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The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the
Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research
(CNRS) on its electronic publishing platform I-Revues.
Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS.
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Scope
The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open
access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.
It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more
traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology, and
educational items in the various related topics for students in Medicine and in Sciences.
Editorial correspondance
Jean-Loup Huret Genetics, Department of Medical Information,
University Hospital
F-86021 Poitiers, France
tel +33 5 49 44 45 46 or +33 5 49 45 47 67
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)
http://AtlasGeneticsOncology.org
© ATLAS - ISSN 1768-3262
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7)
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(7)
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Volume 14, Number 7, July 2010
Table of contents
Gene Section
APLNR (apelin receptor) 627 Yves Audigier
CD9 (CD9 molecule) 630 Laure Humbert, Mario Chevrette
CITED4 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 4) 633 Miguel Torres-Martin, Juan Antonio Rey
ENO1 (Enolase 1, (alpha)) 635 Bogusz Trojanowicz, Cuong Hoang-Vu, Carsten Sekulla
LIMK1 (LIM domain kinase 1) 641 Ratna Chakrabarti
PAX6 (paired box 6) 645 Yi-Hong Zhou
RASSF2 (Ras association (RalGDS/AF-6) domain family member 2) 652 Luke B Hesson, Farida Latif
SEMA3B (sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3B) 662 Munmi Bhattacharyya, Ranjan Tamuli
TNFSF15 (tumor necrosis factor (ligand) superfamily, member 15) 665 Gui-Li Yang, Jian-Wei Qi, Zhi-Song Zhang, Lu-Yuan Li
BAP1 (BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase)) 670 Frédéric Guénard, Francine Durocher
CDA (Cytidine Deaminase) 673 Yoshiro Saito
CKS1B (CDC28 protein kinase regulatory subunit 1B) 676 Yongyou Zhang
COL16A1 (collagen, type XVI, alpha 1) 679 Susanne Grässel, Sabine Ratzinger
COPS2 (COP9 constitutive photomorphogenic homolog subunit 2 (Arabidopsis)) 688 Susanne Jennek, Florian Kraft, Aria Baniahmad
Leukaemia Section
t(3;6)(q27;p21) 692 Jean-Loup Huret
t(3;6)(q27;p21) PIM1/BCL6 694 Jean-Loup Huret
t(11;14)(q13;q32) in multiple myeloma Huret JL, Laï JL
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7)
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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t(3;6)(q27;p21) SFRS3/BCL6 695 Jean-Loup Huret
t(8;20)(p11;q13) 696 Marie-Joëlle Mozziconacci, Christine Pérot
Solid Tumour Section
Esophagus: Barrett's esophagus, dysplasia and adenocarcinoma 698 DunFa Peng, Wael El-Rifai
Head and neck: Retinoblastoma 704 Hayyam Kiratli, Berçin Tarlan
Case Report Section
t(1;21)(p32;q22) as a non-random abnormality in AML M4 710 Lena Reindl, Claudia Haferlach
t(3;7)(q26;q21) as a secondary abnormality in MDS RAEB-2 712 Lena Reindl, Claudia Haferlach
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7)
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 627
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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APLNR (apelin receptor) Yves Audigier
Unite INSERM U-858, I2MR, equipe 13, CHU Rangueil, Bat. L3, BP 84225, 1 avenue Jean-Poulhes, 31432-
Toulouse Cedex 4, France (YA)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/APLNRID44364ch11q12.html DOI: 10.4267/2042/44792
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: AGTRL1; APJ; APJR; FLJ90771;
HG11; MGC45246
HGNC (Hugo): APLNR
Location: 11q12.1
DNA/RNA
Description
1 exon.
Transcription
3.8 kb mRNA; 1140 bp open reading frame.
Protein
Description
380 amino acids.
Expression
Blood vessels, hypothalamus, heart, stomach, colon,
endocrine pancreas, bone, skeletic muscle, spleen.
Localisation
Plasma membrane.
Function
The apelin receptor APJ belongs to the family of G
protein-coupled receptors (O'Dowd et al., 1993; Devic
et al., 1996; Devic et al., 1999; Scott et al., 2007) and is
coupled to a Gi/o protein (Masri et al., 2006). Its
activation leads to the regulation of various
intracellular effectors with the following consequences:
adenylylcyclase inhibition (Masri et al., 2006; Habata
et al., 1999), increase of intracellular calcium (Choe et
al., 2000) and activation of extracellular signal-
regulated kinases (ERKs), PI-3K, Akt or p70S6 kinase
(S6K1) (Masri et al., 2006; Masri et al., 2004 ).
Expression of apelin receptors by the endothelial cell
(Devic et al., 1996; Devic et al., 1999) is associated
with two effects :
1) NO release leading to vessel vasodilatation
(Tatemoto et al., 2001) and peripheral hypotension
(Lee et al., 2000);
2) cell proliferation and migration (Masri et al., 2004;
Kasai et al., 2004) linked to angiogenesis (Cox et al.,
2006).
APLNR (apelin receptor) Audigier Y
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 628
The expression in the central nervous system is high in
hypothalamus (De Mota et al., 2000; O'Carroll et al.,
2000) where receptor activation leads to the decrease of
vasopressin release (De Mota et al., 2004). Activation
of apelin receptors expressed by cardiomyocytes results
in a strong inotropic effect (Szokodi et al., 2002). In
stomach, apelin receptors are expressed by
enterochromaffin-like cells where their stimulation
decreases gastrin-induced acid secretion (Lambrecht et
al., 2006). Apelin receptors may regulate epithelial
proliferation in the colon (Han et al., 2007). Expression
of apelin receptors both in endocrine pancreas and
skeletic muscle contributes to the regulation of insulin
plasma levels and glucose uptake (Sorhede Winzell et
al., 2005; Dray et al., 2008). Apelin signalling also
increases osteoblast proliferation (Xie et al., 2007) and
cytokine expression by T lymphocytes (Habata et al.,
1999).
Mutations
Note
No mutation has been presently described.
Implicated in
Malignant glioma
Note
On a quantitative point of view, APLNR gene
expression is highly upregulated in microvascular
proliferations of malignant gliomas (Kalin et al., 2007).
Various diseases
Note
On a qualitative point of view, two single nucleotide
polymorphisms (SNP) have been reported. A functional
SNP in an Sp1-binding site of APLNR gene is
associated with susceptibility to brain infarction (Hata
et al., 2007). The 212A variant of the APJ receptor
gene is associated with slower heart failure progression
in idiopathic dilated cardiomyopathy (Sarzani et al.,
2007).
References O'Dowd BF, Heiber M, Chan A, Heng HH, Tsui LC, Kennedy JL, Shi X, Petronis A, George SR, Nguyen T. A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene. 1993 Dec 22;136(1-2):355-60
Devic E, Paquereau L, Vernier P, Knibiehler B, Audigier Y. Expression of a new G protein-coupled receptor X-msr is associated with an endothelial lineage in Xenopus laevis. Mech Dev. 1996 Oct;59(2):129-40
Devic E, Rizzoti K, Bodin S, Knibiehler B, Audigier Y. Amino acid sequence and embryonic expression of msr/apj, the mouse homolog of Xenopus X-msr and human APJ. Mech Dev. 1999 Jun;84(1-2):199-203
Habata Y, Fujii R, Hosoya M, Fukusumi S, Kawamata Y, Hinuma S, Kitada C, Nishizawa N, Murosaki S, Kurokawa T, Onda H, Tatemoto K, Fujino M. Apelin, the natural ligand of the
orphan receptor APJ, is abundantly secreted in the colostrum. Biochim Biophys Acta. 1999 Oct 13;1452(1):25-35
Choe W, Albright A, Sulcove J, Jaffer S, Hesselgesser J, Lavi E, Crino P, Kolson DL. Functional expression of the seven-transmembrane HIV-1 co-receptor APJ in neural cells. J Neurovirol. 2000 May;6 Suppl 1:S61-9
De Mota N, Lenkei Z, Llorens-Cortès C. Cloning, pharmacological characterization and brain distribution of the rat apelin receptor. Neuroendocrinology. 2000 Dec;72(6):400-7
Lee DK, Cheng R, Nguyen T, Fan T, Kariyawasam AP, Liu Y, Osmond DH, George SR, O'Dowd BF. Characterization of apelin, the ligand for the APJ receptor. J Neurochem. 2000 Jan;74(1):34-41
O'Carroll AM, Selby TL, Palkovits M, Lolait SJ. Distribution of mRNA encoding B78/apj, the rat homologue of the human APJ receptor, and its endogenous ligand apelin in brain and peripheral tissues. Biochim Biophys Acta. 2000 Jun 21;1492(1):72-80
Tatemoto K, Takayama K, Zou MX, Kumaki I, Zhang W, Kumano K, Fujimiya M. The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regul Pept. 2001 Jun 15;99(2-3):87-92
Szokodi I, Tavi P, Földes G, Voutilainen-Myllylä S, Ilves M, Tokola H, Pikkarainen S, Piuhola J, Rysä J, Tóth M, Ruskoaho H. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ Res. 2002 Sep 6;91(5):434-40
De Mota N, Reaux-Le Goazigo A, El Messari S, Chartrel N, Roesch D, Dujardin C, Kordon C, Vaudry H, Moos F, Llorens-Cortes C. Apelin, a potent diuretic neuropeptide counteracting vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release. Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10464-9
Kasai A, Shintani N, Oda M, Kakuda M, Hashimoto H, Matsuda T, Hinuma S, Baba A. Apelin is a novel angiogenic factor in retinal endothelial cells. Biochem Biophys Res Commun. 2004 Dec 10;325(2):395-400
Masri B, Morin N, Cornu M, Knibiehler B, Audigier Y. Apelin (65-77) activates p70 S6 kinase and is mitogenic for umbilical endothelial cells. FASEB J. 2004 Dec;18(15):1909-11
Sörhede Winzell M, Magnusson C, Ahrén B. The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice. Regul Pept. 2005 Nov;131(1-3):12-7
Cox CM, D'Agostino SL, Miller MK, Heimark RL, Krieg PA. Apelin, the ligand for the endothelial G-protein-coupled receptor, APJ, is a potent angiogenic factor required for normal vascular development of the frog embryo. Dev Biol. 2006 Aug 1;296(1):177-89
Lambrecht NW, Yakubov I, Zer C, Sachs G. Transcriptomes of purified gastric ECL and parietal cells: identification of a novel pathway regulating acid secretion. Physiol Genomics. 2006 Mar 13;25(1):153-65
Masri B, Morin N, Pedebernade L, Knibiehler B, Audigier Y. The apelin receptor is coupled to Gi1 or Gi2 protein and is differentially desensitized by apelin fragments. J Biol Chem. 2006 Jul 7;281(27):18317-26
Xie H, Tang SY, Cui RR, Huang J, Ren XH, Yuan LQ, Lu Y, Yang M, Zhou HD, Wu XP, Luo XH, Liao EY. Apelin and its receptor are expressed in human osteoblasts. Regul Pept. 2006 May 15;134(2-3):118-25
Han S, Wang G, Qiu S, de la Motte C, Wang HQ, Gomez G, Englander EW, Greeley GH Jr. Increased colonic apelin production in rodents with experimental colitis and in humans with IBD. Regul Pept. 2007 Aug 16;142(3):131-7
APLNR (apelin receptor) Audigier Y
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 629
Hata J, Matsuda K, Ninomiya T, Yonemoto K, Matsushita T, Ohnishi Y, Saito S, Kitazono T, Ibayashi S, Iida M, Kiyohara Y, Nakamura Y, Kubo M. Functional SNP in an Sp1-binding site of AGTRL1 gene is associated with susceptibility to brain infarction. Hum Mol Genet. 2007 Mar 15;16(6):630-9
Kälin RE, Kretz MP, Meyer AM, Kispert A, Heppner FL, Brändli AW. Paracrine and autocrine mechanisms of apelin signaling govern embryonic and tumor angiogenesis. Dev Biol. 2007 May 15;305(2):599-614
Sarzani R, Forleo C, Pietrucci F, Capestro A, Soura E, Guida P, Sorrentino S, Iacoviello M, Romito R, Dessì-Fulgheri P, Pitzalis M, Rappelli A. The 212A variant of the APJ receptor gene for the endogenous inotrope apelin is associated with slower heart failure progression in idiopathic dilated cardiomyopathy. J Card Fail. 2007 Sep;13(7):521-9
Scott IC, Masri B, D'Amico LA, Jin SW, Jungblut B, Wehman AM, Baier H, Audigier Y, Stainier DY. The g protein-coupled receptor agtrl1b regulates early development of myocardial progenitors. Dev Cell. 2007 Mar;12(3):403-13
Dray C, Knauf C, Daviaud D, Waget A, Boucher J, Buléon M, Cani PD, Attané C, Guigné C, Carpéné C, Burcelin R, Castan-Laurell I, Valet P. Apelin stimulates glucose utilization in normal and obese insulin-resistant mice. Cell Metab. 2008 Nov;8(5):437-45
This article should be referenced as such:
Audigier Y. APLNR (apelin receptor). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):627-629.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 630
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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CD9 (CD9 molecule) Laure Humbert, Mario Chevrette
The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada
(LH, MC)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/CD9ID995ch12p13.html DOI: 10.4267/2042/44793
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: 5H9; BA2; P24; GIG2; MIC3; MRP-1;
BTCC-1; DRAP-27; TSPAN29
HGNC (Hugo): CD9
Location: 12p13.31
Local order: The CD9 gene is located between the
VWF and the ATP5J2P5 genes.
