by kaempferol, a
dietary flavonoid (Wang et al., 2009).
Coactivators/Corepressors: Like other nuclear
receptors, ERRgamma transcriptional activity is
modulated by binding to other proteins that can serve
as coactivators or corepressors. Coactivators and
corepressors bind directly to nuclear receptors, most
often within the carboxyl-terminal activation function-2
(AF2) domain that participates in ligand-binding but
some can exert their effects by binding to the amino-
terminal AF1 domain or the flexible hinge region of the
receptor (Hall and McDonnell, 2005). Among the
coactivators that have been demonstrated to bind and
activate ERRgamma are PPARGC1A (also known as
PGC-1alpha), TLE1, NCOA1, NCOA2 and, under
certain circumstances, NRIP1 (Gowda et al., 2006;
Sanyal et al., 2004). PPARGC1A is best known as a
coactivator for peroxisome proliferator-activated
receptor gamma, but it is also able to enhance
ERRgamma activity in an AF1-dependent manner
(Hentschke et al., 2002). TLE1 can also enhance
ERRgamma activity by binding to its AF1 domain, and
the coactivator function of TLE1 in this context is
unique because this protein typically functions as a
repressor for Drosophila and mammalian high mobility
group (HMG) box transcription factors. TLE1 also has
no known interactions with classical ERalpha or any
other nuclear receptor (Hentschke and Borgmeyer,
2003). In contrast, NCOA1 and NCOA2 are well-
known AF2-dependent coactivators of ERalpha and
other nuclear receptors, including ERRgamma
(reviewed in Hall and McDonnell, 2005).
Expression
In fetal and adult human tissues, ERRgamma1 and
ERRgamma2 are most highly expressed in the heart,
brain, kidney, and skeletal muscle (Heard et al., 2000),
while ERRgamma3 expression appears to be restricted
to the prostate and adipose tissue (Kojo et al., 2006).
Interestingly, in the mouse ERRgamma is also
expressed in these tissues but is even more abundant in
the brain stem and spinal cord
(http://www.nursa.org/10.1621/datasets.02001).
Localisation
Endogenous ERRgamma is localized to the nucleus in
human breast cancer (Park et al., 2005) and prostate
tissue (Yu et al., 2007), and transfected, exogenous
ERRgamma is also found in the nucleus of tissue
culture cells (Yasumoto et al., 2007).
Function
Molecular function: transcription factor activity, steroid
hormone receptor activity, steroid binding, protein
binding, zinc ion binding.
Biological processes: transcription, positive regulation
of transcription (DNA-dependent).
As a member of the nuclear receptor superfamily,
ERRgamma is a transcription factor. In the mouse,
homozygous knockout of ERR results in death on or
about postnatal day 1 caused by severe cardiac defects
(Alaynick et al., 2007). This is due to a key metabolic
defect whereby the animals are unable to switch from
deriving energy from carbohydrates in utero to lipids as
a neonate because ERRgamma controls the
ESRRG (estrogen-related receptor gamma) Riggins RB
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 755
transcription of essential genes that regulate oxidative
metabolic processes (Giguere, 2008).
Homology
ERRgamma is highly conserved among several species.
At the amino acid level, human ERRgamma is 100%
identical to rat, mouse, and cow ERRgamma, and
99.78% identical to dog and chimpanzee ERRgamma.
Mutations
Germinal
Two recent studies have identified single nucleotide
polymorphisms (SNPs) in ERRgamma. In a genome-
wide association study searching for genes linked to
Type 2 diabetes in an Amish population, Rampersaud
et al. identified the non-coding rs2818781, which is
present in an intron of ERRgamma2 and ERRgamma3
(Rampersaud et al., 2007). The T vs. C allele confers an
increased risk for Type 2 diabetes (O.R. 1.61, p=0.003),
and is also significantly associated with elevated
glucose area under the curve (GAUC), a measure of
impaired glucose tolerance collected during the oral
glucose tolerance test (OGTT).
Two different SNPs in ERRgamma have been linked to
breast cancer risk in a population of Thai women
(Sangrajrang et al., 2009). The non-coding rs1857407
is located in an intron of ERRgamma1, ERRgamma2,
and ERRgamma3, and heterozygotes for the G vs. A
allele have a reduced breast cancer risk (O.R. 0.72,
p=0.022). This risk reduction is even more pronounced
in post-menopausal women (O.R. 0.69, p=0.043). In
contrast, homozygote carriers of the CC (vs. TT) allele
of rs945453 have an elevated breast cancer risk (O.R.
1.66, p=0.034), though this shows no significant
association with pre- vs. post-menopausal status. This
SNP leads to a synonymous change (serine-to-serine) at
position 318 for ERRgamma1, and 295 for
ERRgamma2, ERRgamma3, and ERRgamma4.
Implicated in
Breast cancer
Note
In 2002 Ariazi et al. published a study of ERRgamma
family expression in 38 breast tumors as compared to
normal mammary epithelial cells (MECs) (Ariazi et al.,
2002). ERRgamma mRNA expression is nearly 4-fold
higher in these tumors than in the MECs and is
positively associated with ERalpha and progesterone
receptor (PR) expression. It was therefore concluded
that the correlation of ERRgamma with ERalpha and
PR in breast tumors suggests that ERRgamma
expression is an indicator of good prognosis in breast
cancer (Ariazi et al., 2002), given that women with
ER+/PR+ breast tumors are excellent candidates for
adjuvant endocrine therapy with aromatase inhibitors or
antiestrogens such as Tamoxifen (TAM).
However, TAM therapy is ineffective in approximately
30% of patients with ER+/PR+ breast tumors, and the
majority of women who initially respond to TAM but
go on to acquire resistance to this and other endocrine
agents do so without complete loss of ERalpha
expression (Clarke et al., 2001). Moreover, 4-
hydroxytamoxifen (4HT)-bound ERRgamma is known
to activate transcription at AP1 sites, and elevated AP1
activity has been linked to TAM resistance in multiple
in vitro (Dumont et al., 1996; Zhou et al., 2007) and in
vivo (Johnston et al., 1999; Schiff et al., 2000) studies.
In light of this, we were intrigued to find that that
endogenous expression of ERRgamma is upregulated
during the acquisition of TAM resistance by the
ER+/PR+ SUM44 breast cancer cell line (Riggins et
al., 2008). We subsequently demonstrated that
overexpression of ERRgamma confers Tamoxifen
(TAM) resistance to this and another ERalpha+ breast
cancer cell line, and that ERRgamma-driven AP1
activation plays a dominant role in the resistance
phenotype.
Ovarian cancer
Note
In a study of ovarian cancer specimens, normal ovaries,
and ovarian cancer cell lines, Sun et al. showed that
ERRgamma expression is significantly greater in
ovarian cancer relative to normal tissue (Sun et al.,
2005). However, patients whose tumors were positive
for ERRgamma had significantly improved disease-free
survival, and ERRgamma expression was not
correlated with serum levels of CA-125, a tumor
marker used to monitor ovarian cancer recurrence.
Endometrial cancer
Note
In 2006, Gao et al. reported that ERRgamma mRNA
expression was significantly higher in ERalpha-positive
endometrial carcinoma than normal endometrial
tissues, although patients with ERRgamma-positive
tumors had a reduced occurrence of lymph node
metastases (Gao et al., 2005).
Prostate cancer
Note
In cell culture models of prostate cancer, stable
overexpression of ERRgamma has been shown to
inhibit cell proliferation and survival in vitro and in in
vivo xenograft tumor models (Yu et al., 2007). This
occurs via cell cycle arrest at the G1/S phase transition,
which is induced by upregulation of the cell cycle
inhibitors p21 and p27. ERRgamma activates
transcription at both the p21 and p27 promoters, which
may suggest that ERRgamma has tumor suppressor
activities in prostate cancer.
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Kojo H, Tajima K, Fukagawa M, Isogai T, Nishimura S. A novel estrogen receptor-related protein gamma splice variant lacking a DNA binding domain exon modulates transcriptional activity of a moderate range of nuclear receptors. J Steroid Biochem Mol Biol. 2006 Mar;98(4-5):181-92
Takayanagi S, Tokunaga T, Liu X, Okada H, Matsushima A, Shimohigashi Y. Endocrine disruptor bisphenol A strongly binds to human estrogen-related receptor gamma (ERRgamma) with high constitutive activity. Toxicol Lett. 2006 Dec 1;167(2):95-105
Alaynick WA, Kondo RP, Xie W, He W, Dufour CR, Downes M, Jonker JW, Giles W, Naviaux RK, Giguère V, Evans RM. ERRgamma directs and maintains the transition to oxidative metabolism in the postnatal heart. Cell Metab. 2007 Jul;6(1):13-24
Matsushima A, Kakuta Y, Teramoto T, Koshiba T, Liu X, Okada H, Tokunaga T, Kawabata S, Kimura M, Shimohigashi Y. Structural evidence for endocrine disruptor bisphenol A binding to human nuclear receptor ERR gamma. J Biochem. 2007 Oct;142(4):517-24
Rampersaud E, Damcott CM, Fu M, Shen H, McArdle P, Shi X, Shelton J, Yin J, Chang YP, Ott SH, Zhang L, Zhao Y, Mitchell BD, O'Connell J, Shuldiner AR. Identification of novel candidate genes for type 2 diabetes from a genome-wide association scan in the Old Order Amish: evidence for replication from diabetes-related quantitative traits and from independent populations. Diabetes. 2007 Dec;56(12):3053-62
Vu EH, Kraus RJ, Mertz JE. Phosphorylation-dependent sumoylation of estrogen-related receptor alpha1. Biochemistry. 2007 Aug 28;46(34):9795-804
Yasumoto H, Meng L, Lin T, Zhu Q, Tsai RY. GNL3L inhibits activity of estrogen-related receptor gamma by competing for coactivator binding. J Cell Sci. 2007 Aug 1;120(Pt 15):2532-43
Yu S, Wang X, Ng CF, Chen S, Chan FL. ERRgamma suppresses cell proliferation and tumor growth of androgen-sensitive and androgen-insensitive prostate cancer cells and its implication as a therapeutic target for prostate cancer. Cancer Res. 2007 May 15;67(10):4904-14
ESRRG (estrogen-related receptor gamma) Riggins RB
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 757
Zhou Y, Yau C, Gray JW, Chew K, Dairkee SH, Moore DH, Eppenberger U, Eppenberger-Castori S, Benz CC. Enhanced NF kappa B and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer. BMC Cancer. 2007 Apr 3;7:59
Giguère V. Transcriptional control of energy homeostasis by the estrogen-related receptors. Endocr Rev. 2008 Oct;29(6):677-96
Matsushima A, Teramoto T, Okada H, Liu X, Tokunaga T, Kakuta Y, Shimohigashi Y. ERRgamma tethers strongly bisphenol A and 4-alpha-cumylphenol in an induced-fit manner. Biochem Biophys Res Commun. 2008 Aug 29;373(3):408-13
Riggins RB, Lan JP, Zhu Y, Klimach U, Zwart A, Cavalli LR, Haddad BR, Chen L, Gong T, Xuan J, Ethier SP, Clarke R. ERRgamma mediates tamoxifen resistance in novel models of invasive lobular breast cancer. Cancer Res. 2008 Nov 1;68(21):8908-17
Tremblay AM, Wilson BJ, Yang XJ, Giguère V. Phosphorylation-dependent sumoylation regulates estrogen-related receptor-alpha and -gamma transcriptional activity through a synergy control motif. Mol Endocrinol. 2008 Mar;22(3):570-84
Sangrajrang S, Sato Y, Sakamoto H, Ohnami S, Laird NM, Khuhaprema T, Brennan P, Boffetta P, Yoshida T. Genetic polymorphisms of estrogen metabolizing enzyme and breast cancer risk in Thai women. Int J Cancer. 2009 Aug 15;125(4):837-43
Wang J, Fang F, Huang Z, Wang Y, Wong C. Kaempferol is an estrogen-related receptor alpha and gamma inverse agonist. FEBS Lett. 2009 Feb 18;583(4):643-7
This article should be referenced as such:
Riggins RB. ESRRG (estrogen-related receptor gamma). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):753-757.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 758
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
GAS5 (growth arrest-specific 5 (non-protein coding)) Mirna Mourtada-Maarabouni
Institute for Science and Technology in Medicine, Huxley Building, Keele University, Keele, Staffordshire
ST5 5BG, UK (MMM)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/GAS5ID50217ch1q25.html DOI: 10.4267/2042/44823
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: NCRNA00030; SNHG2
HGNC (Hugo): GAS5
Location: 1q25.1
Note: GAS5 is also designed as small nucleolar RNA
host gene (non-protein coding) 2 and non-protein
coding RNA 30.
1q25 locus displays abnormalities in a number of
cancers, melanoma, prostate, breast and several types
of leukaemia and lymphoma. The GAS5 gene was
isolated from NIH 3T3 cells using subtraction
hybridisation, in a screen intended to isolate potential
tumor suppressor genes. The functions of GAS5 is not
well known as yet, however, emerging evidence
implicates this gene in apoptosis, autoimmune disease,
leukemias and lymphomas, and other cancers.
DNA/RNA
Description
The gene spans about 4.98 kb. Orientation minus
strand. Number of exons: 12. GenBank: AF141346.1.
GAS5 gene hosts multiple small
Representation of five of GAS5 splice variants. Boxes numbered 2 to12 represent exons. U79, U80, U47, U81 and U74 represent the box C/D small nucleolar RNAs (snoRNAs). Horizontal lines represent the intronic sequences. Exons, introns and snoRNAs are not drawn to scale (IMAGE clone 6194071, 1249 bp; IMAGE clone 2598129, 1270 bp; IMAGE clone 3585621, 1396 bp; Gas5 3A, 1802 bp; IMAGE clone 5739605, 1802 bp; IMAGE clone 2761825, 1802 bp).
GAS5 (growth arrest-specific 5 (non-protein coding)) Mourtada-Maarabouni M
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 759
nucleolar RNA (snoRNA) host gene similar to UHG
(U22 host gene) which encode, within the 11 introns of
the human GAS5 gene, ten box C/D snoRNAs
predicted to play a role in the 2'-O-methylation of
rRNA. Its 5' end sequence contains an oligopyrimidine
tract characteristic of the 5'-TOP class of genes.
Transcription
The length of GAS5 transcript is 651 bp (NR_002578
in GenBank). The 5' end sequence of the GAS5
transcript contains an oligopyrimidine tract
characteristic of the 5'-TOP class of genes. GAS5
transcripts display several patterns of alternate splicing.
The initial GAS5 transcript is subject to complex post-
transcriptional processing resulting in several splice
variants. However its putative open reading frame is
small and poorly conserved during even relatively short
periods of evolution, as demonstrated by a number of
disruptions caused by frameshift mutations in several
mouse strains, and by an interruption by a stop codon
after the first 13 amino acids in rat GAS5. The diagram
above shows some of GAS5 splice variants which are
reported to affect cell fate in different ways.
Protein
Note
GAS5 exons do not encode a polypeptide product.
Mutations
Note
Chromosomal rearrangements involving GAS5 have
been identified in a human B-cell lymphoma where
GAS5 gene becomes fused to the BCL6 gene. GAS5 is
also involved in a chromosomal rearrangement with
Notch1 in radiation-induced murine thymic lymphoma.
Implicated in
Regulation of cell growth
Note
The GAS5 gene was isolated from NIH 3T3 cells using
subtraction hybridisation, in a screen intended to isolate
potential tumor suppressor genes. GAS5 is reported to
be ubiquitously expressed during mouse development
and adult life, and also to be expressed only at low
levels in actively growing Friend leukemia and NIH
3T3 cells, with substantially increased abundance in
cells grown to saturation density. The RNA levels of
GAS5 appear to be regulated primarily through
changes in its rate of degradation rather than through
changes in its transcription rate. GAS5 RNA abundance
was also found to be increased by amino acid
deprivation. Studies also have shown that GAS5 is
necessary and sufficient for growth arrest in both
untransformed and leukaemic lymphocytes.
Systemic lupus erythematosus
Note
The GAS5 gene is located in the disease susceptibility
locus in mouse BXSB strain, which develops
glomerulonephritis associated with systemic lupus
erythematosus (SLE). Subsequent studies involving
genetic analysis of a mouse model of SLE have
indicated that GAS5 may well be involved in its
pathology. Besides, the human chromosomal locus
1q25 at which the GAS5 gene is encoded has been
associated with SLE in genetic studies in humans.
Apoptosis/cell cycle regulation
Note
A fragment of GAS5 cDNA has been isolated from a
retroviral cDNA expression library by using an
unbiased functional screen for genes that control
apoptosis in lymphocytes. Further studies have shown
that GAS5 plays an essential role in normal growth
arrest in both T-cell lines and non-transformed
lymphocytes. Overexpression of GAS5 causes both an
enhancement in apoptosis and a decrease in the rate of
progression through the cell cycle in leukeamic T cell
lines and primary lymphocytes. Consistent with this,
downregulation of endogenous GAS5 inhibits
apoptosis and maintains a more rapid cell cycle,
indicating that GAS5 expression is both essential and
sufficient for normal growth arrest in T-cell lines as
well as human peripheral blood T-cells.
Overexpression of certain GAS5 transcripts is reported
to induce growth arrest and apoptosis in several
mammalian cell lines.
Oncogenesis
Note
GAS5 is encoded at 1q25, a locus displaying
abnormalities in a number of cancers, e.g. melanoma,
prostate, breast, and several types of leukaemia and
lymphoma. Gene expression analysis has shown that
GAS5 is up-regulated 3.3-fold (the greatest up-
regulation for any gene in the whole-genome array) by
oncogenic kinases associated with myeloproliferative
disorders. Chromosomal rearrangements involving
GAS5 have also been identified in a human B-cell
lymphoma. GAS5 expression levels are reported to
regulate both the induction of apoptosis and cell cycle
arrest in T-cell lines and non-transformed lymphocytes,
suggesting that it may be very significant in the
development of leukaemia and lymphoma.
Overexpression of certain GAS5 transcripts is reported
to induce growth arrest and apoptosis in several human
cell lines, including human breast cancer cell lines.
GAS5 expression is significantly downregulated in
breast cancer tissue compared with those found in
untransformed breast epithelial tissue from the same
patients, a clear reduction of more than 65% was
GAS5 (growth arrest-specific 5 (non-protein coding)) Mourtada-Maarabouni M
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 760
observed in this study, suggesting that the reduction in
GAS5 expression is an early event in oncogenesis.