DNA/RNA
Description
The gene spans 38 kb of DNA, including a 10 kb intron
separating the first two exons. CD9 encodes 8 exons,
ranging from 63 to 109 base pairs. The coding
sequence is highly conserved between species. The
promoter contains neither TATA nor CAAT boxes, but
does contain several consensus sequences for the
binding of transcription factors (GATA, ETS, E2F, NF-
kB, AP2) as well as three putative Sp1 binding sites.
Transcription
The CD9 transcribed RNA has 1246 bases, of which
684 bases (from 112 (Met) to 795 (Val)) encode the
protein.
Pseudogene
None.
Protein
Description
CD9 is a member of the transmembrane 4 superfamily,
also called the tetraspanin family. As other
tetraspanins, CD9 is a cell-surface protein containing
four hydrophobic transmembrane domains (indicated in
green) and two extracellular domains (illustrated in
violet). CD9 consists of 228 amino acids and weighs
24-27 kDa. CD9 contains four small and highly
conserved hydrophobic transmembrane domains (24-27
amino acids); a small N-terminal (11 amino acids) and
a C-terminal cytoplasmic (7 amino acids) tails, and a
very small intracellular domain (4 amino acids). The
remaining part of the protein is composed of two
extracellular domains (also called loops; a small one of
20 amino acids and a large one of 83 amino acids).
Two disulfide bonds, generated by four well-conserved
cysteine residues (C), stabilize the large extracellular
domain. CD9 also contains a tetraspanin signature
(amino acids 65-89) and a CCG motif (amino acids 152
to 154), but lacks
Genomic organisation of the CD9 gene on chromosome 12.
CD9 (CD9 molecule) Humbert L, Chevrette M
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 631
Structure of the CD9 protein.
other motifs found on other tetraspanins (DW, PxSc3,
Gc4).
Expression
CD9 is expressed by a variety of hematopoietic and
epithelial cells. It is transiently expressed during
development of spinal motoneurons and other fetal
nervous system sites, as well as in hematopoietic
development. CD9 is glycosylated (the glycosylation
site is in the first extracellular loop unlike most
glycosylated tetraspanins where the site is located in
the second extracellular loop) and acylated. CD9 is also
phosphorylated on tyrosine following B-cell activation.
CD9 is up-regulated on activated B and T lymphocytes.
Localisation
In normal cells, CD9 localizes mainly in the
membranes while in cancer cells the protein may also
be detected throughout the cytoplasm.
Function
CD9 can interact or form complexes with many other
proteins, including other tetraspanins, integrins, EWI
molecules, TGF-a, diphtheria toxin receptor, receptor
tyrosine kinase, pregnancy specific glycoproteins, and
proteins of the immune system such as MHC class II
molecules and members of the Ig superfamily.
Moreover, probably because of its localization in the
cell membrane, CD9 is involved in platelet activation
and aggregation, as well as in cell adhesion, spreading,
cell motility and tumor metastasis. CD9 also regulates
paranodal junction formation, and is required for
gamete fusion. Furthermore, CD9 promotes muscle cell
fusion and supports myotube maintenance.
Homology
Although there are variations in the amino acid
sequence in the extracellular loops, the CD9 protein
sequence is very well conserved between species (90%
between human, mice and rat). CD9 share also some
homologies with other tetraspanins, particularly in the
transmembrane domains.
Mutations
Note
Although no genomic CD9 mutation has been reported,
in prostate cancer, there is mention of cDNA mutation
compatible with an RNA editing mechanism. So far,
CD9 has never been implicated in gene fusion that
could result in a modified protein.
Implicated in
Various cancers
Note
Decreased expression of the CD9 protein has been
associated with many types of cancer.
Disease
- Expressed in 90% of non-T cell acute lymphoblastic
leukemia cells and in 50% of chronic lymphocytic
leukemia and acute myeloblastic leukemia.
- Expression inversely correlated with metastatic
potential of melanoma.
- Expression suppresses motility and metastasis of
carcinoma cells.
- Reduction of expression correlated with poor
prognosis in breast, lung and colon carcinomas.
CD9 (CD9 molecule) Humbert L, Chevrette M
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 632
References Boucheix C, Nguyen-van-Cong, Perrot JY, Foubert C, Gross MS, Weil D, Laisney V, Rosenfeld C, Frezal J. Assignment to chromosome 12 of the gene coding for the human cell surface antigen CD9(p24) using the monoclonal antibody ALB6. Ann Genet. 1985;28(1):19-24
Rendu F, Boucheix C, Lebret M, Bourdeau N, Benoit P, Maclouf J, Soria C, Levy-Toledano S. Mechanisms of the mAb ALB6(CD9) induced human platelet activation: comparison with thrombin. Biochem Biophys Res Commun. 1987 Aug 14;146(3):1397-404
Seehafer JG, Tang SC, Slupsky JR, Shaw AR. The functional glycoprotein CD9 is variably acylated: localization of the variably acylated region to a membrane-associated peptide containing the binding site for the agonistic monoclonal antibody 50H.19. Biochim Biophys Acta. 1988 Dec 2;957(3):399-410
Boucheix C, Benoit P, Frachet P, Billard M, Worthington RE, Gagnon J, Uzan G. Molecular cloning of the CD9 antigen. A new family of cell surface proteins. J Biol Chem. 1991 Jan 5;266(1):117-22
Ikeyama S, Koyama M, Yamaoko M, Sasada R, Miyake M. Suppression of cell motility and metastasis by transfection with human motility-related protein (MRP-1/CD9) DNA. J Exp Med. 1993 May 1;177(5):1231-7
Rubinstein E, Benoit P, Billard M, Plaisance S, Prenant M, Uzan G, Boucheix C. Organization of the human CD9 gene. Genomics. 1993 Apr;16(1):132-8
Si Z, Hersey P. Expression of the neuroglandular antigen and analogues in melanoma. CD9 expression appears inversely related to metastatic potential of melanoma. Int J Cancer. 1993 Apr 22;54(1):37-43
Tole S, Patterson PH. Distribution of CD9 in the developing and mature rat nervous system. Dev Dyn. 1993 Jun;197(2):94-106
Higashiyama M, Taki T, Ieki Y, Adachi M, Huang CL, Koh T, Kodama K, Doi O, Miyake M. Reduced motility related protein-1 (MRP-1/CD9) gene expression as a factor of poor prognosis in non-small cell lung cancer. Cancer Res. 1995 Dec 15;55(24):6040-4
Shaw AR, Domanska A, Mak A, Gilchrist A, Dobler K, Visser L, Poppema S, Fliegel L, Letarte M, Willett BJ. Ectopic expression of human and feline CD9 in a human B cell line confers beta 1 integrin-dependent motility on fibronectin and laminin substrates and enhanced tyrosine phosphorylation. J Biol Chem. 1995 Oct 13;270(41):24092-9
Le Naour F, Prenant M, Francastel C, Rubinstein E, Uzan G, Boucheix C. Transcriptional regulation of the human CD9
gene: characterization of the 5'-flanking region. Oncogene. 1996 Aug 1;13(3):481-6
Miyake M, Nakano K, Itoi SI, Koh T, Taki T. Motility-related protein-1 (MRP-1/CD9) reduction as a factor of poor prognosis in breast cancer. Cancer Res. 1996 Mar 15;56(6):1244-9
Cajot JF, Sordat I, Silvestre T, Sordat B. Differential display cloning identifies motility-related protein (MRP1/CD9) as highly expressed in primary compared to metastatic human colon carcinoma cells. Cancer Res. 1997 Jul 1;57(13):2593-7
Maecker HT, Todd SC, Levy S. The tetraspanin superfamily: molecular facilitators. FASEB J. 1997 May;11(6):428-42
Horváth G, Serru V, Clay D, Billard M, Boucheix C, Rubinstein E. CD19 is linked to the integrin-associated tetraspans CD9, CD81, and CD82. J Biol Chem. 1998 Nov 13;273(46):30537-43
Cook GA, Wilkinson DA, Crossno JT Jr, Raghow R, Jennings LK. The tetraspanin CD9 influences the adhesion, spreading, and pericellular fibronectin matrix assembly of Chinese hamster ovary cells on human plasma fibronectin. Exp Cell Res. 1999 Sep 15;251(2):356-71
Tachibana I, Hemler ME. Role of transmembrane 4 superfamily (TM4SF) proteins CD9 and CD81 in muscle cell fusion and myotube maintenance. J Cell Biol. 1999 Aug 23;146(4):893-904
Miyado K, Yamada G, Yamada S, Hasuwa H, Nakamura Y, Ryu F, Suzuki K, Kosai K, Inoue K, Ogura A, Okabe M, Mekada E. Requirement of CD9 on the egg plasma membrane for fertilization. Science. 2000 Jan 14;287(5451):321-4
Seigneuret M, Delaguillaumie A, Lagaudrière-Gesbert C, Conjeaud H. Structure of the tetraspanin main extracellular domain. A partially conserved fold with a structurally variable domain insertion. J Biol Chem. 2001 Oct 26;276(43):40055-64
Ishibashi T, Ding L, Ikenaka K, Inoue Y, Miyado K, Mekada E, Baba H. Tetraspanin protein CD9 is a novel paranodal component regulating paranodal junctional formation. J Neurosci. 2004 Jan 7;24(1):96-102
Kovalenko OV, Metcalf DG, DeGrado WF, Hemler ME. Structural organization and interactions of transmembrane domains in tetraspanin proteins. BMC Struct Biol. 2005 Jun 28;5:11
Wang JC, Bégin LR, Bérubé NG, Chevalier S, Aprikian AG, Gourdeau H, Chevrette M. Down-regulation of CD9 expression during prostate carcinoma progression is associated with CD9 mRNA modifications. Clin Cancer Res. 2007 Apr 15;13(8):2354-61
This article should be referenced as such:
Humbert L, Chevrette M. CD9 (CD9 molecule). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):630-632.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 633
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
CITED4 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 4) Miguel Torres-Martin, Juan Antonio Rey
Unidad de Investigacion del Hospital Universitario La Paz, Madrid, Spain (MTM, JAR)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/CITED4ID44535ch1p34.html DOI: 10.4267/2042/44794
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: MRG2; MRG-2
HGNC (Hugo): CITED4
Location: 1p34.2
DNA/RNA
Description
DNA sequence is located at chromosome 1p.
Transcription
Transcription consists of a single exon without
alternative splicing. mRNA: NM_133467.
Protein
Note
CITED4 protein is 184 amino acid long with a
molecular weight of 18569 Da.
NP_597724.
Description
CITED4 has a characteristic CITED domain motif
conserved in all CITED peptides located at the
carboxyl-terminal domain that binds with p300/CBP.
Expression
In all tissues with special intensity in heart, liver,
pancreas and skeletal muscle.
Localisation
CITED4 has nuclear and cytoplasmatic location. In
most cells it has a nuclear localization, but in others it
was localized in nucleus and cytoplasm.
Function
Binds CBP and tumor suppressor protein EP300 by
carboxy terminus domain (residues 138-184).
Therefore it may be implicated in gene transcription.
As other genes of the family, CITED4 physically
interacts with transcription factor AP-2.
A. Position of CITED4 in the chromosome 1. B. Flanking genes of CITED4.
CITED4 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 4) Torres-Martin M, Rey JA
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 634
Coding and flanking regions of CITED4.
Fox et al. (2002) showed that CITED4 blocks the
binding of hypoxia-inducible factor 1alpha to p300 in
their experiments made in vitro and inhibits hypoxia-
inducible factor-1alpha transactivation and hypoxia-
mediated reporter gene activation. That is the reason
why they concluded that CITED4 might be an inhibitor
of hypoxia-inducible factor 1alpha.
Homology
CITED4 has 2 paralogues (CITED1 and CITED2) in
humans. All of them belong to CITED family, found
only in jawed vertebrates to date (Braganca et al.,
2002).
Mutations
Note
No mutations has been reported yet, but a total of 16
polymorphisms with unknown consequences has been
founded by Tews et al. (2007) and Torres-Martin et al.
(2008).
Implicated in
Oligodendroglioma
Note
CITED4 promoter is methylated in
oligodendrogliomas, especially in those with 1p/19q
deletions. This hypermethylation is responsible of
lower levels of CITED4 mRNA expression, suggesting
a way by which CITED4 is almost silenced by both
hypermethylation and chromosomal deletion (Tews et
al., 2007).
Prognosis
CITED4 hypermethylation in oligodendroglioma
patients is similar to prognosis associated to 1p/19q
deletions. Thus, CITED4 hypermethylation might be an
alternative or even a confirmation of 1p/19q testing.
Breast cancer
Note
Cytoplasmatic translocation and loss of nuclear
expression has been associated with breast cancer by
Fox et al. (2002). This loss may allow p300/CBP to
interact with hypoxia-inducible factor 1a and
oncogenes to enhance their transcriptional activity
leading to an aggressive tumor phenotype (Fox et al.,
2004).
Prognosis
CITED4 is located in the nucleus in normal tissue, but
in breast tumors is present both nuclear and
cytoplasmatic location. This characteristic might be
used as prognosis factor of this kind of tumors.
References Bragança J, Swingler T, Marques FI, Jones T, Eloranta JJ, Hurst HC, Shioda T, Bhattacharya S. Human CREB-binding protein/p300-interacting transactivator with ED-rich tail (CITED) 4, a new member of the CITED family, functions as a co-activator for transcription factor AP-2. J Biol Chem. 2002 Mar 8;277(10):8559-65
Yahata T, Takedatsu H, Dunwoodie SL, Bragança J, Swingler T, Withington SL, Hur J, Coser KR, Isselbacher KJ, Bhattacharya S, Shioda T. Cloning of mouse Cited4, a member of the CITED family p300/CBP-binding transcriptional coactivators: induced expression in mammary epithelial cells. Genomics. 2002 Dec;80(6):601-13
Fox SB, Bragança J, Turley H, Campo L, Han C, Gatter KC, Bhattacharya S, Harris AL. CITED4 inhibits hypoxia-activated transcription in cancer cells, and its cytoplasmic location in breast cancer is associated with elevated expression of tumor cell hypoxia-inducible factor 1alpha. Cancer Res. 2004 Sep 1;64(17):6075-81
Tews B, Roerig P, Hartmann C, Hahn M, Felsberg J, Blaschke B, Sabel M, Kunitz A, Toedt G, Neben K, Benner A, von Deimling A, Reifenberger G, Lichter P. Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q. Oncogene. 2007 Jul 26;26(34):5010-6
Torres-Martín M, Franco-Hernandez C, Martinez-Glez V, de Campos JM, Isla A, Casartelli C, Rey JA. Mutational analysis of the CITED4 gene in glioblastomas. Cancer Genet Cytogenet. 2008 Sep;185(2):114-6
This article should be referenced as such:
Torres-Martin M, Rey JA. CITED4 (Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 4). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):633-634.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 635
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
ENO1 (Enolase 1, (alpha)) Bogusz Trojanowicz, Cuong Hoang-Vu, Carsten Sekulla
AG Experimentelle and Chirurgische Onkologie, Universitatsklinik und Poliklinik fur Allgemein-, Viszeral-
und Gefasschirurgie, Martin-Luther Universitat, Magdeburger Strasse 18, 06097 Halle/S, Germany (BT,
CHV, CS); AG Experimentelle and Chirurgische Onkologie, Universitatsklinik und Poliklinik fur
Kinderchirurgie, Martin-Luther Universitat, Magdeburger Strasse 18, 06097 Halle/S, Germany (BT)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/ENO1ID40453ch1p36.html DOI: 10.4267/2042/44795
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 4.2.1.11; ENO1L1; MBP-1;
MBPB1; MPB-1; MPB1; NNE; PPH; tau-crystallin
HGNC (Hugo): ENO1
Location: 1p36.23
DNA/RNA
Note
Alpha-Enolase (ENO1, alpha enolase, non-neuronal
enolase) is one of the three enolase enzymes, expressed
in a wide variety of tissues. The other two enolase
genes, ENO2 and ENO3, encode gamma (neuron-
specific) and beta (muscle-specific) enolase,
respectively. The active enolase enzymes exist as
homodimers of non-covalently bound subunits. Each
alpha, beta or gamma subunit is encoded by separate
genes. The genomic organisation of ENO1 gene is
identical with that of human gamma-enolase gene. All
the coding exons have exactly the same length and
introns occur at analogous positions.
Description
The ENO1 gene consists of 12 exons distributed over
17718 bp of genomic DNA. Single alpha-enolase
transcript contains two translation initiation positions
and encodes two structurally and functionally distinct
proteins, alpha-enolase enzyme and MYC promotor-
binding protein (MBP-1).
Transcription
Transcription start sites of ENO1 gene are
heterogeneous and spread over 38-bp region located at
116 bp upstream from the initiation codon ATG. These
multiple start sites of transcription in ENO1 gene are
consistent with lack of a canonical TATA box, usually
found at the position 19-27 bp upstream of the cap
sites. It is worth to notice that promoter of ENO1 gene
contains two perfect Myc-Max binding motifs
CACGTC. Other regulatory sites found in the 5'-
flanking region of ENO1 gene include AP1
(T[T/G]AGTCA), AP2 (CCCCAGGC), AP3
(GGGTGTGGAAAG), AP4 (CAGCTGTGG), AP5
(CTGTGGAATG), ATF/CREB ([T/G][A/T]CGTCA),
C2 (CATGTG),
Structure of ENO1 mRNA ; note that nucleotides number (nt), exon positions (1-12) and two translation initiation sites (ATG) are labelled.
ENO1 (Enolase 1, (alpha)) Trojanowicz B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 636
Structure of ENO1/MBP-1 protein; N and C termini, and amino acid (aa) positions are labelled.
CTF/NF1 (TGGCTNNNAGCCAA), E2AE-C beta
(TGGGAATT), E2F (TTTCGCGC), E4TF1
(GGAAGTG), EF-C (GTTGCNNGGCAAC),
MLTF/USF (GGTCACGTGGCC), Ig octamer
(ATTTGCAT), PEA2 (GACCGCA), SP1 (GGGCGG),
CACCC (may function as CAAT boxes) and viral core
(GTGG[A/T][A/T][A/T]G).
Pseudogene
A pseudogene has been identified that is located on the
other arm of the same chromosome (provided by
RefSeq).
Protein
Description
Alpha-Enolase (ENO1), like two other isoenzymes
(gamma-ENO2 and beta-ENO3), is made up of two
identical (homodimer), non-covalently bound alpha
alpha subunits; alpha-Enolase is resolved during 1D-
PAGE as a protein with molecular weight of about 48
kDa (434 amino acids). It was demonstrated that in
brain and neurons, specific enolases may exist as
heterodimers, such as alpha alpha, alpha beta, beta beta,
alpha gamma and gamma gamma. The proportions of
isoenzymes alpha alpha, alpha beta and beta beta
change in heart and muscle during embryonic
development. In both mentioned tissues, isoform alpha
was found predominantly in fetus. In adult heart this
subunit is replaced by types alpha beta and beta beta,
and in muscle by type beta beta. In human adult brain
tissues, apha-type and gamma-type enolase subunits are
present at similar concentrations.
Two identical subunits of alpha-Enolase facilitate each
other in an antiparallel fashion. Each subunit is made
up of two distinct domains: N-terminal domain,
consisting of three beta-sheets and four alpha-helices
(beta3 alpha4 topology), and larger C-terminal domain
with eightfold alpha beta barrel structure with beta beta
alpha alpha(beta alpha)6 topology. This domain
contains two beta-sheets at the beginning, followed by
two alpha-helices and ends with a barrel made up of
alternating beta-sheets and alpha-helices (beta - sheets
are surrounded by the alpha - helices). The N-terminal
of one subunit contacts the C-terminal of the second in
such way, that glutamic acid at position 20 (Glu20)
forms an ionic pair with arginine at position 414
(Arg414).
Alternatively translated product of ENO1 gene, called
MBP-1 (MYC promotor-binding protein), is expressed
as a 37 kDa (338 amino acids) protein and does not
posses the enolase enzyme activity.
Expression
Apha-Enolase is widely expressed in variety of tissues
including liver, brain, kidney, spleen, adipose as well as
thyroid. In comparison with gamma-type subunit found
only in neurons, type alpha subunit was also detected in
astrocytes, ependymal cells, capillary endothelial cells,
Schwann cells and arachnoidal endothelial cells.
Localisation
Alpha-Enolase is most abundantly found in cytoplasm
and also on the cell surface. MBP-1 is localised in the
nucleus.
Function
Enolase enzymes (2-phospho-D-glycerate hydrolases)
catalyse the dehydration of 2-phospho-D-glycerate
(PGA) to phosphoenolopyruvate (PEP) in Emden
Mayerhoff-Parnas glycolytic pathway (catabolic
direction). In anabolic pathway (reverse reaction)
during gluconeogenesis, the same enzyme catalyses
hydration of PEP to PGA (hence it is called
phosphopyruvate hydratase). Metal ions are cofactors
impairing the increase of enolase activity; hence it is
also called metal-activated metalloenzyme. Magnesium
is a natural cofactor causing the highest activity. The
relative activation strength profile of metal ions
involved in the enzyme activity appears in the
following rank of order Mg2+
> Zn2+
> Mn2+
> Fe(II)2+
> Cd2+
> Co2+
, Ni2+
, Sm3+
, Tb3+
and most other divalent
metal ions. In reaction catalyzed by enolases, the alpha-
proton from a carbon adjacent to a carboxylate group of
ENO1 (Enolase 1, (alpha)) Trojanowicz B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 637
Reaction catalyzed by Enolase.
PGA, is abstracted, and PGA is conversed to enolate
anion intermediate. This intermediate is further
processed in a variety of chemical reactions, including
racemization, cycloisomerization and beta-elimination
of either water or ammonia.
The smaller product of ENO1 gene, MBP-1, is known
as c-myc binding protein and negative regulator of its
expression. C-myc is a DNA-binding phosphoprotein
and a key regulator of cell behaviour. Many of c-myc
targeting pathways are deregulated in cancer cells and
contribute to its enhanced expression. There are four c-
myc promoters, designated as P0, P1, P2 and
P3,although in normal and cancer cells most mRNAs
initiate at the P2 promoter. MBP-1 binds in a region
+123 to +153 relative to the c-myc P2 promoter and
probably by preventing the formation of a transcription
initiation complex, decrease c-myc promoter activity.
Hence MBP-1 is considered as tumor suppressor.
ENO1 protein was also found as a structural component
of the eye lenses and was designated as tau-crystalin.
ENO1 enzyme and tau-crystalin are the products of the
same gene. Tau-crystalins are the major components of
vertebrate lens. These proteins are mainly found in
monomeric form with a low enzymatic activity, while
the active ENO1 enzyme exists as a dimer. Irrespective
of ENO1 enzyme activity, its significant presence in
eye lens (23% of the total protein of the lens) clearly
indicate ENO1 structural role in lens and cataracts.
In hypoxic conditions elevated ENO1 levels may
provide protection to the cells by increasing anaerobic
metabolism.
Homology
Currently, amino acid sequences of more than 50
enolase enzymes are known. The five residues that
participate in catalytic activity of this enzyme are
highly conserved throughout evolution. Studies in vitro
revealed that mutant enolase enzymes that differs at
either positions Glu168, Glu211, Lys345, Lys396 or
His159, demonstrated dramatically decreased activity
level. An integral and conserved part of enolases are
two Mg2+
ions that participate in conformational
changes of the active site of enolase and enable binding
of a substrate or its analogues.
Mutations
Note
The ENO1 gene maps to a region of chromosome 1
(1p35-p36) reported to be often deleted in several
human malignancies, including neuroblastoma,
melanoma, pheochromocytoma, breast, liver and colon
cancer. However screening of neuroblastomas at
different stages, failed to detect any mutations in ENO1
gene.
Amplification of ENO1 gene, as well as PAX7 (region
1pter-p33) was found to be a common phenomenon in
squamous cell lung carcinoma.
Implicated in
Non-small cell lung cancer (NSCLC)
Note
Higher expression of ENO1 was demonstrated in
NSCLC tissues as compared with normal lung tissues.
Detection and expression level of ENO1 in primary
tumors were the key factors contributing to overall
patient's survival rates. Relatively higher ENO1 levels
in tumors correlated with poorer survival outcomes and
tumor recurrence.