References Schneider C, King RM, Philipson L. Genes specifically expressed at growth arrest of mammalian cells. Cell. 1988 Sep 9;54(6):787-93
Coccia EM, Cicala C, Charlesworth A, Ciccarelli C, Rossi GB, Philipson L, Sorrentino V. Regulation and expression of a growth arrest-specific gene (gas5) during growth, differentiation, and development. Mol Cell Biol. 1992 Aug;12(8):3514-21
Vacha SJ, Bennett GD, Mackler SA, Koebbe MJ, Finnell RH. Identification of a growth arrest specific (gas 5) gene by differential display as a candidate gene for determining susceptibility to hyperthermia-induced exencephaly in mice. Dev Genet. 1997;21(3):212-22
Fleming JV, Hay SM, Harries DN, Rees WD. Effects of nutrient deprivation and differentiation on the expression of growth-arrest genes (gas and gadd) in F9 embryonal carcinoma cells. Biochem J. 1998 Feb 15;330 ( Pt 1):573-9
Muller AJ, Chatterjee S, Teresky A, Levine AJ. The gas5 gene is disrupted by a frameshift mutation within its longest open reading frame in several inbred mouse strains and maps to murine chromosome 1. Mamm Genome. 1998 Sep;9(9):773-4
Smith CM, Steitz JA. Classification of gas5 as a multi-small-nucleolar-RNA (snoRNA) host gene and a member of the 5'-terminal oligopyrimidine gene family reveals common features of snoRNA host genes. Mol Cell Biol. 1998 Dec;18(12):6897-909
Raho G, Barone V, Rossi D, Philipson L, Sorrentino V. The gas 5 gene shows four alternative splicing patterns without coding for a protein. Gene. 2000 Oct 3;256(1-2):13-7
Smedley D, Sidhar S, Birdsall S, Bennett D, Herlyn M, Cooper C, Shipley J. Characterization of chromosome 1 abnormalities in malignant melanomas. Genes Chromosomes Cancer. 2000 May;28(1):121-5
Fontanier-Razzaq N, Harries DN, Hay SM, Rees WD. Amino acid deficiency up-regulates specific mRNAs in murine embryonic cells. J Nutr. 2002 Aug;132(8):2137-42
Johanneson B, Lima G, von Salomé J, Alarcón-Segovia D, Alarcón-Riquelme ME. A major susceptibility locus for systemic lupus erythemathosus maps to chromosome 1q31. Am J Hum Genet. 2002 Nov;71(5):1060-71
Tsuji H, Ishii-Ohba H, Ukai H, Katsube T, Ogiu T. Radiation-induced deletions in the 5' end region of Notch1 lead to the formation of truncated proteins and are involved in the development of mouse thymic lymphomas. Carcinogenesis. 2003 Jul;24(7):1257-68
Tsao BP. Update on human systemic lupus erythematosus genetics. Curr Opin Rheumatol. 2004 Sep;16(5):513-21
Williams GT, Farzaneh F. The use of gene function to identify the rate-limiting steps controlling cell fate. Cancer Immunol Immunother. 2004 Mar;53(3):160-5
Haywood ME, Rose SJ, Horswell S, Lees MJ, Fu G, Walport MJ, Morley BJ. Overlapping BXSB congenic intervals, in combination with microarray gene expression, reveal novel lupus candidate genes. Genes Immun. 2006 Apr;7(3):250-63
Lelièvre H, Cervera N, Finetti P, Delhommeau F, Vainchenker W, Bertucci F, Birnbaum D. Oncogenic kinases of myeloproliferative disorders induce both protein synthesis and G1 activators. Leukemia. 2006 Oct;20(10):1885-8
Stange DE, Radlwimmer B, Schubert F, Traub F, Pich A, Toedt G, Mendrzyk F, Lehmann U, Eils R, Kreipe H, Lichter P. High-resolution genomic profiling reveals association of chromosomal aberrations on 1q and 16p with histologic and genetic subgroups of invasive breast cancer. Clin Cancer Res. 2006 Jan 15;12(2):345-52
Williams GT, Hughes JP, Stoneman V, Anderson CL, McCarthy NJ, Mourtada-Maarabouni M, Pickard M, Hedge VL, Trayner I, Farzaneh F. Isolation of genes controlling apoptosis through their effects on cell survival. Gene Ther Mol Biol. 2006 Dec 12;10(B):255-262
Mourtada-Maarabouni M, Hedge VL, Kirkham L, Farzaneh F, Williams GT. Growth arrest in human T-cells is controlled by the non-coding RNA growth-arrest-specific transcript 5 (GAS5). J Cell Sci. 2008 Apr 1;121(Pt 7):939-46
Nakamura Y, Takahashi N, Kakegawa E, Yoshida K, Ito Y, Kayano H, Niitsu N, Jinnai I, Bessho M. The GAS5 (growth arrest-specific transcript 5) gene fuses to BCL6 as a result of t(1;3)(q25;q27) in a patient with B-cell lymphoma. Cancer Genet Cytogenet. 2008 Apr 15;182(2):144-9
Mourtada-Maarabouni M, Pickard MR, Hedge VL, Farzaneh F, Williams GT. GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer. Oncogene. 2009 Jan 15;28(2):195-208
This article should be referenced as such:
Mourtada-Maarabouni M. GAS5 (growth arrest-specific 5 (non-protein coding)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):758-760.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 761
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
GBP1 (guanylate binding protein 1, interferon-inducible, 67kDa) Nathalie Britzen-Laurent, Michael Stürzl
Division of Molecular and Experimental Surgery, Department of Surgery, Friedrich-Alexander University,
Schwabachanlage 10, 91054 Erlangen, Germany (NBL, MS)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/GBP1ID50147ch1p22.html DOI: 10.4267/2042/44824
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: GBP-1; HuGBP-1
HGNC (Hugo): GBP1
Location: 1p22.2
Local order: Chromosome 1; starts at 89,290,575 bp
from pter and ends 89,303,631 bp from pter;
size= 13,056 base pairs;
orientation: minus strand (according to hg18-
Mar_2006).
The family of guanylate binding proteins (GBP)
consists of 7 members.
All seven genes are located in 1p22.2.
The human GBP1 gene is telomeric to GBP2 and
centromeric to GBP3.
A schematic representation of the domain structure and the three-dimensional structure of GBP-1. GBP-1 consists of a globular domain (residues 1 to 278), which contains the GTP binding and hydrolysis domains, and of a helical domain (residues 279 to 593) terminated by a polybasic sequence and an isoprenylation motif (CAAX). C= Cysteine, A= aliphatic acid, X= any amino-acid (here a serine, specifically recognized by a farnesyl-transferase).
GBP1 (guanylate binding protein 1, interferon-inducible, 67kDa) Britzen-Laurent N, Stürzl M
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 762
DNA/RNA
Description The GBP1 gene consists of 11 exons (ranging from 102
to 1164 bp) and 10 introns. The coding sequence starts
in the second exon.
Transcription Only one variant mRNA has been described for GBP-1
(Accession Number: NM_002053). This mRNA is
3050 bp long with a coding sequence of 1779 bp. Four
polymorphisms have been described for GBP-1:
c.232A>G (codon 78 Ile>Val), c.498G>C (codon 166
Glu>Asp), c.1046C>G (codon 349 Thr>Ser),
c.1226C>G (codon 409 Ala>Gly).
Pseudogene A pseudogene has been identified for GBP1
(LOC400759 alias FLJ17004) on chromosome 1
(1p22.2, chro 1: 89645826-89663081, according to
hg18-Mar_2006). Two pseudogenes have also been
described in the mouse (pseudomGbp1 and
pseudomGbp2).
Protein
Description GBP-1 belongs to the class of large GTPases that
contains, in addition to the GBPs, three further groups
of proteins, which share structural and biochemical
properties: the dynamins, the Mx proteins and the
atlastins. GBP-1 has a molecular weight of 67 kDa and
its crystal structure has revealed the presence of two
domains: (1) a N-terminal globular alpha/beta domain
harbouring the GTPase activity and (2) a long C-
terminal part organized in an index finger-like domain
composed exclusively of seven alpha-helices (alpha7 -
alpha13). The domains are connected by a short
intermediate region consisting of one alpha-helix and a
short two-stranded beta-sheet. In addition, GBP-1
harbours a C-terminal CAAX isoprenylation motif.
GTPases typically harbour three classical GTP-binding
domains: the phosphate-binding P-loop
GXXXXGK(S/T), the phosphate- and Mg2+
-binding
DXXG motif (G, glycine; K, lysine; S, serine; D,
aspartic acid; T, threonine; and X, any amino acid) and
the guanine nucleotide-specificity providing (N/T)KXD
motif (N, asparagine). In GBP-1 the classical
(N/T)KXD motif is substituted by a conserved
arginine-aspartic acid (RD)-motif (TLRD, with L,
leucine and R, arginine).
Expression GBP-1 was initially shown to be among the most
highly induced proteins in human fibroblasts exposed
to interferon (IFN)-gamma. Subsequently, it was
reported that in vitro hGBP-1 expression can be
induced by IFN-gamma in many different cell types
including endothelial cells, fibroblasts, keratinocytes,
B-cells, T-cells or peripheral blood mononuclear cells.
In vivo expression of hGBP-1 has been predominantly
detected in inflammatory tissues and has been found to
be associated almost exclusively with endothelial cells
and monocytes. It has been shown subsequently that
hGBP-1 expression in endothelial cells is also induced
by other pro-inflammatory cytokines such as IFNalpha,
TNFalpha and IL1alpha/IL1beta. Many other cytokines
(IL-4, IL-6, IL-10, IL-18), chemokines (MCP-1, PF4)
or growth factors (angiopoietin-2, PDGF B/B) tested
did not affect GBP-1 expression in these cells.
Interestingly, the two major angiogenic growth factors
(AGF: bFGF, VEGF) are able to inhibit the expression
of GBP-1 induced by inflammatory cytokines.
Localisation The localization of GBP-1 is primarily cytosolic and its
distribution is granular. Plasma membrane association
at the level of tight junctions has also been described.
In addition, GBP-1 has been shown to be secreted from
IFN-gamma-stimulated endothelial cells through a non-
classical secretion pathway.
Function GTPase activity.
GBP-1 can bind the three nucleotides GTP, GDP and
GMP with a relative low affinity (Kd mant-GMP=0,53 μM,
Kd mant-GDP=2,4 μM, Kdmant-GppNHp=1,1 μM). GBP-1 has
however the ability to hydrolyse GTP to both GDP and
GMP with a high hydrolysis rate (max 95 min-1
). At
physiological temperature GMP is the major product
(90%) of hGBP1. On the contrary to small GTPases
like Ras, GBP-1 does not require the presence of GEF
(GTP exchange factor) or GAP (GTPase activating
protein) proteins for its GTPase activity. In the case of
GBP-1, the GTP hydrolysis is self-stimulated by
oligomerization of the protein.
GBP-1 is involved in IFN-gamma response, either in
infection or in inflammation.
Homology The human GBP family comprises 7 highly
homologous members, all located on the chromosome
1. GBP-1 is to 77% similar to GBP-2, 88% to GBP-3,
56% to GBP-4, 68% to GBP-5, 54% to GBP-6 and
56% to GBP-7. Homologues have been found in
various species like zebrafish, chimpanzee (99%
homology), rat, dog or mouse. GBP-1 shares 59% of
homology with murine GBP-1 and murine GBP-2.
Mutations Note
No somatic or germline mutations have yet been
reported for human GBP-1.
Implicated in
Infection Note
GBP-1 exhibits antiviral activity against vesicular
stomatitis virus and encephalomyocarditis virus. The
GBP1 (guanylate binding protein 1, interferon-inducible, 67kDa) Britzen-Laurent N, Stürzl M
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 763
expression of GBP-1 is also elevated in the blood of
patients with a chronic active Epstein-Barr virus
infection. Furthermore GBP-1 and GBP-2 can
potentiate the inhibitory effects of IFN-gamma on
Chlamydia trachomatis growth. Finally, elevated
concentrations of GBP-1 have been detected in the
cerebrospinal fluid of patients with bacterial
meningitis.
Inflammation
Note
As GBP-1 is mainly expressed in endothelial cells in
vivo in a context of inflammation, its effects have been
extensively studied in these cells. It has been showed in
endothelial cells that GBP-1 mediates the effects of
inflammatory cytokines and inhibits proliferation,
spreading, migration or invasion. GBP-1 is also
involved in the regulation of apoptosis and senescence
in endothelial cells stimulated with IFN-alpha.
Evidence for an implication in cancer has been found
for GBP-1 (see below).
Colorectal carcinomas
Note
GBP-1 protein is strongly expressed in the stroma of
about one third of colorectal carcinomas in association
with an IFN-gamma dominated Th-1-like angiostatic
immune response.
Prognosis
This expression correlates with an increased cancer-
related 5-year survival.
References Cheng YS, Colonno RJ, Yin FH. Interferon induction of fibroblast proteins with guanylate binding activity. J Biol Chem. 1983 Jun 25;258(12):7746-50
Cheng YS, Becker-Manley MF, Chow TP, Horan DC. Affinity purification of an interferon-induced human guanylate-binding protein and its characterization. J Biol Chem. 1985 Dec 15;260(29):15834-9
Schwemmle M, Staeheli P. The interferon-induced 67-kDa guanylate-binding protein (hGBP1) is a GTPase that converts GTP to GMP. J Biol Chem. 1994 Apr 15;269(15):11299-305
Nantais DE, Schwemmle M, Stickney JT, Vestal DJ, Buss JE. Prenylation of an interferon-gamma-induced GTP-binding protein: the human guanylate binding protein, huGBP1. J Leukoc Biol. 1996 Sep;60(3):423-31
Anderson SL, Carton JM, Lou J, Xing L, Rubin BY. Interferon-induced guanylate binding protein-1 (GBP-1) mediates an antiviral effect against vesicular stomatitis virus and encephalomyocarditis virus. Virology. 1999 Mar 30;256(1):8-14
Praefcke GJ, Geyer M, Schwemmle M, Robert Kalbitzer H, Herrmann C. Nucleotide-binding characteristics of human guanylate-binding protein 1 (hGBP1) and identification of the third GTP-binding motif. J Mol Biol. 1999 Sep 17;292(2):321-32
Prakash B, Praefcke GJ, Renault L, Wittinghofer A, Herrmann C. Structure of human guanylate-binding protein 1 representing a unique class of GTP-binding proteins. Nature. 2000 Feb 3;403(6769):567-71
Prakash B, Renault L, Praefcke GJ, Herrmann C, Wittinghofer A. Triphosphate structure of guanylate-binding protein 1 and implications for nucleotide binding and GTPase mechanism. EMBO J. 2000 Sep 1;19(17):4555-64
Guenzi E, Töpolt K, Cornali E, Lubeseder-Martellato C, Jörg A, Matzen K, Zietz C, Kremmer E, Nappi F, Schwemmle M, Hohenadl C, Barillari G, Tschachler E, Monini P, Ensoli B, Stürzl M. The helical domain of GBP-1 mediates the inhibition of endothelial cell proliferation by inflammatory cytokines. EMBO J. 2001 Oct 15;20(20):5568-77
Lubeseder-Martellato C, Guenzi E, Jörg A, Töpolt K, Naschberger E, Kremmer E, Zietz C, Tschachler E, Hutzler P, Schwemmle M, Matzen K, Grimm T, Ensoli B, Stürzl M. Guanylate-binding protein-1 expression is selectively induced by inflammatory cytokines and is an activation marker of endothelial cells during inflammatory diseases. Am J Pathol. 2002 Nov;161(5):1749-59
Guenzi E, Töpolt K, Lubeseder-Martellato C, Jörg A, Naschberger E, Benelli R, Albini A, Stürzl M. The guanylate binding protein-1 GTPase controls the invasive and angiogenic capability of endothelial cells through inhibition of MMP-1 expression. EMBO J. 2003 Aug 1;22(15):3772-82
Naschberger E, Werner T, Vicente AB, Guenzi E, Töpolt K, Leubert R, Lubeseder-Martellato C, Nelson PJ, Stürzl M. Nuclear factor-kappaB motif and interferon-alpha-stimulated response element co-operate in the activation of guanylate-binding protein-1 expression by inflammatory cytokines in endothelial cells. Biochem J. 2004 Apr 15;379(Pt 2):409-20
Praefcke GJ, Kloep S, Benscheid U, Lilie H, Prakash B, Herrmann C. Identification of residues in the human guanylate-binding protein 1 critical for nucleotide binding and cooperative GTP hydrolysis. J Mol Biol. 2004 Nov 12;344(1):257-69
Modiano N, Lu YE, Cresswell P. Golgi targeting of human guanylate-binding protein-1 requires nucleotide binding, isoprenylation, and an IFN-gamma-inducible cofactor. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8680-5
Vestal DJ. The guanylate-binding proteins (GBPs): proinflammatory cytokine-induced members of the dynamin superfamily with unique GTPase activity. J Interferon Cytokine Res. 2005 Aug;25(8):435-43
Ghosh A, Praefcke GJ, Renault L, Wittinghofer A, Herrmann C. How guanylate-binding proteins achieve assembly-stimulated processive cleavage of GTP to GMP. Nature. 2006 Mar 2;440(7080):101-4
Naschberger E, Lubeseder-Martellato C, Meyer N, Gessner R, Kremmer E, Gessner A, Stürzl M. Human guanylate binding protein-1 is a secreted GTPase present in increased concentrations in the cerebrospinal fluid of patients with bacterial meningitis. Am J Pathol. 2006 Sep;169(3):1088-99
Olszewski MA, Gray J, Vestal DJ. In silico genomic analysis of the human and murine guanylate-binding protein (GBP) gene clusters. J Interferon Cytokine Res. 2006 May;26(5):328-52
Pammer J, Reinisch C, Birner P, Pogoda K, Sturzl M, Tschachler E. Interferon-alpha prevents apoptosis of endothelial cells after short-term exposure but induces replicative senescence after continuous stimulation. Lab Invest. 2006 Oct;86(10):997-1007
Degrandi D, Konermann C, Beuter-Gunia C, Kresse A, Würthner J, Kurig S, Beer S, Pfeffer K. Extensive characterization of IFN-induced GTPases mGBP1 to mGBP10 involved in host defense. J Immunol. 2007 Dec 1;179(11):7729-40
Tripal P, Bauer M, Naschberger E, Mörtinger T, Hohenadl C, Cornali E, Thurau M, Stürzl M. Unique features of different
GBP1 (guanylate binding protein 1, interferon-inducible, 67kDa) Britzen-Laurent N, Stürzl M
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 764
members of the human guanylate-binding protein family. J Interferon Cytokine Res. 2007 Jan;27(1):44-52
Ito Y, Shibata-Watanabe Y, Ushijima Y, Kawada J, Nishiyama Y, Kojima S, Kimura H. Oligonucleotide microarray analysis of gene expression profiles followed by real-time reverse-transcriptase polymerase chain reaction assay in chronic active Epstein-Barr virus infection. J Infect Dis. 2008 Mar 1;197(5):663-6
Naschberger E, Croner RS, Merkel S, Dimmler A, Tripal P, Amann KU, Kremmer E, Brueckl WM, Papadopoulos T,
Hohenadl C, Hohenberger W, Stürzl M. Angiostatic immune reaction in colorectal carcinoma: Impact on survival and perspectives for antiangiogenic therapy. Int J Cancer. 2008 Nov 1;123(9):2120-9
Weinländer K, Naschberger E, Lehmann MH, Tripal P, Paster W, Stockinger H, Hohenadl C, Stürzl M. Guanylate binding
protein-1 inhibits spreading and migration of endothelial cells through induction of integrin alpha4 expression. FASEB J. 2008 Dec;22(12):4168-78
Schnoor M, Betanzos A, Weber DA, Parkos CA. Guanylate-binding protein-1 is expressed at tight junctions of intestinal epithelial cells in response to interferon-gamma and regulates barrier function through effects on apoptosis. Mucosal Immunol. 2009 Jan;2(1):33-42
Tietzel I, El-Haibi C, Carabeo RA. Human guanylate binding proteins potentiate the anti-chlamydia effects of interferon-gamma. PLoS One. 2009 Aug 4;4(8):e6499
This article should be referenced as such:
Britzen-Laurent N, Stürzl M. GBP1 (guanylate binding protein 1, interferon-inducible, 67kDa). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):761-764.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 765
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
GPNMB (glycoprotein (transmembrane) nmb) Shyam A Patel, Philip K Lim, Pranela Rameshwar
University of Medicine and Dentistry of New Jersey - New Jersey Medical School,Newark, New Jersey,
USA (SAP, PKL, PR)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/GPNMBID40739ch7p15.html DOI: 10.4267/2042/44825
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: HGFIN; NMB; osteoactivin
HGNC (Hugo): GPNMB
Location: 7p15.3
DNA/RNA
Description
The GPNMB gene maps (Homo sapiens) on the plus
strand of chromosome 7p15 between 23,252,841 and
23,281,254 bp from the promoter and spans 28,414 bp.
Transcription
2 transcript variants:
Variant 1:
- 2775bp, accession #: NM_001005340.1
- the longer transcript
- encodes the longer isoform (isoform a)
- open reading frame from bp 162 to 1880
- 11 exons.
Variant 2:
- accession #: NM_002510.2
- undergoes alternative splicing and uses an in-frame
splice site
- conserved N- and C-terminals compared to isoform a,
but decreased in length.