Other report suggests that ENO1 down-regulation in
patients with NSCLC, predicts more aggressive
biological behaviour. The patients whose tumors
showed decreased ENO1 production had significantly
poorer overall survival when compared with those
without ENO1 reduction.
Also in proteomic studies, ENO1 was one of the
secreted proteins demonstrated to be overexpressed by
NSCLC cell line A549 as compared to controls.
Studies in vitro performed on NSCLC cell line H1299,
revealed that MBP-1 overexpression correlated with
decreased cell proliferation as compared with
corresponding controls. Investigations in vivo
demonstrated tumor suppressive properties of MBP-1.
In mice with induced tumors (injection of H1299)
administration of adenovirus MBP-1 construct
significantly reduced tumor growth and prolonged
animal survival rates.
ENO1 (Enolase 1, (alpha)) Trojanowicz B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 638
Small cell lung cancer
Note
There is some evidence concerning the role of anti-
alpha-enolase antibodies in cancer associated
retinopathy with SCLC. In serum obtained from patient
with a sudden loss of vision, the only detectable
antibodies were those against a 35-kDa anti-retinal
protein. Surgical treatment performed after 1 week and
1 month, led to changes in the antibody response from
antibodies against p35kDa to alpha-enolase after tumor
resection. SCLC may express high levels of alpha-
enolase and anti-alpha-enolase antibodies are typically
detected after diagnosis of cancer.
Thyroid carcinoma
Note
In thyroid oncocytomas, which represent a subgroup of
follicular thyroid carcinoma (FTC),the up-regulation of
ENO1, GPI (glucose phosphate isomerase) and
GAPDH (glyceraldehydes-3-phosphate dehydrogenase)
was identified as metabolic signature of thyroid
carcinoma.
Important role of ENO1 in progression of thyroid
carcinoma was also demonstrated for cell lines
established from FTC. Pre-treatment of these cell lines
with retinoic acid (RA) used in therapy and
chemoprevention of solid cancers, led to decrease in
ENO1 and MBP-1 expression, accompanied by
reduced invasiveness of the thyroid carcinoma cells.
Similar effects were also observed after silencing of
common the MYC promoter-binding domain found in
ENO1 and MBP-1. Both, RA-mediated and siRNA
induced reduction of ENO1/MBP-1 resulted in down-
regulation of c-Myc oncoprotein. It seems that in FTC
the bi-functional role of ENO1 gene products is
diminished and ENO1 posses the enzymatic activity
only. It is worth to notice that ENO1 promoter contains
two MYC binding sites (CACGTG). C-Myc over-
expression and interaction with these sites may result in
increased ENO1 expression and/or energy production.
In well differentiated medullary thyroid carcinomas
MTC the relatively high amount of alpha beta and
gamma gamma enolase isoenzymes was observed,
indicating presumed neuroectodermal origin of these
tumors. In highly undifferentiated and anaplastic
MTCs, the majority of enzyme was represented as
alpha alpha-enolase while alpha gamma-enolase was
only weakly detectable.
Hepatocellular carcinoma (HCC)
Note
In proteomic studies performed on HCC cell lines and
tissues, ENO1 was identified as a protein that showed
stronger expression in tumor tissues when comparing to
nontumorous samples. Additionally, expression of
ENO1 increased with tumor dedifferentiation status.
Significantly higher ENO1 expression was found in
poorly differentiated HCC than in well differentiated
HCC. Moreover, expression of ENO1 positively
correlated with tumor size and venous invasion. Also
reduction of ENO1 by specific siRNAs decreased the
proliferation rates of HCC cell lines and prolonged the
G2/M phase of the cell cycle.
Investigations of MBP-1 revealed its significant
reduction in cirrhosis and even more diminished
expression in HCC. This reduction was surprisingly
accompanied by decrease in c-myc expression.
Breast carcinoma
Note
Increased expression of ENO1 was found in HER-
2/neu positive breast tumors and cell lines when
compared with corresponding controls. HER-2/neu is
the receptor tyrosine kinase found to be overexpressed
in up to 30% of breast cancers and is associated with
increased metastasis rate and poor prognosis.
Introduction of MBP-1 gene into human breast
carcinoma cells MDA-MB-231 and MCF-7 reduced
their ability to penetrate basement membrane matrix
and suppressed tumor formation in athymic nude mice.
It is worth to notice that MCF-7 cell line is estrogen
receptor positive and estrogen dependent for
tumorigenicity.
It was demonstrated that translation of ENO1 mRNA in
MCF-7 cell line is glucose concentration-dependent.
Low glucose concentrations increased the level of
MBP-1 protein accompanied by reduced proliferation
rates. The levels of ENO1 mRNA remained unaffected.
This suggests that effects induced by low glucose
concentrations are mediated by preferential translation
of MBP-1 (using the down-stream ATG codon). In
contrast, physiologic or high glucose concentrations
correlated with reduced levels of MBP-1 protein and
markedly induced growth of the cells. Interestingly the
low glucose group exhibited a dramatic increase in c-
Myc expression, not observed in physiologic or high
glucose conditions. As demonstrated for follicular
thyroid carcinoma cells, also in this case c-Myc might
directly transactivate ENO1 promoter, resulting in an
increase in glucose uptake and elevated proliferation
rates.
Prostate cancer
Note
Investigations performed on human prostate cancer
cells PC3, revealed that tumor suppressive function of
MBP-1 is diminished. Reduction of endogenous MBP-
1 by employing specific siRNAs resulted in decreased
proliferation rates accompanied by inhibition of cyclin
A1 and cyclin B1 expression. Additionally, the cell size
increased after depletion of MBP-1. Introduction of
exogenous MBP-1 restored cyclins expression, leading
to dose-dependent increase in cyclin A1 and B1 levels.
Brain tumors
Note
Generally, the increased levels and activity of alpha
alpha-enolase correlate with brain tumorigenicity. In
ENO1 (Enolase 1, (alpha)) Trojanowicz B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 639
astrocytomas with different degrees of malignancy,
oligodendrogliomas, meningiomas and ependymomas,
alpha alpha-enolase was more abundant than in normal
brain tissues. Among astrocytic tumors, glioblastomas
revealed the highest proportion of alpha alpha-enolase
as compared with control tissues.
Introduction of full length, exogenous ENO1 sequence
into 1p-deleted or other neuroblastoma cell lines, led to
reduction of cell growth. This suggests that in this cell
lines ENO1 is preferentially translated as MBP-1 and
probably does not posses the enolase enzyme activity.
Multiple myeloma (plasma cell myeloma, kahler's disease)
Note
It was demonstrated, that interleukin 6 (IL-6) is
implicated in the in vivo proliferation of malignant
plasma cells in multiple myeloma. Studies in vitro
revealed that myeloma cell line U266 treated with IL-6,
responded with increased levels of MBP-1 and XBP-1
(X-box binding protein).
Acute lung inflammation (pneumonia)
Note
Increased ENO1 cell-surface expression on peripheral
blood monocytes (PBMs) and strong ENO1 production
in mononuclear cells in the alveolar space were
demonstrated for pneumonia patients when compared
with healthy volunteers. Elevated cell-surface
expression of ENO1 on PBMs and on human leukemic
monocyte lymphoma cell line U937, led to increased
plasmin generation, enhanced monocyte migration
through epithelial monolayers and promoted matrix
degradation.
Vasculitis
Note
In sera from patients with clinically proven vaculitis,
anti-neutrophil cytoplasmic antibodies (ANCA) reacted
with proteins present in the granules of human
neutrophils. 37.3 % of these sera contained the
antibodies raised against 48kDa protein, identified
further as cytoplasmic alpha-enolase. Antibodies
directed against enolase protein, recognised only alpha
isoform and were detected in sera giving ANCA
staining pattern.
Disease
Vasculitis (inflammatory destruction of blood vessels).
Nephritis
Note
In two independent studies antibodies raised against
alpha-enolase were detected in 10/41 and 9/33 sera of
patients with clinically proved SLE, respectively. 80%
of patients from the first report and 66.7% from the
second one, suffered from active nephritis.
Disease
Nephritis (renal disease) caused by systemic lupus
erythematosus (SLE, chronic autoimmune connective
tissue disease that can affect any part of the body).
Ulcerative colitis
Note
Alpha-enolase antibodies were found in about 10% of
ulcerative colitis patients.
Crohn's disease
Note
Alpha-enolase antibodies were found in about 18% of
patients with Crohn's disease.
Disease
Crohn's disease (autoimmune, inflammatory disease of
the intestines that may affect any part of the
gastrointestinal tract).
Primary biliary cirrhosis and autoimmune hepatitis
Note
Alpha-enolase antibodies were present in 28.6% of
patients with primary biliary cirrhosis and in 31.6%
with autoimmune hepatitis. Normal subjects revealed
significantly lower levels of alpha-enolase antibodies
when compared with both diseases. Note that
antibodies against beta and gamma enolases were not
found in any serum sample analysed.