Protein
Note
The GPNMB gene, which is the human homolog of
murine osteoactivin, encodes a type I transmembrane
glycoprotein. It has homology to the melanocyte
specific protein precursor pMEL17. GPNMB
expression is inversely correlated with
aggressiveness of melanoma cell lines. GPNMB is
thought to be inversely correlated with metastatic
potential, although limited data is available.
Description
Two protein isoforms exist: isoform a: 572 aa; isoform
b: 560 aa.
Expression
GPNMB is expressed in osteoclasts, dendritic cells,
macrophages, and breast epithelia. Its expression is
nearly undetectable in monocytes but increases upon
conversion of monocytes to macrophages.
Localisation
GPNMB localizes to the plasma membrane, as it is a
type I transmembrane glycoprotein. It is also found in
melanosomes and membrane-bound vesicles in the
cytoplasm.
Function
GPNMB is involved in binding to heparin sulfate and
integrins. It functions in mineralization of bone and
differentiation of osteoblasts. It also functions in
cellular adhesion. It is thought to reduce inflammation
involving macrophages.
Homology
Homo sapiens GPNMB shares sequence homology
with mouse and rat sequences. GPNMB shares
structural homology with neurokinin 1 (NK1) and can
interact with the NK ligand substance P.
Implicated in
Breast cancer
Note
It is unclear to date whether GPNMB plays a tumor
GPNMB (glycoprotein (transmembrane) nmb) Patel SA, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 766
suppressive role or oncogenic role in breast cancer.
Disease
In a murine model, osteoactivin (OA) has been
associated with enhanced invasiveness of breast cancer
cells in vivo, and forced overexpression of OA in
weakly bone metastatic cells lines resulted in increased
migratory and invasive characteristics in vitro (Rose et
al., 2007). Furthermore, analysis of 51 breast cancer
cell lines revealed higher osteoactivin expression than
normal breast MCF-12A cells and in estrogen receptor
negative breast tumors (Rose and Siegel, 2007).
However, other studies with non-tumorigenic human
breast cancer cells have shown that there was increased
migration and evidence of transformation and loss of
contact dependency in the absence of GPNMB/HGFIN
(Metz et al., 2007).
Glioblastoma multiforme (GBM)
Note
In immunocompromised mice, glioma cells expressing
osteoactivin and osteonectin (two strucurally bone-
related genes) developed a highly invasive phenotype
and invaded the brain along blood vessels when
implanted intracranially (Rich et al., 2003).
Disease
Evaluation of 50 GBM patient tumor samples revealed
that 35 out of 50 samples (70%) were positive for
GPNMB wild-type and splice variant transcripts while
the remaining 30% were positive for wild-type only
(Kuan et al., 2006). This is in contrast to normal brain
samples that expressed little or no GPNMB mRNA
(Kuan et al., 2006).
Prognosis
Detection of GPNMB mRNA and surface membrane
protein in glioma cells may potentially be used as a
tumor-associated antigen for targeting by therapeutic
treatment (Kuan et al., 2006).
Melanoma
Note
Analysis of a cDNA library between lowly and highly
metastatic human melanoma showed the preferential
expresion of GPNMB in low-metastatic cell lines
(Weterman et al., 1995). Additionally, transfection of
partial GPNMB cDNA into highly-metastatic
melanoma cell line resulted in slower subcutaneous
tumor growth in nude mice (Weterman et al., 1995).
Disease
A potential therapeutic agent in the treatment of
malignant melanomas is an antibody-drug conjugate
tartgeting GPNMB (Pollack et al., 2007). Intravenous
administration of the immunoconjugate in athymic
mice with human melanoma xenografts showed
inhibition of tumor growth and complete regression of
the tumor (Pollack et al., 2007).
End-stage kidney disease
Note
Macrophages involved in uremia have elevated levels
of GPNMB expression. Its role in end-stage kidney
disease may relate to its role in soft tissue calcification
and arteriosclerosis (Pahl et al., 2009).
Acute liver injury
Note
In normal rat livers, OA was found to be expressed in
high levels in Kupffer cells and peritoneal macrophages
(Haralanova-Ilieva et al., 2005). Upon induction of
acute liver injury after carbon tetrachloride
administration, OA expression was upregulated after 2
days and returned to normal levels after 7 days
(Haralanova-Ilieva et al., 2005). In normal human liver,
OA RNA was not detected while fulminant hepatitis B
and C infections, paracetamol intoxication, and liver
cirrhosis all resulted in positive OA RNA levels
(Haralanova-Ilieva et al., 2005).
Osteopetrosis
Note
OA cDNA was found to be overexpressed 3- to 4-fold
in rats with osteopetrotic bones when compared to
normal rat long bones (Safadi et al., 2001).
Furthermore, OA mRNA was primarily localized in
cuboidal osteoblasts lining bone surfaces (Safadi et al.,
2001).
Disease
Osteopetrosis, also known as marble bone disease, is a
rare hereditary disease which results in thickening and
hardening of bones due to deficient osteoclast activity
(Kumar et al., 2003). OA is expressed at highest levels
in primary osteoblasts and thus, may account for the
imbalance in activity of osteoblasts and osteoclasts in
osteopetrosis (Sadafai et al., 2001).
References Weterman MA, Ajubi N, van Dinter IM, Degen WG, van Muijen GN, Ruitter DJ, Bloemers HP. nmb, a novel gene, is expressed in low-metastatic human melanoma cell lines and xenografts. Int J Cancer. 1995 Jan 3;60(1):73-81
Safadi FF, Xu J, Smock SL, Rico MC, Owen TA, Popoff SN. Cloning and characterization of osteoactivin, a novel cDNA expressed in osteoblasts. J Cell Biochem. 2001;84(1):12-26
Kumar V, Cotran RS, Robbins SL.. Diseases of Bone - Osteopetrosis. Robbins Basic Pathology (7th Edition). 2003:757.
Rich JN, Shi Q, Hjelmeland M, Cummings TJ, Kuan CT, Bigner DD, Counter CM, Wang XF. Bone-related genes expressed in advanced malignancies induce invasion and metastasis in a genetically defined human cancer model. J Biol Chem. 2003 May 2;278(18):15951-7
Haralanova-Ilieva B, Ramadori G, Armbrust T. Expression of osteoactivin in rat and human liver and isolated rat liver cells. J Hepatol. 2005 Apr;42(4):565-72
GPNMB (glycoprotein (transmembrane) nmb) Patel SA, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 767
Kuan CT, Wakiya K, Dowell JM, Herndon JE 2nd, Reardon DA, Graner MW, Riggins GJ, Wikstrand CJ, Bigner DD. Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme. Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):1970-82
Metz RL, Patel PS, Hameed M, Bryan M, Rameshwar P. Role of human HGFIN/nmb in breast cancer. Breast Cancer Res. 2007;9(5):R58
Pollack VA, Alvarez E, Tse KF, Torgov MY, Xie S, Shenoy SG, MacDougall JR, Arrol S, Zhong H, Gerwien RW, Hahne WF, Senter PD, Jeffers ME, Lichenstein HS, LaRochelle WJ. Treatment parameters modulating regression of human melanoma xenografts by an antibody-drug conjugate (CR011-vcMMAE) targeting GPNMB. Cancer Chemother Pharmacol. 2007 Aug;60(3):423-35
Rose AA, Pepin F, Russo C, Abou Khalil JE, Hallett M, Siegel PM. Osteoactivin promotes breast cancer metastasis to bone. Mol Cancer Res. 2007 Oct;5(10):1001-14
Rose AA, Siegel PM. Osteoactivin/HGFIN: is it a tumor suppressor or mediator of metastasis in breast cancer? Breast Cancer Res. 2007;9(6):403
Pahl MV, Vaziri ND, Yuan J, Adler SG. Upregulation of monocyte/macrophage HGFIN (Gpnmb/Osteoactivin) expression in end-stage renal disease. Clin J Am Soc Nephrol. 2010 Jan;5(1):56-61
This article should be referenced as such:
Patel SA, Lim PK, Rameshwar P. GPNMB (glycoprotein (transmembrane) nmb). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):765-767.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 768
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
MBD2 (methyl CpG binding domain protein 2) Heather Owen
Wellcome Trust Centre for Cell Biology, University of Edinburgh, Michael Swann Building, King's
Buildings, Mayfield Road, Edinburgh EH9 3JR, UK (HO)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/MBD2ID41309ch18q21.html DOI: 10.4267/2042/44826
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: DKFZp586O0821; DMTase;
Demethylase; NY-CO-41
HGNC (Hugo): MBD2
Location: 18q21.2
Note: Homologous to MBD3 gene.
DNA/RNA
Description
MBD2 (NM_003927.3) is a gene of 70,583 bp coded
by 7 exons from 33,240,260 to 33,169,677 according to
NCBI reference sequence NT_010966.14 or
51,751,158 to 51,680,575 according to Genome
reference consortium human build 37 GRCh37. There
is an alternative transcript for MBD2 (NM_015832.3)
of 22,111 bp from 33,240,260 to 33,218,149 on NCBI
reference sequence NT_010966.14. This transcript
shares the first 2 exons (coding for the methyl binding
domain) but differs in the 3rd exon, resulting in a
shorter truncated protein.
Transcription
The longer transcript encoded by NM_003927.3,
mRNA length of 2584 bp, is expressed ubiquitiously
(according to symatlas).
The shorter transcript NM_015832.3, mRNA length of
1357 bp is expressed in germ cells (according to
symatlas).
Protein
Description
In somatic tissues MBD2 is expressed from a single
transcript, and is detected by western blot as 2 stable
proteins at approximately 50 kDa (MBD2a) and 30 kDa
(MBD2b). Human MBD2a (Q9UBB5) has 411 amino
acids. It is unknown whether MBD2b is due to use of
an alternative translation start site (creating protein of
262 amino acids) or due to protein
cleavage/processing/degradation.
Human germ cells express a short form of MBD2 from
the alternative transcript with an expected length of 302
amino acids.
Expression
MBD2a and MBD2b are expressed in all tissues tested
with highest levels in spleen and colon nuclei (non-
published observation).
Localisation
MBD2 is a nuclear protein. MBD2-GFP localises to
major satellite in mouse ES cells, but not in DNA
methylation deficient cells (Hendrich and Bird, 1998).
MBD2 is expressed as 2 transcripts. NM_003927.3 coding sequence in blue and NM_015832.3 in red. Boxes represent exons and arrows represent transcriptional start sites.
MBD2 (methyl CpG binding domain protein 2) Owen H
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 769
MBD: methyl binding domain, P: phosphorylation detected.
Function
MBD2 is a methyl binding protein that is thought to
repress gene expression as part of the NuRD complex.
The NuRD complex was identified independently by
four separate groups (Wade et al., 1998; Tong et al.,
1998; Xue et al., 1998; Zhang et al., 1998). NuRD
consists of a chromatin remodelling ATPase Mi2alpha
or beta, histone deacetylase HDAC1/HDAC2, MTA1
or MTA2, RbAp46/RbAp48, p66alpha/beta and can
also contain MBD2 or MBD3. TAP tagged MBD2a
associates with NuRD with equimolar stoichometry
implying that most MBD2a is complexed with NuRD
in cells (Le Guezennec et al., 2006). MBD2 is required
for repression of methylated reporter genes (Hendrich,
2001) and many endogenous target genes of MBD2
have been reported. However the global genomic
targets of MBD2 have not been characterised. MBD2
knock out are viable and fertile, and show only mild
physiological defects. These are abnormal maternal
behaviour and T helper cell deficiencies (Hendrich,
2001; Hutchins, 2002; Hutchins, 2005).
Homology
MBD2 is a member of the methyl-binding domain
proteins (Hendrich and Bird, 1998). Other members of
this family are MeCp2, MBD2, MBD3 and MBD4
(Klose and Bird, 2006). These proteins share a region
of homology (145-213 of MBD2a), which have been
shown to form a stable domain consisting of a beta
sheet, an alpha helix and a positioned loop (Ohki et al.,
2001). The crystal structure of the MBD of MeCP2
MBD2 (methyl CpG binding domain protein 2) Owen H
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 770
complexed with a methylated CpG containing 20mer of
DNA indicates that the protein-DNA interactions are
dependent on water molecules (Ho et al., 2008). The
protein with closest homology to MBD2 is MBD3,
however MBD3 has two crucial amino acid
substitutions in the MBD and does not specifically bind
to methylated DNA (Hendrich and Tweedie, 2003).
Mutations
Note
MBD2 is mutated only infrequently in human cancer
tissues.
Implicated in
Intestinal tumorigenesis
Note
MBD2-/-
APCmin/+
mice have fewer intestinal tumors
and survive longer than MBD2+/+
APCmin
/+ mice
(Sansom, 2003).
These results imply MBD2 is required for
tumorigenesis. Although the mechanism is unknown,
possibilities are listed below:
1) MBD2 may repress tumor supressor genes (therefore
in the absence of MBD2, tumor repressor expression
would be upregulated). In cancer cell lines MBD2 has
been found to bind to methylated regions of tumor
supressor genes GSTP1, p14 and p16 (Stirzaker, 2004;
Le Guezennec, 2006; Martin, 2008).
2) MBD2 may repress a repressor of WNT signalling
(therefore in the absence of MBD2, WNT signalling
would be reduced). One candidate for this is Lect2
(Phesse, 2008).
3) In mice MBD2 is required for normal T cell
differentiation and MBD2-/- mice have impaired
immune responses. This could contribute to the MBD2
requirement in tumor formation in the APCmin/+ strain
(Hutchins, 2002; Hutchins, 2005).
4) Other mechanisms are possible, such as a role of
mbd2 in higher order chromatin or silencing of
heterochromatin regulating tumorigenesis. However
this has not been tested.
Knock down of MBD2 in human cancer cell lines
reduced tumor volume when implanted into nude mice
(Campbell, 2004).
MBD2 expression levels in human cancer tissues have
been analysed in multiple studies with differing results.
One study found MBD2 expression was low in
colorectal and stomach cancers (Kanai, 1999), whereas
other studies found high expression in cancer tissues.
These discrepancies are likely due to differences
between control genes used as well as differences
between cancer tissues.
References Hendrich B, Bird A. Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol Cell Biol. 1998 Nov;18(11):6538-47
Tong JK, Hassig CA, Schnitzler GR, Kingston RE, Schreiber SL. Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature. 1998 Oct 29;395(6705):917-21
Wade PA, Jones PL, Vermaak D, Wolffe AP. A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase. Curr Biol. 1998 Jul 2;8(14):843-6
Xue Y, Wong J, Moreno GT, Young MK, Côté J, Wang W. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol Cell. 1998 Dec;2(6):851-61
Zhang Y, LeRoy G, Seelig HP, Lane WS, Reinberg D. The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities. Cell. 1998 Oct 16;95(2):279-89
Hendrich B, Abbott C, McQueen H, Chambers D, Cross S, Bird A. Genomic structure and chromosomal mapping of the murine and human Mbd1, Mbd2, Mbd3, and Mbd4 genes. Mamm Genome. 1999 Sep;10(9):906-12
Kanai Y, Ushijima S, Nakanishi Y, Hirohashi S. Reduced mRNA expression of the DNA demethylase, MBD2, in human colorectal and stomach cancers. Biochem Biophys Res Commun. 1999 Nov 2;264(3):962-6
Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, Tempst P, Reinberg D, Bird A. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat Genet. 1999 Sep;23(1):58-61
Hendrich B, Guy J, Ramsahoye B, Wilson VA, Bird A. Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev. 2001 Mar 15;15(6):710-23
Ohki I, Shimotake N, Fujita N, Jee J, Ikegami T, Nakao M, Shirakawa M. Solution structure of the methyl-CpG binding domain of human MBD1 in complex with methylated DNA. Cell. 2001 May 18;105(4):487-97
Hutchins AS, Mullen AC, Lee HW, Sykes KJ, High FA, Hendrich BD, Bird AP, Reiner SL. Gene silencing quantitatively controls the function of a developmental trans-activator. Mol Cell. 2002 Jul;10(1):81-91
Bader S, Walker M, McQueen HA, Sellar R, Oei E, Wopereis S, Zhu Y, Peter A, Bird AP, Harrison DJ. MBD1, MBD2 and CGBP genes at chromosome 18q21 are infrequently mutated in human colon and lung cancers. Oncogene. 2003 May 29;22(22):3506-10
Hendrich B, Tweedie S. The methyl-CpG binding domain and the evolving role of DNA methylation in animals. Trends Genet. 2003 May;19(5):269-77
Lin X, Nelson WG. Methyl-CpG-binding domain protein-2 mediates transcriptional repression associated with hypermethylated GSTP1 CpG islands in MCF-7 breast cancer cells. Cancer Res. 2003 Jan 15;63(2):498-504
Sansom OJ, Berger J, Bishop SM, Hendrich B, Bird A, Clarke AR. Deficiency of Mbd2 suppresses intestinal tumorigenesis. Nat Genet. 2003 Jun;34(2):145-7
Campbell PM, Bovenzi V, Szyf M. Methylated DNA-binding protein 2 antisense inhibitors suppress tumourigenesis of human cancer cell lines in vitro and in vivo. Carcinogenesis. 2004 Apr;25(4):499-507
Stirzaker C, Song JZ, Davidson B, Clark SJ. Transcriptional gene silencing promotes DNA hypermethylation through a sequential change in chromatin modifications in cancer cells. Cancer Res. 2004 Jun 1;64(11):3871-7
MBD2 (methyl CpG binding domain protein 2) Owen H
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 771
Berger J, Bird A. Role of MBD2 in gene regulation and tumorigenesis. Biochem Soc Trans. 2005 Dec;33(Pt 6):1537-40
Hutchins AS, Artis D, Hendrich BD, Bird AP, Scott P, Reiner SL. Cutting edge: a critical role for gene silencing in preventing excessive type 1 immunity. J Immunol. 2005 Nov 1;175(9):5606-10
Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci. 2006 Feb;31(2):89-97
Le Guezennec X, Vermeulen M, Brinkman AB, Hoeijmakers WA, Cohen A, Lasonder E, Stunnenberg HG. MBD2/NuRD and MBD3/NuRD, two distinct complexes with different biochemical and functional properties. Mol Cell Biol. 2006 Feb;26(3):843-51
Ho KL, McNae IW, Schmiedeberg L, Klose RJ, Bird AP, Walkinshaw MD. MeCP2 binding to DNA depends upon hydration at methyl-CpG. Mol Cell. 2008 Feb 29;29(4):525-31
Martin V, Jørgensen HF, Chaubert AS, Berger J, Barr H, Shaw P, Bird A, Chaubert P. MBD2-mediated transcriptional repression of the p14ARF tumor suppressor gene in human colon cancer cells. Pathobiology. 2008;75(5):281-7
Phesse TJ, Parry L, Reed KR, Ewan KB, Dale TC, Sansom OJ, Clarke AR. Deficiency of Mbd2 attenuates Wnt signaling. Mol Cell Biol. 2008 Oct;28(19):6094-103
This article should be referenced as such:
Owen H. MBD2 (methyl CpG binding domain protein 2). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):768-771.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 772
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
MEF2D (myocyte enhancer factor 2D) Victor Prima, Lyudmyla G Glushakova, Stephen P Hunger
University of Florida College of Medicine, Gainesville, FL 32610, USA (VP, LGG); Children's Hospital and
the Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA
(SPH)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/MEF2DID43636ch1q22.html DOI: 10.4267/2042/44827
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: DKFZp686I1536
HGNC (Hugo): MEF2D
Location: 1q22
Note: MEF2D is a member of the family of myocyte
enhancer factor MEF2 that includes MEF2A, MEF2B,
MEF2D, MEF2C.
DNA/RNA
Description
12 exons.
Transcription
5888 bp mRNA, coding sequence: from 391 bp to 1956
bp (NCBI, GenBank NM_005920); alternative splicing
in E3 (3alpha1 and 3alpha2) and beta produces 4
splicing isoforms: alpha1, alpha1beta, alpha2,
alpha2beta (Zhu et al., 2005).