References Oskam R, Rijksen G, Lips CJ, Staal GE. Enolase isozymes in differentiated and undifferentiated medullary thyroid carcinomas. Cancer. 1985 Jan 15;55(2):394-9
Wistow GJ, Lietman T, Williams LA, Stapel SO, de Jong WW, Horwitz J, Piatigorsky J. Tau-crystallin/alpha-enolase: one gene encodes both an enzyme and a lens structural protein. J Cell Biol. 1988 Dec;107(6 Pt 2):2729-36
Giallongo A, Oliva D, Calì L, Barba G, Barbieri G, Feo S. Structure of the human gene for alpha-enolase. Eur J Biochem. 1990 Jul 5;190(3):567-73
Moodie FD, Leaker B, Cambridge G, Totty NF, Segal AW. Alpha-enolase: a novel cytosolic autoantigen in ANCA positive vasculitis. Kidney Int. 1993 Mar;43(3):675-81
Aaronson RM, Graven KK, Tucci M, McDonald RJ, Farber HW. Non-neuronal enolase is an endothelial hypoxic stress protein. J Biol Chem. 1995 Nov 17;270(46):27752-7
Ray RB, Steele R, Seftor E, Hendrix M. Human breast carcinoma cells transfected with the gene encoding a c-myc promoter-binding protein (MBP-1) inhibits tumors in nude mice. Cancer Res. 1995 Sep 1;55(17):3747-51
Joseph J, Cruz-Sánchez FF, Carreras J. Enolase activity and isoenzyme distribution in human brain regions and tumors. J Neurochem. 1996 Jun;66(6):2484-90
Weith A, Brodeur GM, Bruns GA, Matise TC, Mischke D, Nizetic D, Seldin MF, van Roy N, Vance J. Report of the second international workshop on human chromosome 1 mapping 1995. Cytogenet Cell Genet. 1996;72(2-3):114-44
ENO1 (Enolase 1, (alpha)) Trojanowicz B, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 640
Akisawa N, Maeda T, Iwasaki S, Onishi S. Identification of an autoantibody against alpha-enolase in primary biliary cirrhosis. J Hepatol. 1997 Apr;26(4):845-51
Merkulova T, Lucas M, Jabet C, Lamandé N, Rouzeau JD, Gros F, Lazar M, Keller A. Biochemical characterization of the mouse muscle-specific enolase: developmental changes in electrophoretic variants and selective binding to other proteins. Biochem J. 1997 May 1;323 ( Pt 3):791-800
Wen XY, Stewart AK, Sooknanan RR, Henderson G, Hawley TS, Reimold AM, Glimcher LH, Baumann H, Malek LT, Hawley RG. Identification of c-myc promoter-binding protein and X-box binding protein 1 as interleukin-6 target genes in human multiple myeloma cells. Int J Oncol. 1999 Jul;15(1):173-8
Feo S, Arcuri D, Piddini E, Passantino R, Giallongo A. ENO1 gene product binds to the c-myc promoter and acts as a transcriptional repressor: relationship with Myc promoter-binding protein 1 (MBP-1). FEBS Lett. 2000 May 4;473(1):47-52
Pratesi F, Moscato S, Sabbatini A, Chimenti D, Bombardieri S, Migliorini P. Autoantibodies specific for alpha-enolase in systemic autoimmune disorders. J Rheumatol. 2000 Jan;27(1):109-15
Rácz A, Brass N, Höfer M, Sybrecht GW, Remberger K, Meese EU. Gene amplification at chromosome 1pter-p33 including the genes PAX7 and ENO1 in squamous cell lung carcinoma. Int J Oncol. 2000 Jul;17(1):67-73
Subramanian A, Miller DM. Structural analysis of alpha-enolase. Mapping the functional domains involved in down-regulation of the c-myc protooncogene. J Biol Chem. 2000 Feb 25;275(8):5958-65
Fan X, Solomon H, Schwarz K, Kew MC, Ray RB, Di Bisceglie AM. Expression of c-myc promoter binding protein (MBP-1), a novel eukaryotic repressor gene, in cirrhosis and human hepatocellular carcinoma. Dig Dis Sci. 2001 Mar;46(3):563-6
Pancholi V. Multifunctional alpha-enolase: its role in diseases. Cell Mol Life Sci. 2001 Jun;58(7):902-20
Chang YS, Wu W, Walsh G, Hong WK, Mao L. Enolase-alpha is frequently down-regulated in non-small cell lung cancer and predicts aggressive biological behavior. Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3641-4
Baris O, Savagner F, Nasser V, Loriod B, Granjeaud S, Guyetant S, Franc B, Rodien P, Rohmer V, Bertucci F, Birnbaum D, Malthièry Y, Reynier P, Houlgatte R. Transcriptional profiling reveals coordinated up-regulation of oxidative metabolism genes in thyroid oncocytic tumors. J Clin Endocrinol Metab. 2004 Feb;89(2):994-1005
Dot C, Guigay J, Adamus G. Anti-alpha-enolase antibodies in cancer-associated retinopathy with small cell carcinoma of the lung. Am J Ophthalmol. 2005 Apr;139(4):746-7
Ejeskär K, Krona C, Carén H, Zaibak F, Li L, Martinsson T, Ioannou PA. Introduction of in vitro transcribed ENO1 mRNA into neuroblastoma cells induces cell death. BMC Cancer. 2005 Dec 16;5:161
Takashima M, Kuramitsu Y, Yokoyama Y, Iizuka N, Fujimoto M, Nishisaka T, Okita K, Oka M, Nakamura K. Overexpression of alpha enolase in hepatitis C virus-related hepatocellular carcinoma: association with tumor progression as determined by proteomic analysis. Proteomics. 2005 Apr;5(6):1686-92
Zhang D, Tai LK, Wong LL, Chiu LL, Sethi SK, Koay ES. Proteomic study reveals that proteins involved in metabolic and detoxification pathways are highly expressed in HER-2/neu-positive breast cancer. Mol Cell Proteomics. 2005 Nov;4(11):1686-96
Chang GC, Liu KJ, Hsieh CL, Hu TS, Charoenfuprasert S, Liu HK, Luh KT, Hsu LH, Wu CW, Ting CC, Chen CY, Chen KC, Yang TY, Chou TY, Wang WH, Whang-Peng J, Shih NY. Identification of alpha-enolase as an autoantigen in lung cancer: its overexpression is associated with clinical outcomes. Clin Cancer Res. 2006 Oct 1;12(19):5746-54
Ghosh AK, Steele R, Ray RB. Knockdown of MBP-1 in human prostate cancer cells delays cell cycle progression. J Biol Chem. 2006 Aug 18;281(33):23652-7
Ghosh AK, Steele R, Ryerse J, Ray RB. Tumor-suppressive effects of MBP-1 in non-small cell lung cancer cells. Cancer Res. 2006 Dec 15;66(24):11907-12
Huang LJ, Chen SX, Luo WJ, Jiang HH, Zhang PF, Yi H. Proteomic analysis of secreted proteins of non-small cell lung cancer. Ai Zheng. 2006 Nov;25(11):1361-7
Yoon SY, Kim JM, Oh JH, Jeon YJ, Lee DS, Kim JH, Choi JY, Ahn BM, Kim S, Yoo HS, Kim YS, Kim NS. Gene expression profiling of human HBV- and/or HCV-associated hepatocellular carcinoma cells using expressed sequence tags. Int J Oncol. 2006 Aug;29(2):315-27
Sedoris KC, Thomas SD, Miller DM. c-myc promoter binding protein regulates the cellular response to an altered glucose concentration. Biochemistry. 2007 Jul 24;46(29):8659-68
Hamaguchi T, Iizuka N, Tsunedomi R, Hamamoto Y, Miyamoto T, Iida M, Tokuhisa Y, Sakamoto K, Takashima M, Tamesa T, Oka M. Glycolysis module activated by hypoxia-inducible factor 1alpha is related to the aggressive phenotype of hepatocellular carcinoma. Int J Oncol. 2008 Oct;33(4):725-31
Trojanowicz B, Winkler A, Hammje K, Chen Z, Sekulla C, Glanz D, Schmutzler C, Mentrup B, Hombach-Klonisch S, Klonisch T, Finke R, Köhrle J, Dralle H, Hoang-Vu C. Retinoic acid-mediated down-regulation of ENO1/MBP-1 gene products caused decreased invasiveness of the follicular thyroid carcinoma cell lines. J Mol Endocrinol. 2009 Mar;42(3):249-60
Wygrecka M, Marsh LM, Morty RE, Henneke I, Guenther A, Lohmeyer J, Markart P, Preissner KT. Enolase-1 promotes plasminogen-mediated recruitment of monocytes to the acutely inflamed lung. Blood. 2009 May 28;113(22):5588-98
This article should be referenced as such:
Trojanowicz B, Hoang-Vu C, Sekulla C. ENO1 (Enolase 1, (alpha)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):635-640.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 641
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
LIMK1 (LIM domain kinase 1) Ratna Chakrabarti
Department of Molecular biology and Microbiology, Burnett School of Biomedical Sciences, University of
Central Florida, 12722 Research Parkway, Orlando, Florida 32826, USA (RC)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/LIMK1ID41159ch7q11.html DOI: 10.4267/2042/44796
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 2.7.11.1; LIMK; LIMK-1
HGNC (Hugo): LIMK1
Location: 7q11.23
Local order: ELN, LIMK1, EIF4H, LAT2.
LIMK1 gene is located at chromosome 7 on the long arm
(q11.23).
DNA/RNA
Description
The gene starts at 73136092 bp from pter and ends at
73174790 bp from pter. Its size is 38699 bases and its
orientation lie in the plus strand. The 5' promoter
region (1.5 kb) contains putative sites for
transcriptional regulation including Sp1, MZF1, AP1
and NF-E2. No consensus TATA box is evident.
Transcription
The transcript contains 16 exons spanning a length of
3.332 kb. The mRNA contains a short 5'UTR but a
long 3' end UTR. Two LIM domains, LIM1 and LIM2
are encoded by the exons 2-4. A single PDZ domain is
encoded by the exons 2-6. A C-terminal domain is
encoded by exons 8-16.
Pseudogene
None identified.
Protein
Description
The LIMK1 protein is composed of 647 amino acids. It
belongs to a unique family of LIM domain containing
dual specificity (serine threonine and tyrosine) protein
kinase. LIMK1 also has a PDZ domain in the middle of
the gene and a kinase domain at the C-terminal end. A
stretch of basic amino acids resembling nuclear
localisation signal is present in the kinase domain and
two nuclear export signal sequences containing
hydrophobic residues are present in the PDZ domain.
A) LIMK1 gene consists of 16 exons. Exons 2-4 encode two LIM domains in tandem. Exons 4-6 encode a PDZ domain and exons 8-16 encode a serine/threonine kinase domain. B) A splice variant of LIMK1 (dLIMK1), which lacks the kinase domain. In this variant, intron 7 was extended to 61 additional bases at the 5' end of exon 8, which caused a frameshift in the LIMK1 ORF and resulted in premature termination after 12 missense mutations in dLIMK1.
LIMK1 (LIM domain kinase 1) Chakrabarti R
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 642
LIMK1 consists of specific domains, nuclear localisation signal (NLS) and nuclear exit signals (NES).
Expression
LIMK1 exhibits tissue specific expression. It is
predominantly expressed in brain but to a moderate
extent in the heart and skeletal muscle. The least
amount of LIMK1 expression was noted in the liver.
LIMK1 is also expressed in lesser amounts in various
human epithelial cell lines and haematopoetic cell lines.
Localisation
LIMK1 is primarily localized in the cytoplasm but also
transported to the nucleus. In the cytoplasm, LIMK1 is
colocalized with microtubules, and actin at the focal
adhesion, stress fiber and at the lamellipodia. In the
mitotic cells, LIMK1 is localized to the centrosomes
until early telophase and to the cleavage furrow during
late telophase.
Function
LIMK1 regulates organization of actin cytoskeleton
through inactivating phosphorylation of the actin
depolymerizing family (ADF) protein cofilin. LIMK1
phosphorylates cofilin at Serine, which inhibits actin
depolymerization and results in accumulation of F
actin. LIMK1 also regulates microtubule stability and
assembly through phosphorylation of p25/TPPP
(tubulin polymerization protein), which destabilizes
microtubules. Activated LIMK1 associates with
gamma-tubulin at the centrosome during mitotic
phases. LIMK1 is a multifunctional protein and is
involved in regulation of cell motility, cell cycle,
cytokinesis and cellular morphology. LIMK1 also
regulates neurite growth, synaptic stability, growth
cone motility, axon formation through modulation of
Golgi dynamics and neuronal differentiation.
Homology
LIMK1 has 50% identity overall and 70% identity in
the kinase domain with another family member
LIMK2. Although both proteins phosphorylate cofilin
and regulate actin cytosketon reorganization current
studies showed that LIMK2 has also different cellular
function.
Mutations
Germinal
Hemizygous deletion of LIMK1 along with Elastin
gene in a 1.5 MB deletion has been noted in patients
with Williams-Beuren syndrome. Patients with
Williams Syndrome exhibit impaired visuospatial
constructive cognition possibly because of loss of
LIMK1 gene.
SNP: A single nucleotide polymorphism of LIMK1 in a
haplotype spanning Elastin gene has been linked to
susceptibility of intracranial aneurysm (IA).
Implicated in
Prostate cancer
Disease
Prostate cancer is the most prevalent malignancy
second to lung cancer in men in the western world.
Although slow growing, a subpopulation of prostate
cancer patients develops highly invasive metastatic
disease that is nonresponsive to anti-androgen therapy
and is usually fatal.
Prognosis
The gold standard for diagnosis of prostate cancer are
the Gleason scores and the serum PSA level. PSA level
is also used for prognostic purposes. LIMK1 expression
may have prognostic value for identification of
metastatic progression as overexpression of LIMK1 has
been noted in metastatic prostate cancer cells.
Cytogenetics
Through cytogenetics method such as CGH and FISH
analysis chromosomal gain in 7q11.2 region or entire
chromosome 7 including 7q11.23 locus has been
reported in some prostate cancer cases.
Oncogenesis
LIMK1 is overexpressed in prostate cancer cells and
tissues compared to benign prostatic hyperplasia.
Because LIMK1 plays an important role in mitosis,
microtubule dynamics and cytokinesis altered
expession of LIMK1 may cause mitotic defects.
Aberrant expression of LIMK1 is also involved in
induction of invasion in prostate cancer cells.
Breast cancer
Disease
Breast cancer is one of the major cancers affecting
women in the western world after skin cancer and
second leading cause of cancer death in women. About
20% of breast cancers are familial and about 10% of
breast cancer is because of inheritence of a mutated
gene. Although the cure rate has been increased
because of the improved diagnostic approaches and
LIMK1 (LIM domain kinase 1) Chakrabarti R
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 643
early detection, the metastatic disease actually has been
increased since 1990.
Prognosis
Overexpression of Her2/neu oncogene product is
considered to be associated with worse prognosis.
LIMK1 expression may have a prognostic value for
metastatic breast cancer as overexpression of LIMK1
has been noted in metastatic breast cancer cells.
Cytogenetics
CGH analysis indicated a gain in chromosome 7 in
majority of the infiltrating ductal carcinoma cases.
Some of the chromosomal gains include the region
encompassing Elastin and LIMK1 loci.
Oncogenesis
Overexpression of LIMK1 has been shown to increase
invasion and metastasis in animals. LIMK1 also
involved in regulation of EGFR turnover through
endocytic pathway in invasive breast cancer cells,
which may have implication in development of an
agressive disease.
Melanoma
Disease
Malignant melanoma is an agressive type of skin
cancer, which often metastasize leading to death. The
progression of melanoma is unpredictable and
sometimes show refractoriness to available
chemotherapy.
Cytogenetics
Chromosomal analysis using tiling array and CGH
showed a gain in chromosome 7 in melanoma cells.
Increased expression of LIMK1 in melanoma cells
(Skmel 28) harboring a break at 7q11.2 has also been
reported.
Williams-beuren syndrome (WBS)
Disease
WBS is a genetic disorder with autosomal dominant
inheritence. WBS is caused by microdeletion at
7q11.23 region with a phenotype of connective tissue
abnormalities, growth and psychomotor retardation,
muscular hypotonia, loss of visuospatial cognition and
behavioural abnormalities.