Protein
Note
MEF2D belongs to MEF2 (myocyte enhancer factor 2)-
like/Type II subfamily of MADS (MCM1, Agamous,
Deficiens, and SRF (serum response factor) box family
of eukaryotic transcriptional regulators).
Description
MEF2D encodes approximately a 521 aa-long protein
(GenBank at NCBI presented 4 isoforms: CRA_a, 521
aa, EAW52952.1; CRA_b, 143 aa, EAW52949.1;
CRA_c, 288 aa, EAW52950.1; CRA_d, 523 aa,
EAW52951.1). It is composed of several domains: the
MADS-box on N terminus (2-78 aa, MAD MEF2 like);
the 29-aa MEF2 domain immediately C-terminal to the
MADS- box (unique to the MEF2 factors); C-terminal
transcriptional activation domains. Both MADS and
MEF2 domains are necessary and sufficient for
dimerization and binding to the DNA sequence
CTA(A/T)4TAG/A. MEF2 domain influences cofactor
interactions (Pollock and Treisman, 1991; Molkentin
and Olson, 1996). Regions: 2-38 aa of the MADS
domain confer DNA binding site specificity; 21-73 aa,
dimerization interface; 59 aa, putative phosphorylation
site.
Expression
High level expression in muscles and neurons, at lower
levels in a wide range of cell types (Black and Olson,
1998).
Localisation
Nuclear (Neely et al., 2009).
Function
DNA binding, transcriptional activation. Transmission
of extracellular signals to the genome, control of cell
differentiation, proliferation, morphogenesis, survival
and apoptosis of a wide range of cell types. Important
in immediate-early development in animals. MEF2D
dimers regulate expression of genes involved in
muscle-specific and/or growth factor-related
transcription.
It seems to be transcriptional effector of mitogenic
signaling pathways initiated by mitogen-activated
protein kinases (MAPKs) including p38 and ERK5
(extracellular signal-related kinase 5)/Big MAPK-1,
and also plays critical roles in calcium-regulated
MEF2D (myocyte enhancer factor 2D) Prima V, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 773
A. Localization of TS-2 chromosome 19 breakpoint via FISH. Metaphase FISH was performed using cosmids containing chromosome 19 genomic DNA. Cosmids that hybridize to the der(19) are located centromeric to the chromosome 19 breakpoint (green signal), while cosmids that hybridize to the der(1) are located telomeric to the chromosome 19 breakpoint (red signal). Split signals on both the der(1) and der(19) chromosomes indicate that the chromosome 19 breakpoint is located within the region homologous to the cosmid. B. Alignment of genomic DNA sequences of TS-2 chromosomes. Genomic sequence (accession AY681494) of der(19) aligned with chromosome 19 (gi: 37552371) and 1 (gi: 37549803) genomic contigs. Non- homologous insert shown in bold uppercase. Genomic sequence (accession AY681493) of der(1) aligned with chromosome 19 and 1 genomic contigs. (Prima et al., 2007).
signaling pathways that control survival of neurons and
T-cells; induces expression of c-jun, a known
transforming oncogene, and has recently been
identified in murine retroviral mutagenesis studies as a
candidate oncogene involved in the pathogenesis of
lymphoid malignancies (Lund et al., 2002; Suzuki et
al., 2002; Han and Prywes, 1995).
Homology
Belongs to MEF2-like/Type II subfamily of MADS
box family of eukaryotic transcriptional regulators. The
MEF2D (myocyte enhancer factor 2D) Prima V, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 774
MADS-box is found so far in a diverse group of
transcription factors from yeast, animals and seed
plants.
Implicated in
Acute lymphoblastic leukemia (ALL)
Hybrid/Mutated gene
A variant t(1;19)(q23;p13.3) 1048 translocation creates
reciprocal DAZAP1/MEF2D and MEF2D/DAZAP1
fusion genes that are expressed in acute lymphoblastic
leukemia (ALL).
DAZAP1 is expressed most abundantly in the testis and
mapped to 19p13.3. DAZAP1 is fused to MEF2D by
the t(1;19); the genomic breakpoints occur in introns of
MEF2D and DAZAP1 (der(1) (Genbank accession
AY681493) and der(19) (accession AY681494)).
der(19) breakpoint is located within the 1500 kilobases
(kb) of DNA telomeric to E2A. Rearrangments are seen
only in TS-2 (ALL cell line) establishing that the
t(1;19) interrupts the 19p13.3 gene DAZAP1 with the
breakpoint region in approximately the middle of the
gene. There is a 5 base pairs insertion at the site of
genomic fusion on the der(19) that is not derived from
either germline chromosome 1 or 19. Homologous
breakpoints occur on the der(1) chromosome with a
deletion of 97 bp and a 21 bp GC-rich insertion.
MEF2D/DAZAP1 and DAZAP1/MEF2D fusion
transcripts are expressed in-frame in TS-2 cells in
addition to wild-type DAZAP1 and MEF2D transcripts
(Prima et al., 2005).
Abnormal protein
In-frame MEF2D/DAZAP1 and DAZAP1/MEF2D
fusion transcripts are expressed in TS-2 cell line and
define the DNA-, RNA-binding, and transcriptional
regulatory properties of the resultant chimeric proteins.
Native DAZAP1 (NP_061832) includes two identified
RNA recognition motifs (RRM) specified by amino
acids 1-87 and 105-190. DAZAP1/MEF2D fusion
cDNAs (accession
AY678451) are predicted to encode a chimeric protein
that contains all of the first DAZAP1 RRM and a
truncated portion of the second RRM joined to the
carboxy terminal portion of MEF2D that includes the
second TAD. Reciprocal MEF2D/DAZAP1 fusion
transcripts (accession AY675556) are predicted to
encode a chimera that includes the MEF2D MADS-
box, MEF2 domain, and the first TAD joined to the
carboxy terminus of DAZAP1 including a truncated
portion of RRM 2.
DAZAP1 bound strongly to poly(U) and poly(G) at 0.1
M NaCl, whereas DAZAP1/MEF2D bound to the same
homopolymers to a lesser degree; MEF2D/DAZAP1
retains DNA-binding properties of wild type MEF2D;
MEF2D/DAZAP1 is a more potent transcriptional
activator than wild type MEF2D. MEF2D-DAZAP1
was co-immunoprecipitated with wild type MEF2D
from HEK293 cells, suggesting that the wild type and
chimeric MEF2D proteins could form heterodimers
and/or associate with one another in a higher order
protein complex in vivo (Yuki et al., 2004).
Oncogenesis
MEF2D and DAZAP1 fusion proteins were identified
as components of novel pathways that contribute to
human leukemogenesis. Both MEF2D/DAZAP1 and
DAZAP1/MEF2D have oncogenic properties, and co-
expression of both fusion proteins is synergistic (Prima
and Hunger, 2007).
MEF2D/DAZAP1 might directly activate transcription
of genes critical for lymphocyte growth and/or survival
such as interleukin-2, a known transcriptional target of
MEF2D in T-cells. Alternatively, MEF2D/DAZAP1
could contribute to leukemogenesis via dysregulated
activation of MAPK-mediated cell proliferation
pathways, analogous to constitutive activation of a
growth factor receptor.
Structural features of wild type and chimeric MEF2D and DAZAP1 proteins. Predicted functional domains of DAZAP1, MEF2D, DAZAP1/MEF2D and MEF2D/DAZAP1 proteins. Arrows indicate predicted protein breakpoints. (RRM- RNA recognition motif; MADS- DNA binding, protein dimerization domain; MEF2- cofactor interactions domain; TAD- transcriptional activation domain) (Prima et al., 2007).
MEF2D (myocyte enhancer factor 2D) Prima V, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 775
References Pollock R, Treisman R. Human SRF-related proteins: DNA-binding properties and potential regulatory targets. Genes Dev. 1991 Dec;5(12A):2327-41
Han TH, Prywes R. Regulatory role of MEF2D in serum induction of the c-jun promoter. Mol Cell Biol. 1995 Jun;15(6):2907-15
Molkentin JD, Olson EN. Combinatorial control of muscle development by basic helix-loop-helix and MADS-box transcription factors. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9366-73
Black BL, Olson EN. Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins. Annu Rev Cell Dev Biol. 1998;14:167-96
Lund AH, Turner G, Trubetskoy A, Verhoeven E, Wientjens E, Hulsman D, Russell R, DePinho RA, Lenz J, van Lohuizen M. Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice. Nat Genet. 2002 Sep;32(1):160-5
Suzuki T, Shen H, Akagi K, Morse HC, Malley JD, Naiman DQ, Jenkins NA, Copeland NG. New genes involved in cancer identified by retroviral tagging. Nat Genet. 2002 Sep;32(1):166-74
Yuki Y, Imoto I, Imaizumi M, Hibi S, Kaneko Y, Amagasa T, Inazawa J. Identification of a novel fusion gene in a pre-B acute lymphoblastic leukemia with t(1;19)(q23;p13). Cancer Sci. 2004 Jun;95(6):503-7
Prima V, Gore L, Caires A, Boomer T, Yoshinari M, Imaizumi M, Varella-Garcia M, Hunger SP. Cloning and functional characterization of MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins created by a variant t(1;19)(q23;p13.3) in acute lymphoblastic leukemia. Leukemia. 2005 May;19(5):806-13
Zhu B, Ramachandran B, Gulick T. Alternative pre-mRNA splicing governs expression of a conserved acidic transactivation domain in myocyte enhancer factor 2 factors of striated muscle and brain. J Biol Chem. 2005 Aug 5;280(31):28749-60
Prima V, Hunger SP. Cooperative transformation by MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins generated by the variant t(1;19) in acute lymphoblastic leukemia. Leukemia. 2007 Dec;21(12):2470-5
Neely MD, Robert EM, Baucum AJ, Colbran RJ, Muly EC, Deutch AY. Localization of myocyte enhancer factor 2 in the rodent forebrain: regionally-specific cytoplasmic expression of MEF2A. Brain Res. 2009 Jun 5;1274:55-65
This article should be referenced as such:
Prima V, Glushakova LG, Hunger SP. MEF2D (myocyte enhancer factor 2D). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):772-775.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 776
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
NDRG1 (N-myc downstream regulated 1) Michel Wissing, Nadine Rosmus, Michael Carducci, Sushant Kachhap
Johns Hopkins Medical Institute, The Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans Street,
CRB-I 162E, Baltimore, MD 21231, USA (MW, NR, MC, SK)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/NDRG1ID41512ch8q24.html DOI: 10.4267/2042/44828
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: CAP43; CMT4D; DRG-1; DRG1; GC4;
HMSNL; NDR1; NMSL; PROXY1; RIT42; RTP;
Rit42; TARG1; TDD5
HGNC (Hugo): NDRG1
Location: 8q24.22
DNA/RNA
Description
NDRG1 consists of 60,085 basepairs, starting at
basepair 134,318,596 and ending at basepair
134,378,680 from the p-terminus. It is a member of the
NDRG family, consisting of NDRG1, NDRG2,
NDRG3 and NDRG4 (of which three isoforms exist:
NDRG-4B, NDRG-4Bvar
and NDRG-4H), which are
part of the alpha/beta hydrolase superfamily.
Transcription
The DNA of NDRG1 contains 16 exons, see diagram
for details about their location. The DNA encodes a 3.0
kb mRNA with a coding region of 1.185 kb.
Protein
Description
NDRG1 is a 43 kD protein, composed of 394 amino
acids, with an iso-electric point of 5.7. NDRG1 has an
alpha/beta hydrolase-fold motif, however, the presence
of hydrolytic catalytic activity is still questionable.
NDRG1 has more than seven phosphorylation sites,
among others a phosphopantetheine attachment site,
protein kinase C, casein kinase II, tyrosine kinase,
protein kinase A and calmodulin kinase II. NRDG1 is
phosphorylated by protein kinase A and calmodulin
kinase II, and is a physiological substrate of SGK1 and
GSK-3-beta kinase, a kinase involved in cancer growth
and progression.
Expression
NDRG1 is relatively ubiquitously expressed in normal
human cells, and especially highly expressed in
prostate, brain, kidney, placenta, ovarian, testicular and
intestinal cells. NDRG1 is mostly found in epithelial
cells.
Localisation
NDRG1 is primarily a cytoplasmic protein. 47.8% of
the NDRG1 is expressed in the cytosol, 26.1% in the
nucleus (such as in prostate epithelial cells), and 8.7%
in the mitochondria (such as in proximal tubule cells in
the kidney). NDRG1 is also found in the adherens
junctions. Additionally, in intestinal and lactating
breast epithelia NDRG1 is located in the plasma
membrane. NDRG1 can also be found in vacuoles, the
peroxisome, early and recycling endosomes, and the
cytoskeleton.
DNA size: 60.05 kb; mRNA size: 2997 bp; 16 exons.
NDRG1 (N-myc downstream regulated 1) Wissing M, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 777
Function
NDRG1 is reported to be a metastasis suppressor gene
which is downregulated in prostate, colon and breast
cancers. It has been found to be a Rab4a effector
protein that recruits to the recycling endosomes in the
Trans Golgi network by binding to the lipid
phosphotidylinositol 4-phosphate (PI4P), where it plays
a role in the recycling of E-cadherin. NDRG1 also
interacts with HSP70. NDRG1 co-localizes with APO
A-I and A-II, and may be involved in lipid transport.
The function of NDRG1 may be controlled at least in
part by phosphorylation. It has also been identified as a
stress response gene, upregulated by homocysteine and
hypoxia. Hif-1-dependent and independent mechanisms
have been implicated in NDRG1 induction. It is also
controlled by AP-1 transcription factors. When exposed
to stress, for example hypoxia, NDRG1 may play a
cytoprotective role in normal healthy cells. There is
evidence that NDRG1 is involved in the induction of
differentiation. NDRG1 is downregulated under
conditions of cell growth. NDRG1 expression peaks in
the G1 and G2/M phases, and is lowest in the S phase.
NDRG1 is also a microtubule-associated protein, which
may play an important role in maintaining spindle
structure during cell division. In the Schwann cells,
NDRG1 is essential for myelin sheath maintenance.
Hence, NDRG1 is a multifunctional protein with roles
that may be tissue- and/or cell-type specific.
Certain transcription factors such as MYC, ERG1,
HIF1-ALPHA bind to the NDRG1 promoter region and
regulate its expression.
NDRG1 is upregulated during colon epithelial cell
differentiation. It is regulated by hormones such as
androgens and estradiol. Small molecules such as N-
hydroxy-N'-phenol-octane-1,8-diotic acid diamide,
calcium ionophores like BAPTA, metal ions such as
Nickel and Cobalt, iron chelators and differentiating
agents like retinoic acid induce NDRG1 expression.
Additionally, NDRG1 is induced during cellular DNA
damage and endoplasmic reticulum stress.
Homology
NDRG1 amino acid sequence is 53% homologous to
NDRG2, 62% to NDRG3, 62% to NDRG4, and 94%
homologous to the mouse analog, Ndr-1 (also known as
TDD5). NDRG1 homologs have been found in
Helianthus, Caenorhabditis, Xenopus and Drosophilia.
Implicated in
Various solid cancers
Disease
Prostate, breast, colon, renal, bladder, pancreatic,
hepatic cancer.
Prognosis
Downregulation of NDRG1 in cancer worsens the
prognosis of cancer. There is an inverse relationship in
the levels of NDRG1 expression and the Gleason grade
of the tumor in prostate cancer. A high PTEN (a tumor
suppressor which positively regulates NDRG1) and
NDRG1 expression improves survival rates in patients
with breast and prostate cancer. In patients with
colorectal cancer, the 2 year survival rate for patients
with high NDRG1-expression was 82.4%, while for
patients with a low NDRG1-expression it was only
69.6%. In pancreatic cancer patients, the median
survival time for patients with high NDRG1-expression
was 24.7 months, while the median survival time for
patients with low NDRG1-expression was only 10.9
months. High expression of NDRG1 in colon tumors
was found to correlate with increased resistance to
irinotecan.
NDRG1 (N-myc downstream regulated 1) Wissing M, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 778
Oncogenesis
An inverse relationship exists between NDRG1 and the
oncogenes N-myc and c-myc, suggesting that members
of the MYC family suppress expression of NDRG1.
Experimental evidence exist that both N-myc and c-
myc downregulate NDRG1 gene expression by directly
binding to NDRG1 promoter.
NDRG1 is downregulated in colon, breast, prostate and
pancreatic neoplasms, by c-myc and N-myc
transcription factors. In cancer cells, NDRG1
expression is consistent through all phases in the cell
cycle, instead of the biphasic expression in normal
cells. PTEN expression is positively related to NDRG1
expression. NDRG1 is induced in cancer cells by
histone deacetylase inhibitors and DNA methyl
transferase inhibitors indicating that NDRG1 is
regulated by chromatin modulation and DNA
methylation.
Although NDRG1 has been reported to be
downregulated in a variety of cancers, it has been
shown to be upregulated in hepatic, pancreatic and
kidney cancers. Induction of NDRG1 in these tumors is
speculated to be in response to tumor stress or hypoxia
and NDRG1 is proposed as a marker of tumor hypoxia.
However, in pancreatic cancer, cellular differentiation
and not hypoxia was demonstrated to be the
determining factor for NDRG1 expression. In renal
cancer, induction of NDRG1 in the tumor tissue was
restricted to infiltrating macrophages and not cancer
cells.
NDRG1 is suggested to be an early target for p53. Loss
of p53 expression in cancer is suggested to reduce
NDRG1 expression. However, p53 knockout mice
show expression of NDRG1, suggesting that there are
other mechanisms regulating NDRG1 levels.
NDRG1 expression plays a role in vitro in primary
tumor growth in prostate, breast, and bladder cancer: a
higher expression of NDRG1 lowers the proliferation
rates of these cancers. In pancreatic and bladder cancer
cells, this reduction was proven in vivo: in pancreatic
cells it was suggested that the reduced proliferation was
caused by NDRG1 by modulating tumor stroma and
angiogenesis. NDRG1 can recruit onto the recycling
endosome in the Trans-Golgi network by binding to
phosphotidylinositol 4-phosphate. There, NDRG1 may
be involved in the transport of various cargo back to the
cells' surface. At the molecular level, NDRG1 may
stabilize the E-cadherin molecule by recycling it back
to the cells' surface, thereby preventing tumor invasion.
Hereditary motor and sensory neuropathy-Lom (HMSNL) / Charcot-Marie-Tooth disease (CMT 4D)
Note
Caused by the Gypsy founder mutation, homozygote
R148X, also called homozygote C564t. In patients with
CMT disease, apart from the R148X mutation, another
disease-causing mutation was identified, namely IVS8-
1G>A (g.2290787G>A), which results in skipping of
exon 9. The homozygote phenotype of this mutation
was very closely related to the phenotype of HMSNL
patients.
Disease
A hereditary autosomal recessive disease, caused by
demyelination of peripheral nerves. It is the most
common form of demyelinating Charcot-Marie-Tooth
disease in the Roma population.
Prognosis
Severe disability in adulthood. It begins consistently in
the first decade of life with a gait disorder, followed by
upper limb weakness in the second decade and, in most
subjects, by deafness setting in in the third decade of
life. Sensory loss affecting all modalities is present;
both this and the motor involvement predominating
distally in the limbs. Skeletal deformity, particularly
foot deformities, are frequent.
Atherosclerosis
Note
Patients with HMSNL were found to have a high total
cholesterol: HDL-C ratio.
Disease
Atherosclerosis is an important factor for the
development of cardiovascular diseases, like
myocardial infarction and angina pectoris. NDRG1
contributes to HDL-C (high-density lipoprotein-
cholesterol) levels most likely by its
phosphopantetheine-binding domain interacting with
the high-density lipoproteins apolipoprotein A-I and A-
II.
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variables and patient outcomes. Clin Cancer Res. 2005 May 1;11(9):3296-302
Chen B, et al. N-myc down-regulated gene 1 modulates the response of term human trophoblasts to hypoxic injury. J Biol Chem. 2006 Feb 3;281(5):2764-72
Kovacevic Z, Richardson DR. The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer. Carcinogenesis. 2006 Dec;27(12):2355-66
Maruyama Y, Ono M, Kawahara A, Yokoyama T, Basaki Y, Kage M, Aoyagi S, Kinoshita H, Kuwano M. Tumor growth suppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/NDRG1/Drg-1 through modulation of angiogenesis. Cancer Res. 2006 Jun 15;66(12):6233-42
Kachhap SK, Faith D, Qian DZ, Shabbeer S, Galloway NL, Pili R, Denmeade SR, DeMarzo AM, Carducci MA. The N-Myc down regulated Gene1 (NDRG1) Is a Rab4a effector involved in vesicular recycling of E-cadherin. PLoS One. 2007 Sep 5;2(9):e844
Ellen TP, Ke Q, Zhang P, Costa M. NDRG1, a growth and cancer related gene: regulation of gene expression and function in normal and disease states. Carcinogenesis. 2008 Jan;29(1):2-8
This article should be referenced as such:
Wissing M, Rosmus N, Carducci M, Kachhap S. NDRG1 (N-myc downstream regulated 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):776-780.
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SLC5A8 (solute carrier family 5 member 8) Julie Di Bernardo, Kerry J Rhoden
Medical Genetics Unit, Department of Gynaecologic, Obstetric and Pediatric Sciences, University of
Bologna, Bologna, Italy (JDB, KJR)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/SLC5A8ID44089ch12q23.html DOI: 10.4267/2042/44829
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: AIT; MGC125354; SMCT; SMCT1
HGNC (Hugo): SLC5A8
Location: 12q23.2
Local order: Telomeric to TMEM16D, centromeric to
UTP20.
DNA/RNA
Description
15 exons, spanning 54023 bp.
Transcription
3286 bases, open reading frame: 1833 bp. No
alternative splicing variants have been reported.
SLC5A8 transcription is regulated by hypermethylation
of CpG-rich islands in the promoter region.
Pseudogene
No pseudogenes identified.
Protein
Description
610 amino acids; 66,560 Da; 13 transmembrane
domains, extracellular N-terminal, cytosolic C-
terminal.
Expression
Gastrointestinal tract (stomach, colon, ileum), kidney,
thyroid, brain, retina, breast, prostate, salivary gland
ducts.
Localisation
Cell membrane; apical membrane in thyrocytes and
colonocytes.
SLC5A8 (solute carrier family 5 member 8) Di Bernardo J, Rhoden KJ
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 782
Diagram drawn following UniProtKB/Swiss-Prot database prediction and maintaining approximate length proportions among extracellular and intracellular segments. Transmembrane segments are represented by rectangles.
Function
Sodium coupled transport of short-chain
monocarboxylates, including lactate, butyrate,
pyruvate, acetate, proprionate, ketone bodies and
nicotinate. The sodium/substrate stoichiometry depends
on the transported substrate. SLC5A8 is considered a
tumor suppressor, and its expression is downregulated
in several kinds of tumor. Its tumor suppressor activity
may be due to its ability to transport and accumulate
histone deacetylase inhibitors such as butyrate and
pyruvate.
- Gastrointestinal tract: colonocyte absorption and
accumulation of short chain fatty acids produced by
bacteria in the intestinal lumen. In particular, butyrate
and pyruvate are inhibitors of histone deacetylases and
are known to promote differentiation in normal colon
epithelial cells but selectively induce apoptosis in
tumor cells.
- Kidney: lactate transport; reabsorption of lactate from
urine to blood.
- Thyroid: unknown function. When first identified,
SLC5A8 was shown to localize on the apical
membrane of thyrocytes and to transport iodide by a
passive mechanism. Lately, this evidence has been
rejected by different groups that showed that iodide is
not a SLC5A8 substrate.
- Brain: transport of lactate and ketone bodies; role in
energy maintenance in neurons.
Homology
Belongs to the SLC superfamily of solute carriers; the
SLC5 family has 12 members to date (SLC5A1-
SLC5A12) and includes Na+-coupled cotransporters
that rely on the Na+ electrochemical gradient to drive
solute transport into cells. 53% identity with SLC5A12,
a sodium/monocarboxylate transporter; 46% identity
with SLC5A5, the Sodium-Iodide Symporter.
Mutations
Germinal
No germinal mutations implicated in human disease to
date.
SLC5A8 knockout mouse (deletion of exons 4 and 5) is
viable and fertile, with no evident malformation;
affected by lactaturia and loss of sodium-dependent
lactate uptake in the colon.
Somatic
No somatic mutations implicated in human disease to
date.
Implicated in
Colorectal cancer
Prognosis
SLC5A8 expression may be a favorable indicator of
colorectal cancer prognosis; higher expression
correlates with longer disease-free survival (Paroder et
al., 2006).
Oncogenesis
SLC5A8 is expressed in normal colon, but is silenced
in colon cancer due to gene methylation. SLC5A8
exerts a tumor suppressor function, possibly due to its
ability to transport and accumulate histone deacetylase
inhibitors such as butyrate and pyruvate.
- 59% of primary colon cancers and colonic adenomas
(dysplastic polyps, precursor lesions of colon cancer),
and 52% of colon cancer cell lines show aberrant
methylation of SLC5A8 exon 1 (Li et al., 2003).
SLC5A8 (solute carrier family 5 member 8) Di Bernardo J, Rhoden KJ
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 783
- 82,5% of serrated adenomas (polyps with mixed
hyperplastic/adenomatous features, precursor lesions of
colon cancer), exhibit tumor-specific
promoter methylation of SLC5A8; methylation of CpG
islands increases with the histological progression of
serrated adenomas (Dong et al., 2005).
- 66.4% of Duke C stage colorectal cancers (i.e.
colorectal cancer with lymph node metastases) express
low levels of SLC5A8 (Paroder et al., 2006).
Papillary thyroid cancer (PTC)
Prognosis
SLC5A8 methylation and silencing of gene expression
is significantly associated with aggressive features of
PTC, including extrathyroidal invasion, lymph node
metastasis, multifocality and advanced tumor stages
(Hu et al., 2006).
Oncogenesis
SLC5A8 expression is selectively down-regulated in
papillary thyroid carcinomas: SLC5A8 is methylated in
90% of classical PTC and in 20% of other PTC
subtypes, including the follicular variant. SLC5A8
methylation and low expression is highly associated
with the prescence of the BRAF T1796A mutation
(Porra et al., 2005; Hu et al., 2006).
Various cancers
Disease
Acute myeloid leukemia (AML), astrocytoma and
oligodendroglioma, breast cancer, gastric cancer, head
and neck squamous cells carcinoma, pancreatic cancer,
prostate cancer.
Oncogenesis
SLC5A8 expression is decreased in various cancers due
to DNA methylation in the SLC5A8 promoter region.
To be noted
Note
Several single nucleotide polymorphisms have been
found, mostly in introns, or resulting in synonymous
codons with no change in amino acid. A single
nonsynonymous coding polymorphism (Phe251Val)
has been reported to negatively affect transport activity.
References Rodriguez AM, Perron B, Lacroix L, Caillou B, Leblanc G, Schlumberger M, Bidart JM, Pourcher T. Identification and characterization of a putative human iodide transporter located at the apical membrane of thyrocytes. J Clin Endocrinol Metab. 2002 Jul;87(7):3500-3
Li H, Myeroff L, Smiraglia D, Romero MF, Pretlow TP, Kasturi L, Lutterbaugh J, Rerko RM, Casey G, Issa JP, Willis J, Willson JK, Plass C, Markowitz SD. SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8412-7
Coady MJ, Chang MH, Charron FM, Plata C, Wallendorff B, Sah JF, Markowitz SD, Romero MF, Lapointe JY. The human
tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter. J Physiol. 2004 Jun 15;557(Pt 3):719-31
Gopal E, Fei YJ, Sugawara M, Miyauchi S, Zhuang L, Martin P, Smith SB, Prasad PD, Ganapathy V. Expression of slc5a8 in kidney and its role in Na(+)-coupled transport of lactate. J Biol Chem. 2004 Oct 22;279(43):44522-32
Miyauchi S, Gopal E, Fei YJ, Ganapathy V. Functional identification of SLC5A8, a tumor suppressor down-regulated in colon cancer, as a Na(+)-coupled transporter for short-chain fatty acids. J Biol Chem. 2004 Apr 2;279(14):13293-6
Ueno M, Toyota M, Akino K, Suzuki H, Kusano M, Satoh A, Mita H, Sasaki Y, Nojima M, Yanagihara K, Hinoda Y, Tokino T, Imai K. Aberrant methylation and histone deacetylation associated with silencing of SLC5A8 in gastric cancer. Tumour Biol. 2004 May-Jun;25(3):134-40
Dong SM, Lee EJ, Jeon ES, Park CK, Kim KM. Progressive methylation during the serrated neoplasia pathway of the colorectum. Mod Pathol. 2005 Feb;18(2):170-8
Ganapathy V, Gopal E, Miyauchi S, Prasad PD. Biological functions of SLC5A8, a candidate tumour suppressor. Biochem Soc Trans. 2005 Feb;33(Pt 1):237-40
Gopal E, Fei YJ, Miyauchi S, Zhuang L, Prasad PD, Ganapathy V. Sodium-coupled and electrogenic transport of B-complex vitamin nicotinic acid by slc5a8, a member of the Na/glucose co-transporter gene family. Biochem J. 2005 May 15;388(Pt 1):309-16
Hong C, Maunakea A, Jun P, Bollen AW, Hodgson JG, Goldenberg DD, Weiss WA, Costello JF. Shared epigenetic mechanisms in human and mouse gliomas inactivate expression of the growth suppressor SLC5A8. Cancer Res. 2005 May 1;65(9):3617-23
Porra V, Ferraro-Peyret C, Durand C, Selmi-Ruby S, Giroud H, Berger-Dutrieux N, Decaussin M, Peix JL, Bournaud C, Orgiazzi J, Borson-Chazot F, Dante R, Rousset B. Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas. J Clin Endocrinol Metab. 2005 May;90(5):3028-35
Gupta N, Martin PM, Prasad PD, Ganapathy V. SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter. Life Sci. 2006 Apr 18;78(21):2419-25
Hu S, Liu D, Tufano RP, Carson KA, Rosenbaum E, Cohen Y, Holt EH, Kiseljak-Vassiliades K, Rhoden KJ, Tolaney S, Condouris S, Tallini G, Westra WH, Umbricht CB, Zeiger MA, Califano JA, Vasko V, Xing M. Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. Int J Cancer. 2006 Nov 15;119(10):2322-9
Paroder V, Spencer SR, Paroder M, Arango D, Schwartz S Jr, Mariadason JM, Augenlicht LH, Eskandari S, Carrasco N. Na(+)/monocarboxylate transport (SMCT) protein expression correlates with survival in colon cancer: molecular characterization of SMCT. Proc Natl Acad Sci U S A. 2006 May 9;103(19):7270-5
Thangaraju M, Gopal E, Martin PM, Ananth S, Smith SB, Prasad PD, Sterneck E, Ganapathy V. SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases. Cancer Res. 2006 Dec 15;66(24):11560-4
Martin PM, Dun Y, Mysona B, Ananth S, Roon P, Smith SB, Ganapathy V. Expression of the sodium-coupled monocarboxylate transporters SMCT1 (SLC5A8) and SMCT2 (SLC5A12) in retina. Invest Ophthalmol Vis Sci. 2007 Jul;48(7):3356-63
SLC5A8 (solute carrier family 5 member 8) Di Bernardo J, Rhoden KJ
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 784
Park JY, Zheng W, Kim D, Cheng JQ, Kumar N, Ahmad N, Pow-Sang J. Candidate tumor suppressor gene SLC5A8 is frequently down-regulated by promoter hypermethylation in prostate tumor. Cancer Detect Prev. 2007;31(5):359-65
Bennett KL, Karpenko M, Lin MT, Claus R, Arab K, Dyckhoff G, Plinkert P, Herpel E, Smiraglia D, Plass C. Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma. Cancer Res. 2008 Jun 15;68(12):4494-9
Frank H, Gröger N, Diener M, Becker C, Braun T, Boettger T. Lactaturia and loss of sodium-dependent lactate uptake in the colon of SLC5A8-deficient mice. J Biol Chem. 2008 Sep 5;283(36):24729-37
Ganapathy V, Thangaraju M, Gopal E, Martin PM, Itagaki S, Miyauchi S, Prasad PD. Sodium-coupled monocarboxylate transporters in normal tissues and in cancer. AAPS J. 2008;10(1):193-9
Park JY, Helm JF, Zheng W, Ly QP, Hodul PJ, Centeno BA, Malafa MP. Silencing of the candidate tumor suppressor gene
solute carrier family 5 member 8 (SLC5A8) in human pancreatic cancer. Pancreas. 2008 May;36(4):e32-9
Thangaraju M, Cresci G, Itagaki S, Mellinger J, Browning DD, Berger FG, Prasad PD, Ganapathy V. Sodium-coupled transport of the short chain fatty acid butyrate by SLC5A8 and its relevance to colon cancer. J Gastrointest Surg. 2008 Oct;12(10):1773-81; discussion 1781-2
Ganapathy V, Thangaraju M, Prasad PD. Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. Pharmacol Ther. 2009 Jan;121(1):29-40
Thangaraju M, Carswell KN, Prasad PD, Ganapathy V. Colon cancer cells maintain low levels of pyruvate to avoid cell death caused by inhibition of HDAC1/HDAC3. Biochem J. 2009 Jan 1;417(1):379-89
This article should be referenced as such:
Di Bernardo J, Rhoden KJ. SLC5A8 (solute carrier family 5 member 8). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):781-784.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 785
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TMPRSS4 (transmembrane protease, serine 4) Youngwoo Park
Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon,
Korea (YP)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/TMPRSS4ID42594ch11q23.html DOI: 10.4267/2042/44830
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 3.4.21.-; MT-SP2; TMPRSS3
HGNC (Hugo): TMPRSS4
Location: 11q23.3
Note: Not to be confused with TMPRSS3 (21q22.3),
which was originally named for TMPRSS4 (11q23.3).
DNA/RNA
Description
TMPRSS4 gene approximately extends 41.38 kb-long
on chromosome 11 in the region p23.3, containing 13
exons.
Transcription
Two alternative splicing variants have been described,
producing transcripts of 2.12 kb and 1.98 kb,
respectively.
Protein
Description
TMPRSS4 is a 437 amino acid type II transmembrane
serine protease (TTSPs) which are expressed at the cell
surface and are thus ideally located to regulate cell-cell
and cell-matrix interactions.
Expression
TMPRSS4 is highly expressed in pancreatic, colon,
lung and gastric cancer tissues, and TMPRSS4 is also
broadly expressed in a variety of human cancer cell
lines, such as NCI-H322, Colo205 and HCT15.
Localisation
Membrane; single-pass type II membrane protein.
Function
TMPRSS4 plays a role in invasion, metastasis,
migration and adhesion, as well as in the EMT in
cancer cells.
TMPRSS4 is a 437 amino acid single-pass type II membrane protein. It contains a Serine protease domain at the C-terminus, followed by a Scavenger receptor cysteine-rich domain (SRDR) and a Low Density Lipoprotein Receptor Class A domain. Letters H, D and S in the serine protease domain indicate the position of the three catalytic residues histidine, aspartate and serine, respectively.
TMPRSS4 (transmembrane protease, serine 4) Park Y
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 786
Loss of E-cadherin transcript, a hallmark of EMT, was
induced by TMPRSS4. It also modulates cell growth in
a cell type-dependent manner. TMPRSS4 expression is
upregulated in lung cancer tissues compared with
normal tissues, and various cancer cell lines themselves
express TMPRSS4 at various levels.
Homology
TMPRSS4 is a type II transmembrane serine protease
(TTSPs) which contains a serine protease domain.
Human TTSPs, which consists of 17 members, were
grouped into four subfamilies based on similarity in
domain structure and phylogenetic analysis of the
serine protease domains, namely the matriptase, corin,
hepsin/TMPRSS and HAT/DESC subfamilies.
Implicated in
Colon cancer
Oncogenesis
TMPRSS4 is an important mediator of invasion,
metastasis, migration, adhesion and EMT (epithelial-
mesenchymal transition) in human epithelial colon
cancer cells and also modulates in vitro cell growth in a
cell type- and/or signaling context dependent manner,
suggesting that TMPRSS4 may represent a novel
therapeutic target for cancer.
TMPRSS4 overexpression induces an EMT associated
with SIP1/ZEB2 induction and E-cadherin loss in
SW480 cells, and also promotes metastasis of SW480
cells.
TMPRSS4 overexpression is associated with
morphological changes and actin cytoskeleton
rearrangement.
Pancreatic cancer
Oncogenesis
TMPRSS4 is strongly expressed in a subset of
pancreatic cancer and various other cancer tissues, and
its expression correlates with the metastatic potential of
the pancreatic cancer cell lines.
Multidomain structure of human TTSPs. Human TTSPs were grouped into four subfamilies based on similarity in domain structure and phylogenetic analysis of the serine protease domains, namely the matriptase, corin, hepsin/TMPRSS and HAT/DESC subfamilies. Consensus domains are shown above. Each diagram was drawn using the web-based SMART software (http://smart.embl-heidelberg.de) with TTSP amino acid sequences obtained from GenBank. Abbreviations: CUB, Cls/Clr, urchin embryonic growth factor and bone morphogenic protein-1 domain; DESC1, differentially expressed squamous cell carcinoma gene 1; FRZ, frizzled domain; HAT, human airway trypsin-like protease; LDLA, low-density lipoprotein receptor domain class A; MAM, a meprin, A5 antigen and receptor protein phosphatase m domain; MSPL, mosaic serine protease long-form; Polyserase-1, polyserine protease-1; SEA, a single sea urchin sperm protein, enteropeptidase, agrin domain; SR, scavenger receptor cysteine-rich domain; TM, transmembrane domain. Letters H, D and S in the serine protease domain (active) indicate the position of the three catalytic residues histidine, aspartate and serine, respectively. Letter A in the serine protease domain (inactive) indicates a serine to alanine exchange.