Prognosis
The presence of supravalvular aortic stenosis,
pulmonary stenosis, developmental retardation and
characteristic facial features in children between 18 to
30 months.
Cytogenetics
Chromosome analyses showed a deletion at the LIMK1
locus at 7q11.23 caused by a distal recombination event
at the common telomeric breakpoint.
Alzheimer disease (AD)
Disease
Dystrophic neurites are found to be associated with
Alzheimer's pathology. Altered structures of axons and
dendrites, deposition of amyloid plaques leading to
neurofibrillary tangle formation in AD pathology are
responsible for dementia and cognitive disorder in
Alzheimer's patients.
Prognosis
Deposition of fibrillar amyloid beta in the brain is one
of the events towards developing Alzheimer Disease.
LIMK1 has been shown to be involved in amyloid
beta-induced neuronal degeneration.
Immunofluorescence analysis showed an increased
number of phosphorylated LIMK1 positive neurons in
the areas of brain with AD pathology. Inhibition of
cofilin phosphorylation prevented neuronal
degeneration, which supports the involvement of
LIMK1 in AD.
Intracranial Aneurysm
Disease
Intracranial aneurysm is the localized dilation of the
blood vessel which could be fatal upon rupture causing
hemorrhage in the subarachnoid space. It occurs more
frequently in adults than children and in women than
men. Risk factors include family history of aneurysm
and inherited disorders including polycystic kidney
disease.
Cytogenetics
Genome wide linkage studies indicated a significant
association between SNP in LIMK1 promoter sequence
at 7q11.2 locus and incidence of IA in Japanese and
Korean patients. The SNP in the promoter sequence of
LIMK1 [C(-187)T] introduced an additional
transcription factor (AP2) binding site, which leads to a
reduced transcription of LIMK1 mRNA.
References Mizuno K, Okano I, Ohashi K, Nunoue K, Kuma K, Miyata T, Nakamura T. Identification of a human cDNA encoding a novel protein kinase with two repeats of the LIM/double zinc finger motif. Oncogene. 1994 Jun;9(6):1605-12
Tassabehji M, Metcalfe K, Fergusson WD, Carette MJ, Dore JK, Donnai D, Read AP, Pröschel C, Gutowski NJ, Mao X, Sheer D. LIM-kinase deleted in Williams syndrome. Nat Genet. 1996 Jul;13(3):272-3
Higuchi O, Amano T, Yang N, Mizuno K. Inhibition of activated Ras-induced neuronal differentiation of PC12 cells by the LIM domain of LIM-kinase 1. Oncogene. 1997 Apr 17;14(15):1819-25
Jenkins RB, Qian J, Lee HK, Huang H, Hirasawa K, Bostwick DG, Proffitt J, Wilber K, Lieber MM, Liu W, Smith DI. A molecular cytogenetic analysis of 7q31 in prostate cancer. Cancer Res. 1998 Feb 15;58(4):759-66
Edwards DC, Gill GN. Structural features of LIM kinase that control effects on the actin cytoskeleton. J Biol Chem. 1999 Apr 16;274(16):11352-61
Alers JC, Rochat J, Krijtenburg PJ, Hop WC, Kranse R, Rosenberg C, Tanke HJ, Schröder FH, van Dekken H. Identification of genetic markers for prostatic cancer progression. Lab Invest. 2000 Jun;80(6):931-42
LIMK1 (LIM domain kinase 1) Chakrabarti R
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 644
Davila M, Frost AR, Grizzle WE, Chakrabarti R. LIM kinase 1 is essential for the invasive growth of prostate epithelial cells: implications in prostate cancer. J Biol Chem. 2003 Sep 19;278(38):36868-75
Endo M, Ohashi K, Sasaki Y, Goshima Y, Niwa R, Uemura T, Mizuno K. Control of growth cone motility and morphology by LIM kinase and Slingshot via phosphorylation and dephosphorylation of cofilin. J Neurosci. 2003 Apr 1;23(7):2527-37
Yoshioka K, Foletta V, Bernard O, Itoh K. A role for LIM kinase in cancer invasion. Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7247-52
Rosso S, Bollati F, Bisbal M, Peretti D, Sumi T, Nakamura T, Quiroga S, Ferreira A, Cáceres A. LIMK1 regulates Golgi dynamics, traffic of Golgi-derived vesicles, and process extension in primary cultured neurons. Mol Biol Cell. 2004 Jul;15(7):3433-49
Eaton BA, Davis GW. LIM Kinase1 controls synaptic stability downstream of the type II BMP receptor. Neuron. 2005 Sep 1;47(5):695-708
Gorovoy M, Niu J, Bernard O, Profirovic J, Minshall R, Neamu R, Voyno-Yasenetskaya T. LIM kinase 1 coordinates microtubule stability and actin polymerization in human endothelial cells. J Biol Chem. 2005 Jul 15;280(28):26533-42
Okamoto I, Pirker C, Bilban M, Berger W, Losert D, Marosi C, Haas OA, Wolff K, Pehamberger H. Seven novel and stable translocations associated with oncogenic gene expression in malignant melanoma. Neoplasia. 2005 Apr;7(4):303-11
Akagawa H, Tajima A, Sakamoto Y, Krischek B, Yoneyama T, Kasuya H, Onda H, Hori T, Kubota M, Machida T, Saeki N, Hata A, Hashiguchi K, Kimura E, Kim CJ, Yang TK, Lee JY,
Kimm K, Inoue I. A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms. Hum Mol Genet. 2006 May 15;15(10):1722-34
Bagheri-Yarmand R, Mazumdar A, Sahin AA, Kumar R. LIM kinase 1 increases tumor metastasis of human breast cancer cells via regulation of the urokinase-type plasminogen activator system. Int J Cancer. 2006 Jun 1;118(11):2703-10
Heredia L, Helguera P, de Olmos S, Kedikian G, Solá Vigo F, LaFerla F, Staufenbiel M, de Olmos J, Busciglio J, Cáceres A, Lorenzo A. Phosphorylation of actin-depolymerizing factor/cofilin by LIM-kinase mediates amyloid beta-induced degeneration: a potential mechanism of neuronal dystrophy in Alzheimer's disease. J Neurosci. 2006 Jun 14;26(24):6533-42
Nishimura Y, Yoshioka K, Bernard O, Bereczky B, Itoh K. A role of LIM kinase 1/cofilin pathway in regulating endocytic trafficking of EGF receptor in human breast cancer cells. Histochem Cell Biol. 2006 Nov;126(5):627-38
Chakrabarti R, Jones JL, Oelschlager DK, Tapia T, Tousson A, Grizzle WE. Phosphorylated LIM kinases colocalize with gamma-tubulin in centrosomes during early stages of mitosis. Cell Cycle. 2007 Dec 1;6(23):2944-52
Jönsson G, Dahl C, Staaf J, Sandberg T, Bendahl PO, Ringnér M, Guldberg P, Borg A. Genomic profiling of malignant melanoma using tiling-resolution arrayCGH. Oncogene. 2007 Jul 12;26(32):4738-48
This article should be referenced as such:
Chakrabarti R. LIMK1 (LIM domain kinase 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):641-644.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 645
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
PAX6 (paired box 6) Yi-Hong Zhou
Department of Neurological Surgery, Department of Biological Chemistry (joint), University of California,
Irvine, Med Sci I, Room C214, Irvine, CA 92697, USA (YHZ)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/PAX6ID211ch11p13.html DOI: 10.4267/2042/44797
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: AN; AN2; D11S812E; MGC17209;
MGDA; Oculorhombin; WAGR
HGNC (Hugo): PAX6
Location: 11p13
DNA/RNA
Description
The PAX6 coding region extends over a genomic
interval of 16-17 kb and comprise 10 (isoform a) and
11 exons (isoform b).
Transcription
Three transcripts have been identified, originating from
alternative promoter usage (variant 3) or alternative
splicing (variant 2, additional in-frame coding 42 bp
exon downstream of exon 5 of variant 1); transcription
is from centromere to telomere.
Protein
Description
PAX6 belongs to the paired box family of transcription
factors, contains two DNA binding domains, a paired
box (PD) and a paired-type homeodomain (HD), and a
carboxyl-terminal transactivation domain rich of
proline, serine, and threonine (PST).
Expression
PAX6, predominately in form of PAX6a, is expressed
in the developing sensory organs (including eye, nasal
and olfactory tissues), central nervous system
(including forebrain, hindbrain, and spinal cord), and
endocrine system (including anterior pituitary gland
and pancreas) in human and rodent (Walther and
Gruss., 1991; Stoykova and Gruss., 1994; Davis and
Reed., 1996; Terzic and Saraga-Babic., 1999; Pinson et
al., 2005). PAX6 expression is sustained into adulthood
in certain areas of the brain, including, hippocampal
dentate gyrus (Maekawa et al., 2005; Nacher et al.,
2005), ependymal layer and the subventricular zone of
the lateral ventricle (Hack et al., 2005; Kohwi et al.,
2005), radial glia-like cells (Gubert et al., 2009), and in
mature endocrine cells in pancreas (St-Onge et al.,
1997). PAX6 transcription is regulated by two
promoters, P0 and P1, which are remarkably conserved
in evolution in both of their nucleotide sequence
arrangement and functional control of special and
temporal expression of PAX6 in development (Xu and
Saunders, 1997; Okladnova et al., 1998a; Williams et
al., 1998; Xu and
PAX6 (paired box 6) Zhou YH
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 646
There are two isoforms of PAX6, PAX6a and PAX6b with additional 14 extra amino acids in the paired box DNA binding domain. PAX6a, 423 amino acids, ~47 kDa; PAX6b, 436 amino acids, ~49 kDa.
Saunders, 1998; Kammandel et al., 1999; Plaza et al.,
1999a; Xu et al., 1999; Tyas et al., 2006), involving
multiple transcription factors, such as POU factor Brn-
3B, TFCP2, SP1, the basic helix-loop-helix
transcription factor NeuroD/BETA2, CCCTC binding
factor CTCF, PPARgamma (Plaza et al., 1999b; Zheng
et al., 2001; Schinner et al., 2002; Marsich et al., 2003;
Li et al., 2006; Wu et al., 2006). PAX6 expression is
also regulated by a long range downstream enhancer
(Kleinjan et al., 2006) and is under autoregulation
(Grocott et al., 2007) and post modification by HIPK2
and protein phosphatase 1 (Kim et al., 2006; Yan et al.,
2007). A promoter-associated polymorphic repeat was
found to modulate PAX6 expression in human brain
(Okladnova et al., 1998b).
Localisation
Nuclear.
Function
Loss of Pax6 function in rodent mutant and knock-out
model revealed that Pax6 is a key regulator of a
multitude of developmental processes of sensory
system, including eye, nasal and olfactory (Hill et al.,
1991; Grindley et al., 1995; Quinn et al., 1996; van
Raamsdonk and Tilghman, 2000; Singh et al., 2002;
van Heyningen and Williamson, 2002; Collinson et al.,
2003; Davis et al., 2003; Brill et al., 2008), CNS
(Matsuo et al., 1993; Schmahl et al., 1993; Stoykova et
al., 1996; Grindley et al., 1997; Osumi et al., 1997;
Mastick et al., 1997; Warren and Price, 1997; Gotz et
al., 1998; Sun et al., 1998; Engelkamp et al., 1999;
Kawano et al., 1999; Pratt et al., 2000; Stoykova et al.,
2000; Estivill-Torrus et al., 2002; Pratt et al., 2002;
Talamillo et al., 2003; Quinn et al., 2007), pituitary
(Bentley et al., 1999; Kioussi et al., 1999) and pancreas
(Sander et al., 1997; St-Onge et al., 1997; Dohrmann et
al., 2000; Zhang et al., 2003). Pax6 function in
development of fundamental sensory processes and
central nervous system, particularly of the
photoreceptive organ, are remarkably conserved in
evolution (Halder et al., 1995; Gehring et al., 2005).
PAX6 funciton in development were found to be under
control of Shh, notch and EGFR signaling (Ericson et
al., 1997; Kumar and Moses, 2001; Onuma et al., 2002;
Li and Lu, 2005), essential for neural stem cell
proliferation, multipotency, and neurogenesis in many
regions of the central nervous system (Warren et al.,
1999; Bishop et al., 2000; Toresson et al., 2000;
Marquardt et al., 2001; Yamasaki et al., 2001; Yun et
al., 2001; Estivill-Torrus et al., 2002; Heins et al.,
2002; Simpson and Price, 2002; Tyas et al., 2003;
Collinson et al., 2004; Haubst et al., 2004; Nomura and
Osumi, 2004; Schuurmans et al., 2004; Maekawa et al.,
2005; Bel-Vialar et al., 2007; Duparc et al., 2007;
Quinn et al., 2007; Canto-Soler et al., 2008; Oron-
Karni et al., 2008; Osumi et al., 2008), and appears to
control the balance between neural stem cell self-
renewal and neurogenesis under a dose-dependent
manner (Sansom et al., 2009).