TMPRSS4 (transmembrane protease, serine 4) Park Y
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 787
References Wallrapp C, Hähnel S, Müller-Pillasch F, Burghardt B, Iwamura T, Ruthenbürger M, Lerch MM, Adler G, Gress TM. A novel transmembrane serine protease (TMPRSS3) overexpressed in pancreatic cancer. Cancer Res. 2000 May 15;60(10):2602-6
Jarzab B, Wiench M, Fujarewicz K, Simek K, Jarzab M, Oczko-Wojciechowska M, Wloch J, Czarniecka A, Chmielik E, Lange D, Pawlaczek A, Szpak S, Gubala E, Swierniak A. Gene expression profile of papillary thyroid cancer: sources of variability and diagnostic implications. Cancer Res. 2005 Feb 15;65(4):1587-97
Kebebew E, Peng M, Reiff E, Duh QY, Clark OH, McMillan A. ECM1 and TMPRSS4 are diagnostic markers of malignant thyroid neoplasms and improve the accuracy of fine needle aspiration biopsy. Ann Surg. 2005 Sep;242(3):353-61; discussion 361-3
Yamada H, Shinmura K, Tsuneyoshi T, Sugimura H. Effect of splice-site polymorphisms of the TMPRSS4, NPHP4 and ORCTL4 genes on their mRNA expression. J Genet. 2005 Aug;84(2):131-6
Kebebew E, Peng M, Reiff E, McMillan A. Diagnostic and extent of disease multigene assay for malignant thyroid neoplasms. Cancer. 2006 Jun 15;106(12):2592-7
Choi SY, Shin HC, Kim SY, Park YW. Role of TMPRSS4 during cancer progression. Drug News Perspect. 2008 Oct;21(8):417-23
Jung H, Lee KP, Park SJ, Park JH, Jang YS, Choi SY, Jung JG, Jo K, Park DY, Yoon JH, Park JH, Lim DS, Hong GR, Choi C, Park YK, Lee JW, Hong HJ, Kim S, Park YW. TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial-mesenchymal transition. Oncogene. 2008 Apr 17;27(18):2635-47
Li BH, Yang XZ, Li PD, Yuan Q, Liu XH, Yuan J, Zhang WJ. IL-4/Stat6 activities correlate with apoptosis and metastasis in colon cancer cells. Biochem Biophys Res Commun. 2008 May 2;369(2):554-60
Chaipan C, Kobasa D, Bertram S, Glowacka I, Steffen I, Tsegaye TS, Takeda M, Bugge TH, Kim S, Park Y, Marzi A, Pöhlmann S. Proteolytic activation of the 1918 influenza virus hemagglutinin. J Virol. 2009 Apr;83(7):3200-11
Choi SY, Bertram S, Glowacka I, Park YW, Pöhlmann S. Type II transmembrane serine proteases in cancer and viral infections. Trends Mol Med. 2009 Jul;15(7):303-12
This article should be referenced as such:
Park Y. TMPRSS4 (transmembrane protease, serine 4). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):785-787.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 788
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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TSPAN8 (tetraspanin 8) Uwe Matthias Galli
Department of Tumour Cell Biology, University Hospital of Surgery, Heidelberg, Germany (UMG)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/TSPAN8ID42585ch12q21.html DOI: 10.4267/2042/44831
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: CO-029; TM4SF3; Tspan-8
HGNC (Hugo): TSPAN8
Location: 12q21.1
DNA/RNA
The human Tspan8 gene contains 9 exons and 8 introns
and was predicted to span over 32,9 kb appoximately of
the genomic DNA. Transcript length: 1130 bps,
translation length: 237 residues.
Tetraspanin 8 has a short amino- and carboxy-terminal tail, a small intracellular loop between transmembrane region 2 (TM2) and TM3, a small extracellular loop (ECL1) between TM1 and TM2 and a large extracellular loop (ECL2) between TM3 and TM4. Extracellular loop 2 contains six conserved cysteine residues (red) including the CCG motif; disulphide bonds are indicated. The transmembrane regions 1 and 4 have polar amino acids (green), the cytoplasmic domains contain palmitoylation sites (pink) and the carboxy-terminal domain contains a sorting motif (blue).
TSPAN8 (tetraspanin 8) Galli UM
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 789
Protein
Description
Tspan8 is a member of the transmembrane 4
superfamily, also known as the tetraspanin family.
Expression
Tetraspanin 8 is expressed in squamous epithelial cells
(not epidermis), capillary endothelial cells, nerves,
smooth and striated muscle cells, and subpopulations of
hematopoietic progenitor cells.
Function
Like other tetraspanins, Tspan8 act as a "molecular
facilitator" by forming a web in glycolipid-enriched
membrane microdomains, called TEM (tetraspanin
enriched membrane domains). Tspan8 associates with
additional tetraspanins, integrins, preferentially CD49c,
CD104, but also CD49d. It is directly associated with
EWI-F, CD13 and intersectin 2. Via its associated
molecules Tspan8 becomes involved in cell adhesion
and motility as well as signal transduction. Motility
promotion mostly proceeds via its association with
CD104 and is in line with pronounced metastatic
spread of Tspan8 overexpressing tumors as described
for hepatocellular cancer. Similar to other tetraspanins,
Tspan8 is abundantly present in exosomes, where it
accounts via its association with CD49d for endothelial
cell and endothelial cell progenitor targeting with the
consequence of endothelial cell activation and
endothelial cell progenitor maturation.
Regulates cell motility and survival and is involved in
the promotion of angiogenesis.
Mutations
Note
Not known in Homo sapiens.
Implicated in
Tumors of the gastrointestinal tract
Note
CO-029 is associated with tumor progression and is
supposed to promote metastasis formation. It has been
described as a marker of several types of carcinomas
and sarcomas. In gastrointestinal tumors the expression
of CO-029 has been associated with a poor pognosis.
Disease
Gastric tumors, colorectal tumors, pancreatic tumors
and liver tumors.
Hepatocellular carcinoma (HCC)
Note
Tetraspanin CO-029 was found to be frequently and
significantly overexpressed in HCC. CO-029 was
overexpressed in poorly differentiated HCCs compared
with well to moderately differentiated tumors, and in
HCCs showing intrahepatic spreading compared with
those without spreading.
References Szala S, Kasai Y, Steplewski Z, Rodeck U, Koprowski H, Linnenbach AJ. Molecular cloning of cDNA for the human tumor-associated antigen CO-029 and identification of related transmembrane antigens. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6833-7
Claas C, Seiter S, Claas A, Savelyeva L, Schwab M, Zöller M. Association between the rat homologue of CO-029, a metastasis-associated tetraspanin molecule and consumption coagulopathy. J Cell Biol. 1998 Apr 6;141(1):267-80
Kanetaka K, Sakamoto M, Yamamoto Y, Yamasaki S, Lanza F, Kanematsu T, Hirohashi S. Overexpression of tetraspanin CO-029 in hepatocellular carcinoma. J Hepatol. 2001 Nov;35(5):637-42
Kanetaka K, Sakamoto M, Yamamoto Y, Takamura M, Kanematsu T, Hirohashi S. Possible involvement of tetraspanin CO-029 in hematogenous intrahepatic metastasis of liver cancer cells. J Gastroenterol Hepatol. 2003 Nov;18(11):1309-14
Gesierich S, Paret C, Hildebrand D, Weitz J, Zgraggen K, Schmitz-Winnenthal FH, Horejsi V, Yoshie O, Herlyn D, Ashman LK, Zöller M. Colocalization of the tetraspanins, CO-029 and CD151, with integrins in human pancreatic adenocarcinoma: impact on cell motility. Clin Cancer Res. 2005 Apr 15;11(8):2840-52
Le Naour F, André M, Greco C, Billard M, Sordat B, Emile JF, Lanza F, Boucheix C, Rubinstein E. Profiling of the tetraspanin web of human colon cancer cells. Mol Cell Proteomics. 2006 May;5(5):845-57
Kuhn S, Koch M, Nübel T, Ladwein M, Antolovic D, Klingbeil P, Hildebrand D, Moldenhauer G, Langbein L, Franke WW, Weitz J, Zöller M. A complex of EpCAM, claudin-7, CD44 variant isoforms, and tetraspanins promotes colorectal cancer progression. Mol Cancer Res. 2007 Jun;5(6):553-67
Zhou Z, Ran YL, Hu H, Pan J, Li ZF, Chen LZ, Sun LC, Peng L, Zhao XL, Yu L, Sun LX, Yang ZH. TM4SF3 promotes esophageal carcinoma metastasis via upregulating ADAM12m expression. Clin Exp Metastasis. 2008;25(5):537-48
Zöller M. Tetraspanins: push and pull in suppressing and promoting metastasis. Nat Rev Cancer. 2009 Jan;9(1):40-55
This article should be referenced as such:
Galli UM. TSPAN8 (tetraspanin 8). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):788-789.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 790
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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TXN (thioredoxin) Zhe Chen, Eiji Yoshihara, Hajime Nakamura, Hiroshi Masutani, Junji Yodoi
Department of Biological Responses, Institute for Virus Research, Kyoto University, Shogoin, Kawahara-
cho, Sakyo-ku, Kyoto, Japan (ZC, EY, HN, HM, JY)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/TXNID44354ch9q31.html DOI: 10.4267/2042/44832
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: ADF; DKFZp686B1993; MGC61975;
SASP; TRDX; TRX; TRX1; Trx
HGNC (Hugo): TXN
Location: 9q31.3
Local order: 9q telomere-3'TXN 5'-centromere.
DNA/RNA
Description
5 exons, 5' part of exon 1 and 3' part of exon 5 are non-
coding.
Transcription
508 bps mRNA, transcribed in a telomere to
centromere direction.
Chromosome : 9, Location : 9q31. (Please visit http://www.ncbi.nlm.nih.gov for more details).
5 exons of thioredoxin. (Please visit http://www.ncbi.nlm.nih.gov for more details).
TXN (thioredoxin) Chen Z, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 791
Alternative splicing of human thioredoxin (lacking
exon 2 and 3) was reported in cancer cells.
Thioredoxin (TRX/TXN/ADF) expression is induced
by a variety of physiochemical stresses, including virus
infection, mitogens, UV-irradiation, hydrogen
peroxide, ischemia reperfusion and so on. Natural
substances including hemin, estrogen, prostaglandins,
sulforaphane, and cAMP can also induce the expression
and secretion of TRX. Geranylgeranylacetone (GGA),
an acyclic polyisoprenoid as anti-ulcer drug, or tert-
butylhydroquinone (tBHQ), a xenobiotics, can also
induce TRX expression.
The 5' flanking sequence of TRX gene contains a series
of stress-responsive elements, antioxidant responsive
element (ARE), cAMP responsive element (CRE),
xenobiotics responsive element (XRE) and Sp1.
Protein
Note
Thioredoxin is a 12 kDa ubiquitous protein that has
disulfide-reducing activity. The structural fold of
thioredoxin, including redox-active site, is called
"TRX-family domain", which is shared by other TRX
superfamily proteins.
Description
In 1964, thioredoxin, named by one Swedish group,
was first identified from extracts of Escherichia coli B
as hydrogen donor from NADPH to ribonucleotide
reductase. Human thioredoxin was originally cloned by
a Japanese group as an IL-2Ralpha (CD25) induced
factor in HTLV-1 infected T-cell lines and designated
as Adult T cell leukemia derived factor (ADF). It was
also cloned independently by a French group as an IL-1
like growth factor produced by Epstein-Barr virus-
transformed cells.
Thioredoxin is a 12 kDa multifunctional protein with a
redox-active site (Cys-Gly-Pro-Cys), which is involved
in dithiol/disulfide exchange reaction. Reduced TRX
can reduce protein disulfide bonds and oxidized TRX is
reduced by NADPH and thioredoxin reductase.
Expression
Thioredoxin is ubiquitously expressed in normal tissues
or cells. Plasma levels of TRX in normal individuals
vary between 10 and 80 ng/mL. The plasma TRX level
is elevated in certain human diseases including HIV
infection and cancer. As mentioned above, thioredoxin
can also be induced by various physiochemical stress
and some natural agents or drugs.
Localisation
Thioredoxin is mainly localized in the cytoplasm.
Under environmental stress, such as UVB irradiation,
PMA, H2O2, hypoxia, the cancer drug cisplatin, hemin
and so on, it can translocate to the nucleus, possibly
participating to the regulation of nuclear transcription
factors, such as Ref-1. Thioredoxin can also be secreted
in response to oxidative stress and function as a
cytokine to alleviate inflammation. The secretion
mechanism of thioredoxin remains unclear.
Thioredoxin accumulation in the membrane fraction
has long been implied by Holmgren's group in 1989.
Later it is found to be expressed on the surface of
HUVECs (human umbilical vein endothelial cells),
including lipid raft which may be involved in redox
signalling.
Function
Thioredoxin plays an important role in scavenging
reactive oxygen intermediates (ROIs) produced in
various oxidative stress. Redox-associated signal
transduction inside the cell may be attributed to
enhanced DNA binding ability of several transcription
factors, such as Ref-1, AP-1, NF-kappaB, which have
been proved to be modulated directly or indirectly by
thioredoxin. Acting as an intracellular reductase,
thioredoxin promotes cellular proliferation to alleviate
oxidative stress. Besides reducing activity, thioredoxin
inhibit apoptosis through direct binding to apoptosis
signal regulating kinase-1 (ASK-1). Thioredoxin is
essential for early differentiation and morphogenesis of
mouse embryo. Thioredoxin-transgenic (TRX-TG)
mice are more resistant to oxidative stress and survive
longer than normal mice.
Extracellular thioredoxin shows cytokine or
chemokine-like effects. It was reported to show
mitogenic effects on leukemia cells, which is also
dependent on the presence of reducing agents like 2-
ME, and the intact active di-thiol site. It was also
reported to show cytoprotective effects through
suppressing the production of some inflammatory
cytokines.
Active site and conserved domain of thioredoxin. (Please see http://www.ncbi.nlm.nih.gov for more details).
TXN (thioredoxin) Chen Z, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 792
Chemotactic effects of thioredoxin was also observed
which may be immune cell type specific and dose
dependent since TRX in higher concentration (>1
microg/ml) in circulation shows anti-chemotactic
effects. How extracellular thioredoxin interacts with
potential target proteins at the plasma membrane may
be a key for clarifying the complicated mechanisms.
Several TRX-binding proteins have been identified so
far. Reduced TRX in cytosol can bind ASK-1, which
activate c-Jun N-terminal kinase (JNK) and p38 MAPK
kinase pathway and is required for TNF-a-induced
apoptosis. TRX also regulates transcription factor by
interaction with redox factor 1 (Ref-1), which has a
reducing activity and apurine/apyrimidine
endonuclease repair activity. TRX was also reported to
bind conserved DNA binding domain of glucocorticoid
receptor under oxidative conditions to regulate nuclear
receptor-mediated signal transduction. More well-
known binding partner of TRX is thioredoxin binding
protein-2 (TBP-2/TXNIP/VDUP-1). TBP-2 can
downregulate the expression and the reducing activity
of TRX.
TBP-2 shows potent growth suppressive effect and
until recently it was reported to be a metabolic
mediator of lipid and glucose metabolisms. All these
findings suggest that TRX/TBP-2 binding may regulate
redox and metabolic responses in vivo.
Homology
Thioredoxin is ubiquitously expressed in different
organisms. Chicken, mouse, rat and bovine TRXs have
also been cloned. Human and other mammalian TRXs
contain, in addition to the two cysteins in Trp-Cys32-
Gly-Pro-Cys35-Lys, three other Cys redidues, Cys62,
Cys69, and Cys73 (numbers are based on human TRX),
which are not found in TRX of bacterial origins. The
C-terminal Cys73 residue of mammalian TRX is shown
to be involved in dimmer formation.
Proteins sharing the similar active sites Cys-Xxx-Yyy-
Cys, are called as members of TRX superfamily. TRX-
2 is one homologous protein of TRX, which also
contains Cys-Gly-Pro-Cys active site. However, TRX-2
is located in mitochondrial with extra N-terminal
mitochondrial translocation signal peptide. TRX2 may
play an important role in the mitochondria-mediated
apotosis. Other TRX superfamilly proteins consist of
MIF (macrophage migration inhibitory factor), PDI
(protein disulfide isomerase), TMX, glutaredoxin,
nucleoredoxin, etc... These proteins have different
redox-relative functions in respective cellular
compartment.
Implicated in
Various cancers
Note
Elevated expression of thioredoxin was reported in
various human cancers, including hepatocellular
carcinoma, pancreatic, lung, cervical, gastric, colorectal
cancer, adult T cell leukemia, myeloma, non-Hodgkin
lymphoma, and acute lymphocytic leukemia. The
overexpression of TRX in cancer cells seems to be
associated with the growth promotion of cancer cells, a
worse prognosis for patients, and the development of
resistance to anti-cancer agents.
However, there is no evidence showing that
exogenously administered rhTRX promotes the growth
of cancer, although exogenous rhTRX may alleviate
local or systemic inflammatory disorders in these
cancer patients.
Prognosis
In non-small cell lung carcinomas, intracellular TRX
expression is indicative of a more aggressive tumor
phenotype and worse prognosis.
Oncogenesis
Unknown.
Adult T cell leukemia (ATL), acquired immunodeficiency syndrome (AIDS), hepatitis C virus (HCV), originated from virus infection
Note
As mentioned above, human thioredoxin was first
cloned as a secreted adult T cell leukemia (ATL)
derived factor. Its expression is markedly enhanced in
HTLV-I-infected T cells.
The elevated level of plasma thioredoxin was reported
in AIDS patients with worse prognosis and inversely
correlated with intracellular glutathion level.
In hepatitis C virus infection, serum levels of TRX is
also elevated. The serum TRX levels of patients with
HCV infection increased with their serum ferritin levels
and the progression of liver fibrosis. Furthermore,
serum thioredoxin and ferritin are good markers for the
efficacy of interferon therapy.
Prognosis
As above, the plasma or serum level of thioredoxin is a
good marker for oxidative stress associated with virus
infection, so as to be possibily used in clinics.
Oncogenesis
Unknown.
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Teshigawara K, Maeda M, Nishino K, Nikaido T, Uchiyama T, Tsudo M, Wano Y, Yodoi J. Adult T leukemia cells produce a lymphokine that augments interleukin 2 receptor expression. J Mol Cell Immunol. 1985;2(1):17-26
Wollman EE, d'Auriol L, Rimsky L, Shaw A, Jacquot JP, Wingfield P, Graber P, Dessarps F, Robin P, Galibert F. Cloning and expression of a cDNA for human thioredoxin. J Biol Chem. 1988 Oct 25;263(30):15506-12
TXN (thioredoxin) Chen Z, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 793
Holmgren A. Thioredoxin and glutaredoxin systems. J Biol Chem. 1989 Aug 25;264(24):13963-6
Tagaya Y, Maeda Y, Mitsui A, Kondo N, Matsui H, Hamuro J, Brown N, Arai K, Yokota T, Wakasugi H. ATL-derived factor (ADF), an IL-2 receptor/Tac inducer homologous to thioredoxin; possible involvement of dithiol-reduction in the IL-2 receptor induction. EMBO J. 1989 Mar;8(3):757-64
Wakasugi N, Tagaya Y, Wakasugi H, Mitsui A, Maeda M, Yodoi J, Tursz T. Adult T-cell leukemia-derived factor/thioredoxin, produced by both human T-lymphotropic virus type I- and Epstein-Barr virus-transformed lymphocytes, acts as an autocrine growth factor and synergizes with interleukin 1 and interleukin 2. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8282-6
Matthews JR, Wakasugi N, Virelizier JL, Yodoi J, Hay RT. Thioredoxin regulates the DNA binding activity of NF-kappa B by reduction of a disulphide bond involving cysteine 62. Nucleic Acids Res. 1992 Aug 11;20(15):3821-30
Rubartelli A, Bajetto A, Allavena G, Wollman E, Sitia R. Secretion of thioredoxin by normal and neoplastic cells through a leaderless secretory pathway. J Biol Chem. 1992 Dec 5;267(34):24161-4
Chen KS, DeLuca HF. Isolation and characterization of a novel cDNA from HL-60 cells treated with 1,25-dihydroxyvitamin D-3. Biochim Biophys Acta. 1994 Sep 13;1219(1):26-32
Gasdaska PY, Oblong JE, Cotgreave IA, Powis G. The predicted amino acid sequence of human thioredoxin is identical to that of the autocrine growth factor human adult T-cell derived factor (ADF): thioredoxin mRNA is elevated in some human tumors. Biochim Biophys Acta. 1994 Aug 2;1218(3):292-6
Kaghad M, Dessarps F, Jacquemin-Sablon H, Caput D, Fradelizi D, Wollman EE. Genomic cloning of human thioredoxin-encoding gene: mapping of the transcription start point and analysis of the promoter. Gene. 1994 Mar 25;140(2):273-8
Kitaoka Y, Sorachi K, Nakamura H, Masutani H, Mitsui A, Kobayashi F, Mori T, Yodoi J. Detection of adult T-cell leukemia-derived factor/human thioredoxin in human serum. Immunol Lett. 1994 Jul;41(2-3):155-61
Holmgren A, Björnstedt M. Thioredoxin and thioredoxin reductase. Methods Enzymol. 1995;252:199-208
Schenk H, Vogt M, Dröge W, Schulze-Osthoff K. Thioredoxin as a potent costimulus of cytokine expression. J Immunol. 1996 Jan 15;156(2):765-71
Taniguchi Y, Taniguchi-Ueda Y, Mori K, Yodoi J. A novel promoter sequence is involved in the oxidative stress-induced expression of the adult T-cell leukemia-derived factor (ADF)/human thioredoxin (Trx) gene. Nucleic Acids Res. 1996 Jul 15;24(14):2746-52
Hirota K, Matsui M, Iwata S, Nishiyama A, Mori K, Yodoi J. AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3633-8
Kurooka H, Kato K, Minoguchi S, Takahashi Y, Ikeda J, Habu S, Osawa N, Buchberg AM, Moriwaki K, Shisa H, Honjo T. Cloning and characterization of the nucleoredoxin gene that encodes a novel nuclear protein related to thioredoxin. Genomics. 1997 Feb 1;39(3):331-9
Nakamura H, Nakamura K, Yodoi J. Redox regulation of cellular activation. Annu Rev Immunol. 1997;15:351-69
Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 1998 May 1;17(9):2596-606
Hirota K, Murata M, Sachi Y, Nakamura H, Takeuchi J, Mori K, Yodoi J. Distinct roles of thioredoxin in the cytoplasm and in the nucleus. A two-step mechanism of redox regulation of transcription factor NF-kappaB. J Biol Chem. 1999 Sep 24;274(39):27891-7
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Kakolyris S, Giatromanolaki A, Koukourakis M, Powis G, Souglakos J, Sivridis E, Georgoulias V, Gatter KC, Harris AL. Thioredoxin expression is associated with lymph node status and prognosis in early operable non-small cell lung cancer. Clin Cancer Res. 2001 Oct;7(10):3087-91
Sun QA, Kirnarsky L, Sherman S, Gladyshev VN. Selenoprotein oxidoreductase with specificity for thioredoxin and glutathione systems. Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3673-8
Hirota K, Nakamura H, Masutani H, Yodoi J. Thioredoxin superfamily and thioredoxin-inducing agents. Ann N Y Acad Sci. 2002 May;957:189-99
Bai J, Nakamura H, Kwon YW, Hattori I, Yamaguchi Y, Kim YC, Kondo N, Oka S, Ueda S, Masutani H, Yodoi J. Critical roles of thioredoxin in nerve growth factor-mediated signal transduction and neurite outgrowth in PC12 cells. J Neurosci. 2003 Jan 15;23(2):503-9
Bloomfield KL, Osborne SA, Kennedy DD, Clarke FM,
Tonissen KF. Thioredoxin-mediated redox control of the transcription factor Sp1 and regulation of the thioredoxin gene promoter. Gene. 2003 Nov 13;319:107-16
Hosoda A, Kimata Y, Tsuru A, Kohno K. JPDI, a novel endoplasmic reticulum-resident protein containing both a BiP-interacting J-domain and thioredoxin-like motifs. J Biol Chem. 2003 Jan 24;278(4):2669-76
Kim YC, Yamaguchi Y, Kondo N, Masutani H, Yodoi J. Thioredoxin-dependent redox regulation of the antioxidant responsive element (ARE) in electrophile response. Oncogene. 2003 Mar 27;22(12):1860-5
TXN (thioredoxin) Chen Z, et al.