PAX6 binds as a monomer to relatively long (15-22 bp)
DNA binding sites, and the 14 aa insertion in the paired
domain allows different binding affinity to DNA
sequences between PAX6a and PAX6b (Epstein et al.,
1994a; Epstein et al., 1994b). Through binding to
different DNA sequences via usage of various DNA
binding motifs alone or in combination, PAX6 controls
the expression of various downstream target genes
involved in complex gene regulatory networks for cell
proliferation, adhesion, migration, and neurogenesis
(Schmahl et al., 1993; Caric et al., 1997; Sander et al.,
1997; Sax et al., 1997; Tang et al., 1997; Duncan et al.,
1998; Beimesche et al., 1999; Meech et al., 1999;
Singh et al., 2000; Sivak et al., 2000; Zhou et al., 2000;
Chauhan et al., 2002; Mishra et al., 2002; Skala-
Rubinson et al., 2002; Zhou et al., 2002; Andrews and
Mastick, 2003; Davis et al., 2003; Horie et al., 2003;
Tyas et al., 2003; Cvekl et al., 2004; Grinchuk et al.,
2005; Mayes et al., 2006; Holm et al., 2007; Tuoc and
Stoykova, 2008). Not only reduced, but also increases
level of PAX6 gene dosage also cause defects in
developmental processes that are sensitive to PAX6
dosage, including eye organogenesis and corticogenesis
(Schedl et al., 1996; Berger et al., 2007; Manuel et al.,
2007).
Homology
PAX6 shares homology through the conserved paired
box domain with the other members of the nine PAX
gene family.
Mutations
Germinal
Heterozygous intragenic mutation of PAX6, that causes
loss of function of one copy of the PAX6 gene, is the
cause of aniridia syndrome (Ton et al., 1991; Glaser et
al., 1992; Prosser and van Heyningen, 1998; Robinson
et al., 2008; Hingorani et al., 2009; MRC Human
Genetics Unit) and cerebral malformation, olfactory
dysfunction, absence of the pineal gland and unilateral
polymicrogyria (Sisodiya et al., 2001; Free et al., 2003;
Mitchell et al., 2003; Bamiou et al., 2007a; Bamiou et
al., 2007b).
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Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 647
PAX6 3' deletion also results in aniridia, autism and
mental retardation (Davis et al., 2008).
Implicated in
Brain cancer
Note
The expression level of PAX6 in human glioma cell
lines was shown to be negatively associated with the
degree of tumorigenicity. PAX6 expression level is
lower in glioblastoma compared to the adjacent normal
tissue and to the anaplastic astrocytoma previously
formed in the same patient (Zhou et al., 2003). Ectopic
expression of PAX6 in glioma cell lines suppressed cell
anchorage independent growth, ability to survive under
oxidative stress induced by cell detachment, ability to
invade partially by suppression of MMP2 gene
expression, ability to induce angiogenesis by initiating
a new signaling pathway independent of PI3K/Akt-
HIF1A signaling to suppress VEGFA, and overall
tumor growth after intracranial implantation in
immunocompromised mouse brain (Zhou et al., 2005;
Mayes et al., 2006; Chang et al., 2007; Zhou et al.,
2009). Mutation analysis for PAX6 in gliomas failed to
identify PAX6 mutation in its coding and regulating
regions, suggesting involvement of epigenetic
mechanisms in the silencing of PAX6 in glioma (Pinto
et al., 2007). PAX6 expression is activated in glioma
cell line with re-introduction of a normal ch.10,
suggesting that PAX6 is regulated by a gene(s) on
ch.10 (Zhou et al., 2005).
Prognosis
PAX6 is a factor related to a longer survival prognosis
for astrocytic gliomas (Zhou et al., 2003).
Pancreatic cancer
Note
PAX6 is expressed in pancreatic adenocarcinoma and
is downregulated during induction of terminal
differentiation (Lang et al., 2008). In pancreatic
carcinoma cell lines, PAX6 bind directly to an
enhancer element in the MET promoter and activate the
expression of the MET gene (Mascarenhas et al.,
2009).
Bladder cancer
Note
Methylation of PAX6-promoters is increased in early
bladder cancer and in normal mucosa adjacent to pTa
tumours (Hellwinkel et al., 2008).
Familial adenomatous polyposis (FAP) related carcinoma
Note
PAX6 gene is methylated in FAP-related carcinoma.
Patients with familial adenomatous polyposis (FAP)
have a high risk of developing duodenal carcinomas
(Berkhout et al., 2007).
WAGR syndrome
Note
WAGR syndrome can have aniridia due to deletion of
chromosome 11 including PAX6 (Gronskov et al.,
2001; Chao et al., 2003). However, PAX6 mutation is
only found in aniridia patient, not WAGR syndrome
associated anomalies (Robinson et al., 2008).
References Hill RE, Favor J, Hogan BL, Ton CC, Saunders GF, Hanson IM, Prosser J, Jordan T, Hastie ND, van Heyningen V. Mouse small eye results from mutations in a paired-like homeobox-containing gene. Nature. 1991 Dec 19-26;354(6354):522-5
Ton CC, Hirvonen H, Miwa H, Weil MM, Monaghan P, Jordan T, van Heyningen V, Hastie ND, Meijers-Heijboer H, Drechsler M. Positional cloning and characterization of a paired box- and homeobox-containing gene from the aniridia region. Cell. 1991 Dec 20;67(6):1059-74
Walther C, Gruss P. Pax-6, a murine paired box gene, is expressed in the developing CNS. Development. 1991 Dec;113(4):1435-49
Glaser T, Walton DS, Maas RL. Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene. Nat Genet. 1992 Nov;2(3):232-9
Matsuo T, Osumi-Yamashita N, Noji S, Ohuchi H, Koyama E, Myokai F, Matsuo N, Taniguchi S, Doi H, Iseki S. A mutation in the Pax-6 gene in rat small eye is associated with impaired migration of midbrain crest cells. Nat Genet. 1993 Apr;3(4):299-304
Schmahl W, Knoedlseder M, Favor J, Davidson D. Defects of neuronal migration and the pathogenesis of cortical malformations are associated with Small eye (Sey) in the mouse, a point mutation at the Pax-6-locus. Acta Neuropathol. 1993;86(2):126-35
Epstein J, Cai J, Glaser T, Jepeal L, Maas R. Identification of a Pax paired domain recognition sequence and evidence for DNA-dependent conformational changes. J Biol Chem. 1994 Mar 18;269(11):8355-61
Epstein JA, Glaser T, Cai J, Jepeal L, Walton DS, Maas RL. Two independent and interactive DNA-binding subdomains of the Pax6 paired domain are regulated by alternative splicing. Genes Dev. 1994 Sep 1;8(17):2022-34
Stoykova A, Gruss P. Roles of Pax-genes in developing and adult brain as suggested by expression patterns. J Neurosci. 1994 Mar;14(3 Pt 2):1395-412
Grindley JC, Davidson DR, Hill RE. The role of Pax-6 in eye and nasal development. Development. 1995 May;121(5):1433-42
Halder G, Callaerts P, Gehring WJ. New perspectives on eye evolution. Curr Opin Genet Dev. 1995 Oct;5(5):602-9
Davis JA, Reed RR. Role of Olf-1 and Pax-6 transcription factors in neurodevelopment. J Neurosci. 1996 Aug 15;16(16):5082-94
Quinn JC, West JD, Hill RE. Multiple functions for Pax6 in mouse eye and nasal development. Genes Dev. 1996 Feb 15;10(4):435-46
Schedl A, Ross A, Lee M, Engelkamp D, Rashbass P, van Heyningen V, Hastie ND. Influence of PAX6 gene dosage on development: overexpression causes severe eye abnormalities. Cell. 1996 Jul 12;86(1):71-82
PAX6 (paired box 6) Zhou YH
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 648
Stoykova A, Fritsch R, Walther C, Gruss P. Forebrain patterning defects in Small eye mutant mice. Development. 1996 Nov;122(11):3453-65
Carić D, Gooday D, Hill RE, McConnell SK, Price DJ. Determination of the migratory capacity of embryonic cortical cells lacking the transcription factor Pax-6. Development. 1997 Dec;124(24):5087-96
Ericson J, Rashbass P, Schedl A, Brenner-Morton S, Kawakami A, van Heyningen V, Jessell TM, Briscoe J. Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling. Cell. 1997 Jul 11;90(1):169-80
Grindley JC, Hargett LK, Hill RE, Ross A, Hogan BL. Disruption of PAX6 function in mice homozygous for the Pax6Sey-1Neu mutation produces abnormalities in the early development and regionalization of the diencephalon. Mech Dev. 1997 Jun;64(1-2):111-26
Mastick GS, Davis NM, Andrew GL, Easter SS Jr. Pax-6 functions in boundary formation and axon guidance in the embryonic mouse forebrain. Development. 1997 May;124(10):1985-97
Osumi N, Hirota A, Ohuchi H, Nakafuku M, Iimura T, Kuratani S, Fujiwara M, Noji S, Eto K. Pax-6 is involved in the specification of hindbrain motor neuron subtype. Development. 1997 Aug;124(15):2961-72
Sander M, Neubüser A, Kalamaras J, Ee HC, Martin GR, German MS. Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development. Genes Dev. 1997 Jul 1;11(13):1662-73
Sax CM, Cvekl A, Piatigorsky J. Transcriptional regulation of the mouse alpha A-crystallin gene: binding of USF to the -7/+5 region. Gene. 1997 Feb 7;185(2):209-16
St-Onge L, Sosa-Pineda B, Chowdhury K, Mansouri A, Gruss P. Pax6 is required for differentiation of glucagon-producing alpha-cells in mouse pancreas. Nature. 1997 May 22;387(6631):406-9
Tang HK, Chao LY, Saunders GF. Functional analysis of paired box missense mutations in the PAX6 gene. Hum Mol Genet. 1997 Mar;6(3):381-6
Warren N, Price DJ. Roles of Pax-6 in murine diencephalic development. Development. 1997 Apr;124(8):1573-82
Xu ZP, Saunders GF. Transcriptional regulation of the human PAX6 gene promoter. J Biol Chem. 1997 Feb 7;272(6):3430-6
Duncan MK, Haynes JI 2nd, Cvekl A, Piatigorsky J. Dual roles for Pax-6: a transcriptional repressor of lens fiber cell-specific beta-crystallin genes. Mol Cell Biol. 1998 Sep;18(9):5579-86
Götz M, Stoykova A, Gruss P. Pax6 controls radial glia differentiation in the cerebral cortex. Neuron. 1998 Nov;21(5):1031-44
Okladnova O, Syagailo YV, Mössner R, Riederer P, Lesch KP. Regulation of PAX-6 gene transcription: alternate promoter usage in human brain. Brain Res Mol Brain Res. 1998 Oct 1;60(2):177-92
Okladnova O, Syagailo YV, Tranitz M, Stöber G, Riederer P, Mössner R, Lesch KP. A promoter-associated polymorphic repeat modulates PAX-6 expression in human brain. Biochem Biophys Res Commun. 1998 Jul 20;248(2):402-5
Prosser J, van Heyningen V. PAX6 mutations reviewed. Hum Mutat. 1998;11(2):93-108
Sun T, Pringle NP, Hardy AP, Richardson WD, Smith HK. Pax6 influences the time and site of origin of glial precursors in the ventral neural tube. Mol Cell Neurosci. 1998 Nov;12(4-5):228-39
Williams SC, Altmann CR, Chow RL, Hemmati-Brivanlou A, Lang RA. A highly conserved lens transcriptional control element from the Pax-6 gene. Mech Dev. 1998 May;73(2):225-9
Xu ZP, Saunders GF. PAX6 intronic sequence targets expression to the spinal cord. Dev Genet. 1998;23(4):259-63
Beimesche S, Neubauer A, Herzig S, Grzeskowiak R, Diedrich T, Cierny I, Scholz D, Alejel T, Knepel W. Tissue-specific transcriptional activity of a pancreatic islet cell-specific enhancer sequence/Pax6-binding site determined in normal adult tissues in vivo using transgenic mice. Mol Endocrinol. 1999 May;13(5):718-28
Bentley CA, Zidehsarai MP, Grindley JC, Parlow AF, Barth-Hall S, Roberts VJ. Pax6 is implicated in murine pituitary endocrine function. Endocrine. 1999 Apr;10(2):171-7