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Matthias LJ, Hogg PJ. Redox control on the cell surface: implications for HIV-1 entry. Antioxid Redox Signal. 2003 Feb;5(1):133-8
Sadek CM, Jiménez A, Damdimopoulos AE, Kieselbach T, Nord M, Gustafsson JA, Spyrou G, Davis EC, Oko R, van der Hoorn FA, Miranda-Vizuete A. Characterization of human thioredoxin-like 2. A novel microtubule-binding thioredoxin expressed predominantly in the cilia of lung airway epithelium and spermatid manchette and axoneme. J Biol Chem. 2003 Apr 11;278(15):13133-42
Watson WH, Pohl J, Montfort WR, Stuchlik O, Reed MS, Powis G, Jones DP. Redox potential of human thioredoxin 1 and identification of a second dithiol/disulfide motif. J Biol Chem. 2003 Aug 29;278(35):33408-15
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Haugstetter J, Blicher T, Ellgaard L. Identification and characterization of a novel thioredoxin-related transmembrane protein of the endoplasmic reticulum. J Biol Chem. 2005 Mar 4;280(9):8371-80
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This article should be referenced as such:
Chen Z, Yoshihara E, Nakamura H, Masutani H, Yodoi J. TXN (thioredoxin). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):790-794.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 795
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
t(1;12)(q21;q24) Sang-Guk Lee, Tae Sung Park, Jong Rak Choi
Department of Laboratory Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-
gu, Seoul 120-752, Korea (SGL); Department of Laboratory Medicine, Kyung Hee University College of
Medicine, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-702, Korea (TSP); Department of Laboratory
Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Korea
(JRC)
Published in Atlas Database: September 2009
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0112q21q24ID1531.html DOI: 10.4267/2042/45124
This article is an update of : Huret JL. t(1;12)(q21;q24). Atlas Genet Cytogenet Oncol Haematol 2009;13(11):880. 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
Clinics and pathology
Disease
Acute myeloid leukaemia (AML), myelodysplastic
syndrome (MDS)
Epidemiology
Only 3 cases to date, a 24-year-old female patient with
a M2-AML, a patient with a treatment related AML (t-
AML), and a 48-year-old patient with MDS (Koo et al.,
1998; Olney et al., 2002; Park et al., 2009). Although it
is a rare chromosomal abnormality, it may be an
aberration related to myeloid neoplasms including
AML and MDS.
Prognosis
No detailed data available. However, one of them (Park
et al., 2009) received bone marrow transplantation;
complete donor chimerism was maintained for thirteen
months until last follow up.
t(1;12)(q21;q24) Lee SG, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 796
Cytogenetics
Cytogenetics morphological
It shows balanced chromosomal translocation between
1q21 and 12q24.
Additional anomalies
The patient with a M2-AML also had an i(17q).
The patient with a MDS had +8, +der(12)t(1;12)
additionally.
Genes involved and proteins
Note
The genes involved in this anomaly are unknown.
References Koo SH, Kwon GC, Chun HJ, Park JW. Cytogenetic and fluorescence in situ hybridization analyses of hematologic
malignancies in Korea. Cancer Genet Cytogenet. 1998 Feb;101(1):1-6
Olney HJ, Mitelman F, Johansson B, Mrózek K, Berger R, Rowley JD. Unique balanced chromosome abnormalities in treatment-related myelodysplastic syndromes and acute myeloid leukemia: report from an international workshop. Genes Chromosomes Cancer. 2002 Apr;33(4):413-23
Park TS, Lee SG, Song J, Kim JS, Choi JR. A novel t(1;12)(q21;q24) in a patient with myelodysplastic syndrome. Ann Hematol. 2010 May;89(5):513-6
This article should be referenced as such:
Lee SG, Park TS, Choi JR. t(1;12)(q21;q24). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):795-796.
Leukaemia Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 797
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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t(1;14)(q21;q32), t(1;22)(q21;q11) Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: September 2009
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0114q21q32ID1548.html DOI: 10.4267/2042/44833
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
Non Hodgkin lymphoma and acute lymphoblastic
lymphoma.
Phenotype/cell stem origin
23 cases to date: follicular lymphomas (FL, n=9),
diffuse large B-cell lymphomas (DLBCL, n=5),
marginal zone lymphoma (n=1), other B-cell non
Hodgkin lymphomas, not otherwise specified (NHL
NOS, n=4), pre-B acute lymphoblastic leukaemia (B-
ALL, n=1), B-cell clonal hyperplasia without any sign
of malignant transformation (n=1), and a myeloma cell
line (Koduru et al., 1987; Oscier et al., 1996; Pinkerton
et al., 1992; Willis et al., 1998; Callanan et al., 2000;
Dyomin et al., 2000; Gilles et al., 2000; Chen et al.,
2001; Hatzivassiliou et al., 2001; Le Baccon et al.,
2001; Mohamed et al., 2001; Sato et al., 2001; Bosga-
Bouwer et al., 2003; Sonoki et al., 2004; Keller et al.,
2006; Johnson et al., 2009).
Also a case of T-cell angioimmunoblastic lymphoma
was described with this translocation, but it is likely
that IgH was not involved in the cancer process in the
latter case (Kanda-Akano et al., 2004).
Epidemiology
There were 9 male and 5 female patients. Median age
was 56-57 years (range 30-81 years, data from 14
patients).
Prognosis
Insufficient data.
Cytogenetics
Cytogenetics morphological
The t(1;14)(q21;q32) was found in 12 of 23 cases, and
the t(1;22)(q21;q11) was found in 11 of 23 cases, a
much higher percentage than for the variant
translocations of the t(8;14)(q24;q32), or those of the
t(14;18)(q32;q21). No case with t(1;2)(q21;p11) has so
far been described.
Surprisingly also was that out of 11 well documented
cases of t(1;14), there was no one case with a t(14;18),
whereas out 8 well documented cases of t(1;22), 100%
of the cases also had a t(14;18).
Additional anomalies
Out of 16 cases with complete data on the karyotype,
the translocation was found as the sole anomaly in 2
cases, and complex karyotypes were found in 13 cases.
Accompanying anomalies were the following there was
a t(14;18)(q32;q21) in 8 cases, only found in FL or in
"NHL-NOS" cases, +7 in 5 cases, the rare
t(8;9)(q24;p13) was found in 3 instances, +18 in 3
cases, +X, +12, +18, a 3q27 rearrangement, a del(6q), a
del(7q), and/or a del(13q) in 2 cases each, +3, +8, +9,
+17, a t(2;12)(p11;p13), a t(8;14)(q24;q32), a
t(18;22)(q21;q11), and/or an i(6p) in one case each.
Genes involved and proteins
Note
In 14q32 sits IgH, and IgL in 22q11.
The translocation t(1;14 or 22)(q21;q32 or q11) is
heterogeneous, since different cases have shown
different genes in 1q21 deregulated by the
translocation:
t(1;14)(q21;q32), t(1;22)(q21;q11) Huret JL
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 798
- BCL9 (Willis et al., 1998). BCL9 binds to CTNNB1
(beta-catenin) and is required for Wnt signal
transduction (Kramps et al., 2002). BCL9 starts at
145479806 and ends at 145564639 bp from pter.
- MUC1 (Dyomin et al., 2000; the same case was
independantly reported in Gilles et al., 2000). MUC1 is
a membrane bound mucin expressed on the surface of
epithelial cells to in protect epithelia (Carson, 2008).
MUC1 starts at 153424924 and ends at 153429324 bp
from pter.
- FCRL4 and/or FCRL5 (Hatzivassiliou et al., 2001;
Sonoki et al., 2004). FCRL4 is a cell surface receptor
related to the Fc receptor, inhibitory receptor
superfamily, and cell adhesion molecule (CAM)
families (Falini et al., 2003). FCRL4 starts at
155810163 and ends at 155834494 bp from pter.
- FCGR2B (Callanan et al., 2000; Chen et al., 2001).
FCGR2B is a Low affinity IgG Fc receptor (Callanan
and Leroux, 2002). FCGR2B starts at 159899564 and
ends at 159914575 bp from pter.
As a matter of fact, these translocations span 1q21 to
1q23. Also, many other genes of interest are in the area
delimited by BCL9 and FCGR2B (see
http://atlasgeneticsoncology.org/Indexbychrom/idxa_1.
html "Ordered by Location").
From the very short sample of cases for each partner
gene, it is impossible to delineate different entities with
different epidemiologies and prognoses. They are
therefore needed, for clinical goals.
Result of the chromosomal anomaly
Fusion protein
Oncogenesis
No fusion protein, but promoter exchange; the
immunoglobulin gene enhancer stimulates the
expression of the partner gene.
References Koduru PR, Filippa DA, Richardson ME, Jhanwar SC, Chaganti SR, Koziner B, Clarkson BD, Lieberman PH, Chaganti RS. Cytogenetic and histologic correlations in malignant lymphoma. Blood. 1987 Jan;69(1):97-102
Pinkerton PH, Reis MD, DeCoteau J, Srigley JR, Dubé ID, London B. A lineage-specific t(1;14)(q21;q32) as an early event in development of B-cell clonal expansion. Cancer Genet Cytogenet. 1992 Dec;64(2):166-9
Oscier DG, Gardiner A, Mould S. Structural abnormalities of chromosome 7q in chronic lymphoproliferative disorders. Cancer Genet Cytogenet. 1996 Nov;92(1):24-7
Willis TG, Zalcberg IR, Coignet LJ, Wlodarska I, Stul M, Jadayel DM, Bastard C, Treleaven JG, Catovsky D, Silva ML, Dyer MJ. Molecular cloning of translocation t(1;14)(q21;q32) defines a novel gene (BCL9) at chromosome 1q21. Blood. 1998 Mar 15;91(6):1873-81
Callanan MB, Le Baccon P, Mossuz P, Duley S, Bastard C, Hamoudi R, Dyer MJ, Klobeck G, Rimokh R, Sotto JJ, Leroux
D. The IgG Fc receptor, FcgammaRIIB, is a target for deregulation by chromosomal translocation in malignant lymphoma. Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):309-14
Dyomin VG, Palanisamy N, Lloyd KO, Dyomina K, Jhanwar SC, Houldsworth J, Chaganti RS. MUC1 is activated in a B-cell lymphoma by the t(1;14)(q21;q32) translocation and is rearranged and amplified in B-cell lymphoma subsets. Blood. 2000 Apr 15;95(8):2666-71
Gilles F, Goy A, Remache Y, Shue P, Zelenetz AD. MUC1 dysregulation as the consequence of a t(1;14)(q21;q32) translocation in an extranodal lymphoma. Blood. 2000 May 1;95(9):2930-6
Chen W, Palanisamy N, Schmidt H, Teruya-Feldstein J, Jhanwar SC, Zelenetz AD, Houldsworth J, Chaganti RS. Deregulation of FCGR2B expression by 1q21 rearrangements in follicular lymphomas. Oncogene. 2001 Nov 15;20(52):7686-93
Hatzivassiliou G, Miller I, Takizawa J, Palanisamy N, Rao PH, Iida S, Tagawa S, Taniwaki M, Russo J, Neri A, Cattoretti G, Clynes R, Mendelsohn C, Chaganti RS, Dalla-Favera R. IRTA1 and IRTA2, novel immunoglobulin superfamily receptors expressed in B cells and involved in chromosome 1q21 abnormalities in B cell malignancy. Immunity. 2001 Mar;14(3):277-89
Le Baccon P, Leroux D, Dascalescu C, Duley S, Marais D, Esmenjaud E, Sotto JJ, Callanan M. Novel evidence of a role for chromosome 1 pericentric heterochromatin in the pathogenesis of B-cell lymphoma and multiple myeloma. Genes Chromosomes Cancer. 2001 Nov;32(3):250-64
Mohamed AN, Palutke M, Eisenberg L, Al-Katib A. Chromosomal analyses of 52 cases of follicular lymphoma with t(14;18), including blastic/blastoid variant. Cancer Genet Cytogenet. 2001 Apr 1;126(1):45-51
Sato Y, Kobayashi H, Suto Y, Olney HJ, Davis EM, Super HG, Espinosa R 3rd, Le Beau MM, Rowley JD. Chromosomal instability in chromosome band 12p13: multiple breaks leading to complex rearrangements including cytogenetically undetectable sub-clones. Leukemia. 2001 Aug;15(8):1193-202
Callanan M, Leroux D.. FCGR2B. Atlas Genet Cytogenet Oncol Haematol. February 2002. URL: http://AtlasGeneticsOncology.org/Genes/FCGR2BID397.html
Kramps T, Peter O, Brunner E, Nellen D, Froesch B, Chatterjee S, Murone M, Züllig S, Basler K. Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex. Cell. 2002 Apr 5;109(1):47-60
Bosga-Bouwer AG, van Imhoff GW, Boonstra R, van der Veen A, Haralambieva E, van den Berg A, de Jong B, Krause V, Palmer MC, Coupland R, Kluin PM, van den Berg E, Poppema S. Follicular lymphoma grade 3B includes 3 cytogenetically defined subgroups with primary t(14;18), 3q27, or other translocations: t(14;18) and 3q27 are mutually exclusive. Blood. 2003 Feb 1;101(3):1149-54
Falini B, Tiacci E, Pucciarini A, Bigerna B, Kurth J, Hatzivassiliou G, Droetto S, Galletti BV, Gambacorta M, Orazi A, Pasqualucci L, Miller I, Kuppers R, Dalla-Favera R, Cattoretti G. Expression of the IRTA1 receptor identifies intraepithelial and subepithelial marginal zone B cells of the mucosa-associated lymphoid tissue (MALT). Blood. 2003 Nov 15;102(10):3684-92
Kanda-Akano Y, Nomura K, Fujita Y, Horiike S, Nishida K, Nagai M, Miura I, Nakamura S, Seto M, Iida S, Ueda R, Taniwaki M. Molecular-cytogenetic characterization of non-Hodgkin's lymphoma with double and cryptic translocations of the immunoglobulin heavy chain gene. Leuk Lymphoma. 2004 Aug;45(8):1559-67
t(1;14)(q21;q32), t(1;22)(q21;q11) Huret JL
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 799
Sonoki T, Willis TG, Oscier DG, Karran EL, Siebert R, Dyer MJ. Rapid amplification of immunoglobulin heavy chain switch (IGHS) translocation breakpoints using long-distance inverse PCR. Leukemia. 2004 Dec;18(12):2026-31
Keller CE, Nandula S, Vakiani E, Alobeid B, Murty VV, Bhagat G. Intrachromosomal rearrangement of chromosome 3q27: an under recognized mechanism of BCL6 translocation in B-cell non-Hodgkin lymphoma. Hum Pathol. 2006 Aug;37(8):1093-9
Carson DD. The cytoplasmic tail of MUC1: a very busy place. Sci Signal. 2008 Jul 8;1(27):pe35
Johnson NA, Savage KJ, Ludkovski O, Ben-Neriah S, Woods R, Steidl C, Dyer MJ, Siebert R, Kuruvilla J, Klasa R, Connors JM, Gascoyne RD, Horsman DE. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood. 2009 Sep 10;114(11):2273-9
This article should be referenced as such:
Huret JL. t(1;14)(q21;q32), t(1;22)(q21;q11). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):797-799.
Leukaemia Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 800
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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dic(9;20)(p11-13;q11) Jon C Strefford
Cancer Genomics Group, Cancer Sciences Division, University of Southampton, UK (JCS)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/dic920ID1143.html DOI: 10.4267/2042/44834
This article is an update of : Gibbons B. dic(9;20)(p11-13;q11). Atlas Genet Cytogenet Oncol Haematol 1999;3(3):144 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 lymphoblastic leukaemia (ALL)
Phenotype/cell stem origin
B-cell precursor acute lymphoblastic leukemia (BCP-
ALL).
Prognosis
On a limited series, the median patient age is 3 years,
the female/male ratio of 2.0 has been reported. Risk
group stratification was nonstandard risk in 79%. The
event-free survival and overall survival at 5 years for
the 24 Nordic cases was 0.62 and 0.82, respectively.
Thus, although relapses are quite common, post-relapse
treatment of many patients is successful.
Cytogenetics
Cytogenetics morphological
Chromosomes 7, 9, 12 and 20 are frequently involved
in the formation of dicentric chromosomes in BCP-
ALL. The dic(9;20)(p11~13;q11) occurs in approx 2%
and approx 0.5% of childhood and adult BCP-ALL,
respectively. FISH has shown that dic(9;20) contains
the centromere of both chromosomes, resulting in loss
of 9p and 20q material. It is a subtle chromosome
abnormality, often appearing as monosomy 20,
sometimes with apparent deletion of 9p; confirmation
of the dic(9;20) translocation is obtained by FISH
(Figure 1).
Cytogenetics molecular
Even at the cytogenetic level, considerable breakpoint
heterogeneity is apparent on both chromosomes. Array-
based comparative genomic hybridization (aCGH),
with BAC clones at tiling resolution, has shown
clustering of breakpoints within 9p13.2 (genomic
position 37.1-38.7 Mb) and 20q11.2 (29.2-30.8 Mb).
Recent FISH mapping data has confirmed this
heterogeneity in a large series of dic(9;20) patients
(Figure 2).
Additional anomalies
The dic(9;20) can occur as a sole cytogenetic
abnormality, or in the context of a more complex
karyotype. Gains of chromosome X and 21 are the most
frequency additional findings in these patients.
Diagnostic FISH data shows that the dic(9;20) can
occur in the presence of the BCR-ABL1 and ETV6-
RUNX1 fusion genes.
Genes involved and proteins
PAX5
Location
9p13
DNA/RNA
The paired box 5 gene (PAX5) extends over 200 kb of
genomic DNA and contains 10 exons.
dic(9;20)(p11-13;q11) Strefford JC
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 801
Figure 1. Top: The left shows a G-banded karyogram of the dic(9;20). Monosomy 20 and the dicentric chromosome are highlighted with black arrows. The right shows a metaphase from the same patient using paints for chromosomes 9 (green) and 20 (red). The dicentric is shown by the white arrow - Courtesy Jon C Strefford; Bottom: M-FISH - Courtesy Melanie Zenger and Claudia Haferlach.
Protein
The gene encodes a transcription factor, with a highly
conserved DNA-binding domain, known as a paired
box. PAX5 is a 42 kDa protein of 391 amino acids that
encodes the B-cell lineage specific activator protein
that is expressed at early, but not late stages of B-cell
differentiation. The protein is expressed during B-cell
lineage commitment during early B-cell development
and maintenance.
Result of the chromosomal anomaly
Hybrid gene
Note
FISH analysis has shown that in spite of the breakpoint
heterogeneity, the PAX5 gene is targeted at high
frequencies, by a variety of genetic
mechanisms. Breakpoints proximal to PAX5 can be in
euchromatic or heterochromatic regions of the
chromosome and result in deletion of PAX5 in the
majority of cases. Less frequently, breakpoints can
occur within the PAX5 gene and result in aberrant
fusion sequences with regions of chromosome 20.
Breakpoint cloning experiments have shown PAX5
sequence juxtaposed to several genes on 20q including
ASXL1, C20ORF112 and KIF3B (Figure 3).
The genes involved in these fusion sequences are either
in opposing orientation, or in the same orientation and
out-of-frame, suggesting the biological consequence of
these fusion events in loss of function.
Quantitative PCR (qRT-PCR) has confirmed disruption
of PAX5 in the context of the dic(9;20), by showing
deregulated expression of PAX5 and several key
downstream PAX5 target genes, including, BLK, EBF1
and FLT3. In the case of PAX5-C20ORF112, it has
been shown that the C-terminal of the PAX5 protein is
dic(9;20)(p11-13;q11) Strefford JC
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 802
replaced by that of the partner gene, which does not
change the affinity for the protein to bind to recognition
sites, but does effect the expression of certain
downstream PAX5 target genes. Furthermore,
transfected vectors encoding the PAX5-C20ORF112
are able to suppress the transcriptional activity of wild-
type PAX5, leading to the inhibition of B-cell
development. Sequence analysis and genomic
quantitative PCR have also shown that the PAX5 allele
not involved in the translocation can be targeted by
mutations and homozygous deletions.
Further sequence analysis of the dic(9;20) is beginning
to unravel the heterogeneity on chromosome 20, and
identify recurrent targets. It has been suggested that
C20ORF112 may be the recurrent target gene on
chromosome 20, but this has not been supported by
other studies. In addition to C20ORF112, FISH and
molecular investigations have implicated the recurrent
involvement of ASXL1.
Advances in recent years have expanded our
understanding of the dic(9;20), most notably with the
identification of PAX5 on 9p. However, there are
exceptionally rare cases where PAX5 is not deleted or
fused though mutations of deletions beyond the
resolution of FISH cannot be excluded. The key genes
on 20q remain to be fully elucidated.
Figure 2. Breakpoint heterogeneity on chromosome 9 and 20 in the dic(9;20). A partial idiogram for each of the chromosomes is shown on the left for chromosomes 9 and 20. Each black filled square shows the position of a FISH probe in relation to the gene of interest. Each column shows an individual patient with the position and extent of the deleted region represented by vertical red bar.
dic(9;20)(p11-13;q11) Strefford JC
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 803
Figure 3. Schematic of PAX5 fusion sequences. The exons of the PAX5 and partner genes are shown in red and pink respectively. The gene orientation is shown by the horizontal arrow. Below each schematic is the corresponding predicted protein structure and domains.
References Rieder H, Schnittger S, Bodenstein H, Schwonzen M, Wörmann B, Berkovic D, Ludwig WD, Hoelzer D, Fonatsch C. dic(9;20): a new recurrent chromosome abnormality in adult acute lymphoblastic leukemia. Genes Chromosomes Cancer. 1995 May;13(1):54-61
Slater R, Smit E, Kroes W, Bellomo MJ, Mühlematter D, Harbott J, Behrendt H, Hählen K, Veerman AJ, Hagemeijer A. A non-random chromosome abnormality found in precursor-B lineage acute lymphoblastic leukaemia: dic(9;20)(p1?3;q11). Leukemia. 1995 Oct;9(10):1613-9
Heerema NA, Maben KD, Bernstein J, Breitfeld PP, Neiman RS, Vance GH. Dicentric (9;20)(p11;q11) identified by fluorescence in situ hybridization in four pediatric acute lymphoblastic leukemia patients. Cancer Genet Cytogenet. 1996 Dec;92(2):111-5
Clark R, Byatt SA, Bennett CF, Brama M, Martineau M, Moorman AV, Roberts K, Secker-Walker LM, Richards S, Eden OB, Goldstone AH, Harrison CJ. Monosomy 20 as a pointer to dicentric (9;20) in acute lymphoblastic leukemia. Leukemia. 2000 Feb;14(2):241-6
An Q, Wright SL, Konn ZJ, Matheson E, Minto L, Moorman AV, Parker H, Griffiths M, Ross FM, Davies T, Hall AG, Harrison CJ, Irving JA, Strefford JC. Variable breakpoints target PAX5 in patients with dicentric chromosomes: a model for the basis of unbalanced translocations in cancer. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17050-4
Forestier E, Gauffin F, Andersen MK, Autio K, Borgström G, et al. Clinical and cytogenetic features of pediatric dic(9;20)(p13.2;q11.2)-positive B-cell precursor acute lymphoblastic leukemias: a Nordic series of 24 cases and review of the literature. Genes Chromosomes Cancer. 2008 Feb;47(2):149-58
Kawamata N, Ogawa S, Zimmermann M, Niebuhr B, Stocking C, Sanada M, Hemminki K, Yamatomo G, Nannya Y, Koehler R, Flohr T, Miller CW, Harbott J, Ludwig WD, Stanulla M, Schrappe M, Bartram CR, Koeffler HP. Cloning of genes involved in chromosomal translocations by high-resolution single nucleotide polymorphism genomic microarray. Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11921-6
An Q, Wright SL, Moorman AV, Parker H, Griffiths M, Ross FM, Davies T, Harrison CJ, Strefford JC. Heterogeneous breakpoints in patients with acute lymphoblastic leukemia and the dic(9;20)(p11-13;q11) show recurrent involvement of genes at 20q11.21. Haematologica. 2009 Aug;94(8):1164-9
Strefford JC, An Q, Harrison CJ. Modeling the molecular consequences of unbalanced translocations in cancer: lessons from acute lymphoblastic leukemia. Cell Cycle. 2009 Jul 15;8(14):2175-84
This article should be referenced as such:
Strefford JC. dic(9;20)(p11-13;q11). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):800-803.
Solid Tumour Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 804
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Ovary: inv(10)(q11q11) in ovarian germ cell tumors Douglas S Richardson, Lois M Mulligan
Department of Pathology and Molecular Medicine, Division of Cancer Biology and Genetics, Cancer
Research Institute, Queen's University, Kingston, ON, Canada (DSR, LMM)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Tumors/inv10q11q11OvaryGermID5465.html DOI: 10.4267/2042/44835
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
Ovarian germ cell (OGC) tumours arise in the primitive
germ cells of the ovary and primarily affect younger
women. Struma ovarii are the most common
monodermal teratomas arising from OGCs. Struma
Ovarii are characterized by a composition of at least
50% mature thyroid tissue. Two reports have shown
that oncogenic mutations characteristic of thyroid
carcinoma in situ, most notably mutations found in
thyroid follicular cells that give rise to papillary thyroid
carcinoma (PTC), can be found within the thyroid
tissue of Struma Ovarii. These mutations can promote
oncogenesis, resulting in initiation of PTC within the
teratoma.
Clinics and pathology
Disease
Papillary thyroid carcinoma arising in struma ovarii.
Phenotype / cell stem origin
Struma ovarii originate from ovarian germ cells.
Malignant transformation of these monodermal
teratomas primarily occurs in follicular-like cells of the
thyroid tissue contained within struma ovarii,
producing a tumour that resembles papillary thyroid
carcinoma.
Treatment
Surgical resection of tumour, 131
I radioablation therapy.
Cytogenetics
Cytogenetics Molecular
inv(10)(q11q11)
Genes involved and proteins
Note
The inv(10)(q11q11) fuses the promoter and 5' coding
regions of NCOA4 to the 3' kinase domain coding
region of RET.
RET
Location
10q11.21
Protein
RET encodes a 175 kDa transmembrane receptor
tyrosine kinase that is required for development of the
kidney and enteric nervous system. Three isoforms of
RET have been identified that arise through 3'
alternative splicing involving exons 19, 20 and 21, and
encode proteins of 1072, 1106, and 1114 amino acids.
NCOA4
Location
10q11.23
Protein
NCOA4 is a 70 kDa co-activator protein that serves to
enhance transcriptional activity downstream of the
androgen receptor, other steroid receptors, and
peroxisome proliferator-activated receptor gamma.
Diagrammatic representation of RET and NCOA4 exon locations on Chromosome 10. Introns and exons are to scale within respective genes. Breakpoints within each gene are indicated (BP).
Ovary: inv(10)(q11q11) in ovarian germ cell tumors Richardson DS, Mulligan LM
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 805
Diagrammatic representation of RET/NCOA4 (PTC3) fusion protein. Amino acids surrounding each breakpoint (arrows) are indicated, and numbered according to their position within RET or NCOA4, respectively. Peptide sequences from RET are in red, from NCOA4 in green. The transmembrane domain (TM) of RET is shown in yellow. IC - intracellular domain.
Result of the chromosomal anomaly
Hybrid Gene
The RET/NCOA4 fusion gene is also referred to as
PTC3.
Description
The inv(10)(q11q11) results in fusion of exons 1-6 of
NCOA4 with exon 12-through to the C-terminus of
RET.
Detection
RT-PCR, Southern blot, and FISH (see Zu et al., 2006
for detailed methods).
Fusion Protein
The RET/NCOA4 fusion protein is also referred to as
PTC3. Chimeric protein consisting of the tyrosine
kinase domain of RET fused downstream of the
homodimerization domain of NCOA4. Constitutive
dimerization of fusion proteins results in continuous
downstream signalling through canonical cell growth
and proliferation pathways, promoting oncogenesis.
Description
Fusion protein consists of amino acids 1-238 of
NCOA4 and 712-C-terminus of RET. The N-terminal
region donated by NCOA4 contains a
homodimerization domain that results in constitutive
dimerization and activation of the RET kinase domain
in the C-terminal region of the molecule. Constitutive
activation increases signalling through a number of
downstream signalling pathways involved in cell
proliferation and survival, promoting oncogenesis.
Expression / Localisation
Cytoplasm.
Oncogenesis
RET/NCOA4 fusion proteins have been implicated
in the oncogenesis of papillary thyroid carcinoma.
To be noted Although RET/NCOA4 fusion proteins are known to
play a role in initiating papillary thyroid carcinoma,
they can also occur as a late mutational event. As with
all tumours, care must be taken in attributing
oncogenesis to a single genetic event.
References Santoro M, et al. Molecular characterization of RET/PTC3; a novel rearranged version of the RETproto-oncogene in a human thyroid papillary carcinoma. Oncogene. 1994 Feb;9(2):509-16
Makani S, Kim W, Gaba AR. Struma Ovarii with a focus of papillary thyroid cancer: a case report and review of the literature. Gynecol Oncol. 2004 Sep;94(3):835-9
Elisei R, Romei C, Castagna MG, Lisi S, Vivaldi A, Faviana P, Marinò M, Ceccarelli C, Pacini F, Pinchera A. RET/PTC3 rearrangement and thyroid differentiation gene analysis in a struma ovarii fortuitously revealed by elevated serum thyroglobulin concentration. Thyroid. 2005 Dec;15(12):1355-61
Zhu Z, Ciampi R, Nikiforova MN, Gandhi M, Nikiforov YE. Prevalence of RET/PTC rearrangements in thyroid papillary carcinomas: effects of the detection methods and genetic heterogeneity. J Clin Endocrinol Metab. 2006 Sep;91(9):3603-10
Boutross-Tadross O, Saleh R, Asa SL. Follicular variant papillary thyroid carcinoma arising in struma ovarii. Endocr Pathol. 2007 Fall;18(3):182-6
Yassa L, Sadow P, Marqusee E. Malignant struma ovarii. Nat Clin Pract Endocrinol Metab. 2008 Aug;4(8):469-72
Richardson DS, Gujral TS, Peng S, Asa SL, Mulligan LM. Transcript level modulates the inherent oncogenicity of RET/PTC oncoproteins. Cancer Res. 2009 Jun 1;69(11):4861-9
This article should be referenced as such:
Richardson DS, Mulligan LM. Ovary: inv(10)(q11q11) in ovarian germ cell tumors. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):804-805.
Case Report Section Paper co-edited with the European LeukemiaNet
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 806
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Dicentric dic(7;9)(p11;p11): a new case in childhood ALL Elvira D Rodrigues Pereira Velloso, Carolina Kassab, Silvia Helena A Figueira, Denise Tiemi
Noguchi, Eliana Carla Armelin Benites, Cristóvão L P Mangueira, Fábio Morato de Oliveira
Clinical Laboratory, Hospital Israelita Albert Einstein, Sao Paulo, Brazil (EDRPV, CK, SHAF, CLPM);
Instituto de Clinicas Pediatricas Bolivar Risso - GRENDACC, Sao Paulo, Brazil (DTN, ECAB);
Cytogenetics and Onco-Hematology, FMRP USP, Brazil (FMDO)
Published in Atlas Database: September 2009
Online updated version : http://AtlasGeneticsOncology.org/Reports/dic0709RodriguesID100043.html DOI: 10.4267/2042/44836
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
Age and sex
13 years old female patient.
Previous history
No preleukemia. No previous malignancy. No inborn
condition of note.
Organomegaly
Hepatomegaly, splenomegaly, enlarged lymph nodes,
no central nervous system involvement.
Blood
WBC: 28.5X 109/l
HB: 6.6g/dl
Platelets: 110X 109/l
Blasts: 64%
Bone marrow: 72.4% of lymphoid blast cells.
Cyto-Pathology Classification
Cytology
ALL-L1
Immunophenotype
Blast cells positivity for: CD 34, HLA, CD10, CD19,
CD22 and cCD79a.
Rearranged Ig Tcr
Not done.
Pathology
Not done.
Electron microscopy
Not done.
Diagnosis
Common B (B-II) ALL at diagnosis.
Survival
Date of diagnosis: 02-2009
Treatment: Chemotherapy with BFM95 for
intermediate risk.
Complete remission: remission was obtained after the
first induction cycle.
Treatment related death: no
Relapse: no
Status: Alive. Last follow up: 04-2009
Survival: 1 month
Karyotype
Sample: Bone marrow
Culture time: 24h and 48 h without stimulating agents
Banding: GAW- band
Results:
45,XX,-7,+mar[11]/45,XX,dic(7;9)(p11;p11)[9]
/46,XX[4]
Karyotype at Relapse: not applied.
Other molecular cytogenetics technics:
Spectral Karyotyping (SKY) using SkyPaint ASR
(Applied Spectral Imaging). The marker seen in the
first clone was elucidated as a derivative chromosome 9
Dicentric dic(7;9)(p11;p11): a new case in childhood ALL Rodrigues Pereira Velloso ED, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 807
(figure 3). The study confirm the der(7;9) seen in the
second clone (figure 4).
Other Molecular Studies
Technics: Not done.
Figure 1: G-banding karyotype showing the first clone with monosomy 7 and one marker (recognized as a der(9) after sky study).
Figure 2: Partial G- banding karyotypes showing the second clone with dic(7;9)(p11;p11).
Figure 3: Sky study showing the first clone with monosomy 7 and a der(9).
Dicentric dic(7;9)(p11;p11): a new case in childhood ALL Rodrigues Pereira Velloso ED, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 808
Figure 4: Sky study showing the second clone with dic(7;9)(p11;p11).
Comments
The case presented here is, to our knowledge, the 19th
reported case of dic (7;9)(p11;p11) in acute
lymphoblastic leukemia. From the literature review, 10
patients were less than 15 years old, seven with FAB
L1 morphology, like our patient. She presented a
enlarged liver and spleen, as ten and six of the cases
reported in the studies, but without hyperleukocytosis,
which was common for ALL patients with
simultaneous dic(7;9) and t(9;22), present in 9 of 18
cases.
The prognostic significance of this abnormality remains
controversial. Russo et al. suggested that the deletion of
tumor suppressor genes located on 7p is associated with
an adverse prognostic factor in ALL.
Heerema et al. related that abnormalities in
chromosome 9p are associated with increased relapse
in children with ALL, probably because the
inactivation of the tumor suppressor genes CDKN2 and
CDKN1, mapped to 9p21-22. In the series of Pan et al.
(2006), the prognosis of the patients with dic(7;9) and
t(9;22) is worse than that of those with isolated
dic(7;9).
From the 18 cases, 11 have no data of survival, 4
achieved long term remission and 3 died. Our children
remain in clinical remission 45 days after induction
therapy with intermediate risk BFM 95 (Berlin-
Frankfurt-Munster) protocol.
References Raimondi SC, Privitera E, Williams DL, Look AT, Behm F, Rivera GK, Crist WM, Pui CH. New recurring chromosomal translocations in childhood acute lymphoblastic leukemia. Blood. 1991 May 1;77(9):2016-22
Russo C, Carroll A, Kohler S, Borowitz M, Amylon M, Homans A, Kedar A, Shuster J, Land V, Crist W. Philadelphia chromosome and monosomy 7 in childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood. 1991 Mar 1;77(5):1050-6
Heerema NA, Sather HN, Sensel MG, Liu-Mares W, Lange BJ, Bostrom BC, Nachman JB, Steinherz PG, Hutchinson R, Gaynon PS, Arthur DC, Uckun FM. Association of chromosome arm 9p abnormalities with adverse risk in childhood acute lymphoblastic leukemia: A report from the Children's Cancer Group. Blood. 1999 Sep 1;94(5):1537-44
Pan J, Xue Y, Wu Y, Wang Y, Shen J. Dicentric (7;9)(p11;p11) is a rare but recurrent abnormality in acute lymphoblastic leukemia: a study of 7 cases. Cancer Genet Cytogenet. 2006 Sep;169(2):159-63
Smith A, Das P, O'Reilly J, Patsouris C, Campbell LJ. Three adults with acute lymphoblastic leukemia and dic(7;9)(p11.2;p11). Cancer Genet Cytogenet. 2006 Apr 1;166(1):86-8
This article should be referenced as such:
Rodrigues Pereira Velloso ED, Kassab C, Figueira SHA, Noguchi DT, Armelin Benites EC, Mangueira CLP, de Oliveira FM. Dicentric dic(7;9)(p11;p11): a new case in childhood ALL. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8):806-808.
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