Engelkamp D, Rashbass P, Seawright A, van Heyningen V. Role of Pax6 in development of the cerebellar system. Development. 1999 Aug;126(16):3585-96
Kammandel B, Chowdhury K, Stoykova A, Aparicio S, Brenner S, Gruss P. Distinct cis-essential modules direct the time-space pattern of the Pax6 gene activity. Dev Biol. 1999 Jan 1;205(1):79-97
Kawano H, Fukuda T, Kubo K, Horie M, Uyemura K, Takeuchi K, Osumi N, Eto K, Kawamura K. Pax-6 is required for thalamocortical pathway formation in fetal rats. J Comp Neurol. 1999 May 31;408(2):147-60
Kioussi C, O'Connell S, St-Onge L, Treier M, Gleiberman AS, Gruss P, Rosenfeld MG. Pax6 is essential for establishing ventral-dorsal cell boundaries in pituitary gland development. Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14378-82
Meech R, Kallunki P, Edelman GM, Jones FS. A binding site for homeodomain and Pax proteins is necessary for L1 cell adhesion molecule gene expression by Pax-6 and bone morphogenetic proteins. Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2420-5
Plaza S, Hennemann H, Möröy T, Saule S, Dozier C. Evidence that POU factor Brn-3B regulates expression of Pax-6 in neuroretina cells. J Neurobiol. 1999 Nov 15;41(3):349-58
Plaza S, Saule S, Dozier C. High conservation of cis-regulatory elements between quail and human for the Pax-6 gene. Dev Genes Evol. 1999 Mar;209(3):165-73
Terzić J, Saraga-Babić M. Expression pattern of PAX3 and PAX6 genes during human embryogenesis. Int J Dev Biol. 1999 Sep;43(6):501-8
Warren N, Caric D, Pratt T, Clausen JA, Asavaritikrai P, Mason JO, Hill RE, Price DJ. The transcription factor, Pax6, is required for cell proliferation and differentiation in the developing cerebral cortex. Cereb Cortex. 1999 Sep;9(6):627-35
Xu PX, Zhang X, Heaney S, Yoon A, Michelson AM, Maas RL. Regulation of Pax6 expression is conserved between mice and flies. Development. 1999 Jan;126(2):383-95
Bishop KM, Goudreau G, O'Leary DD. Regulation of area identity in the mammalian neocortex by Emx2 and Pax6. Science. 2000 Apr 14;288(5464):344-9
Dohrmann C, Gruss P, Lemaire L. Pax genes and the differentiation of hormone-producing endocrine cells in the pancreas. Mech Dev. 2000 Mar 15;92(1):47-54
Pratt T, Vitalis T, Warren N, Edgar JM, Mason JO, Price DJ. A role for Pax6 in the normal development of dorsal thalamus and its cortical connections. Development. 2000 Dec;127(23):5167-78
PAX6 (paired box 6) Zhou YH
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 649
Singh S, Stellrecht CM, Tang HK, Saunders GF. Modulation of PAX6 homeodomain function by the paired domain. J Biol Chem. 2000 Jun 9;275(23):17306-13
Sivak JM, Mohan R, Rinehart WB, Xu PX, Maas RL, Fini ME. Pax-6 expression and activity are induced in the reepithelializing cornea and control activity of the transcriptional promoter for matrix metalloproteinase gelatinase B. Dev Biol. 2000 Jun 1;222(1):41-54
Stoykova A, Treichel D, Hallonet M, Gruss P. Pax6 modulates the dorsoventral patterning of the mammalian telencephalon. J Neurosci. 2000 Nov 1;20(21):8042-50
Toresson H, Potter SS, Campbell K. Genetic control of dorsal-ventral identity in the telencephalon: opposing roles for Pax6 and Gsh2. Development. 2000 Oct;127(20):4361-71
van Raamsdonk CD, Tilghman SM. Dosage requirement and allelic expression of PAX6 during lens placode formation. Development. 2000 Dec;127(24):5439-48
Zhou Y, Zheng JB, Gu X, Li W, Saunders GF. A novel Pax-6 binding site in rodent B1 repetitive elements: coevolution between developmental regulation and repeated elements? Gene. 2000 Mar 21;245(2):319-28
Grønskov K, Olsen JH, Sand A, Pedersen W, Carlsen N, Bak Jylling AM, Lyngbye T, Brøndum-Nielsen K, Rosenberg T. Population-based risk estimates of Wilms tumor in sporadic aniridia. A comprehensive mutation screening procedure of PAX6 identifies 80% of mutations in aniridia. Hum Genet. 2001 Jul;109(1):11-8
Kumar JP, Moses K. EGF receptor and Notch signaling act upstream of Eyeless/Pax6 to control eye specification. Cell. 2001 Mar 9;104(5):687-97
Marquardt T, Ashery-Padan R, Andrejewski N, Scardigli R, Guillemot F, Gruss P. Pax6 is required for the multipotent state of retinal progenitor cells. Cell. 2001 Apr 6;105(1):43-55
Sisodiya SM, Free SL, Williamson KA, Mitchell TN, Willis C, Stevens JM, Kendall BE, Shorvon SD, Hanson IM, Moore AT, van Heyningen V. PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans. Nat Genet. 2001 Jul;28(3):214-6
Yamasaki T, Kawaji K, Ono K, Bito H, Hirano T, Osumi N, Kengaku M. Pax6 regulates granule cell polarization during parallel fiber formation in the developing cerebellum. Development. 2001 Aug;128(16):3133-44
Yun K, Potter S, Rubenstein JL. Gsh2 and Pax6 play complementary roles in dorsoventral patterning of the mammalian telencephalon. Development. 2001 Jan;128(2):193-205
Zheng JB, Zhou YH, Maity T, Liao WS, Saunders GF. Activation of the human PAX6 gene through the exon 1 enhancer by transcription factors SEF and Sp1. Nucleic Acids Res. 2001 Oct 1;29(19):4070-8
Chauhan BK, Reed NA, Yang Y, Cermák L, Reneker L, Duncan MK, Cvekl A. A comparative cDNA microarray analysis reveals a spectrum of genes regulated by Pax6 in mouse lens. Genes Cells. 2002 Dec;7(12):1267-83
Estivill-Torrus G, Pearson H, van Heyningen V, Price DJ, Rashbass P. Pax6 is required to regulate the cell cycle and the rate of progression from symmetrical to asymmetrical division in mammalian cortical progenitors. Development. 2002 Jan;129(2):455-66
Heins N, Malatesta P, Cecconi F, Nakafuku M, Tucker KL, Hack MA, Chapouton P, Barde YA, Götz M. Glial cells generate neurons: the role of the transcription factor Pax6. Nat Neurosci. 2002 Apr;5(4):308-15
Mishra R, Gorlov IP, Chao LY, Singh S, Saunders GF. PAX6, paired domain influences sequence recognition by the homeodomain. J Biol Chem. 2002 Dec 20;277(51):49488-94
Onuma Y, Takahashi S, Asashima M, Kurata S, Gehring WJ. Conservation of Pax 6 function and upstream activation by Notch signaling in eye development of frogs and flies. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2020-5
Pratt T, Quinn JC, Simpson TI, West JD, Mason JO, Price DJ. Disruption of early events in thalamocortical tract formation in mice lacking the transcription factors Pax6 or Foxg1. J Neurosci. 2002 Oct 1;22(19):8523-31
Schinner S, Dellas C, Schroder M, Heinlein CA, Chang C, Fischer J, Knepel W. Repression of glucagon gene transcription by peroxisome proliferator-activated receptor gamma through inhibition of Pax6 transcriptional activity. J Biol Chem. 2002 Jan 18;277(3):1941-8
Simpson TI, Price DJ. Pax6; a pleiotropic player in development. Bioessays. 2002 Nov;24(11):1041-51
Singh S, Mishra R, Arango NA, Deng JM, Behringer RR, Saunders GF. Iris hypoplasia in mice that lack the alternatively spliced Pax6(5a) isoform. Proc Natl Acad Sci U S A. 2002 May 14;99(10):6812-5
Skala-Rubinson H, Vinh J, Labas V, Kahn A, Phan DT. Novel target sequences for Pax-6 in the brain-specific activating regions of the rat aldolase C gene. J Biol Chem. 2002 Dec 6;277(49):47190-6
van Heyningen V, Williamson KA. PAX6 in sensory development. Hum Mol Genet. 2002 May 15;11(10):1161-7
Zhou YH, Zheng JB, Gu X, Saunders GF, Yung WK. Novel PAX6 binding sites in the human genome and the role of repetitive elements in the evolution of gene regulation. Genome Res. 2002 Nov;12(11):1716-22
Andrews GL, Mastick GS. R-cadherin is a Pax6-regulated, growth-promoting cue for pioneer axons. J Neurosci. 2003 Oct 29;23(30):9873-80
Chao LY, Mishra R, Strong LC, Saunders GF. Missense mutations in the DNA-binding region and termination codon in PAX6. Hum Mutat. 2003 Feb;21(2):138-45
Collinson JM, Quinn JC, Hill RE, West JD. The roles of Pax6 in the cornea, retina, and olfactory epithelium of the developing mouse embryo. Dev Biol. 2003 Mar 15;255(2):303-12
Davis J, Duncan MK, Robison WG Jr, Piatigorsky J. Requirement for Pax6 in corneal morphogenesis: a role in adhesion. J Cell Sci. 2003 Jun 1;116(Pt 11):2157-67
Free SL, Mitchell TN, Williamson KA, Churchill AJ, Shorvon SD, Moore AT, van Heyningen V, Sisodiya SM. Quantitative MR image analysis in subjects with defects in the PAX6 gene. Neuroimage. 2003 Dec;20(4):2281-90
Horie M, Sango K, Takeuchi K, Honma S, Osumi N, Kawamura K, Kawano H. Subpial neuronal migration in the medulla oblongata of Pax-6-deficient rats. Eur J Neurosci. 2003 Jan;17(1):49-57
Marsich E, Vetere A, Di Piazza M, Tell G, Paoletti S. The PAX6 gene is activated by the basic helix-loop-helix transcription factor NeuroD/BETA2. Biochem J. 2003 Dec 15;376(Pt 3):707-15
Mitchell TN, Free SL, Williamson KA, Stevens JM, Churchill AJ, Hanson IM, Shorvon SD, Moore AT, van Heyningen V, Sisodiya SM. Polymicrogyria and absence of pineal gland due to PAX6 mutation. Ann Neurol. 2003 May;53(5):658-63
Talamillo A, Quinn JC, Collinson JM, Caric D, Price DJ, West JD, Hill RE. Pax6 regulates regional development and
PAX6 (paired box 6) Zhou YH
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 650
neuronal migration in the cerebral cortex. Dev Biol. 2003 Mar 1;255(1):151-63
Tyas DA, Pearson H, Rashbass P, Price DJ. Pax6 regulates cell adhesion during cortical development. Cereb Cortex. 2003 Jun;13(6):612-9
Zhang X, Heaney S, Maas RL. Cre-loxp fate-mapping of Pax6 enhancer active retinal and pancreatic progenitors. Genesis. 2003 Jan;35(1):22-30
Zhou YH, Tan F, Hess KR, Yung WK. The expression of PAX6, PTEN, vascular endothelial growth factor, and epidermal growth factor receptor in gliomas: relationship to tumor grade and survival. Clin Cancer Res. 2003 Aug 15;9(9):3369-75
Collinson JM, Chanas SA, Hill RE, West JD. Corneal development, limbal stem cell function, and corneal epithelial cell migration in the Pax6(+/-) mouse. Invest Ophthalmol Vis Sci. 2004 Apr;45(4):1101-8
Cvekl A, Yang Y, Chauhan BK, Cveklova K. Regulation of gene expression by Pax6 in ocular cells: a case of tissue-preferred expression of crystallins in lens. Int J Dev Biol. 2004;48(8-9):829-44
Haubst N, Berger J, Radjendirane V, Graw J, Favor J, Saunders GF, Stoykova A, Götz M. Molecular dissection of Pax6 function: the specific roles of the paired domain and homeodomain in brain development. Development. 2004 Dec;131(24):6131-40
Nomura T, Osumi N. Misrouting of mitral cell progenitors in the Pax6/small eye rat telencephalon. Development. 2004 Feb;131(4):787-96
Schuurmans C, Armant O, Nieto M, Stenman JM, Britz O, Klenin N, Brown C, Langevin LM, Seibt J, Tang H, Cunningham JM, Dyck R, Walsh C, Campbell K, Polleux F, Guillemot F. Sequential phases of cortical specification involve Neurogenin-dependent and -independent pathways. EMBO J. 2004 Jul 21;23(14):2892-902
Gehring WJ. New perspectives on eye development and the evolution of eyes and photoreceptors. J Hered. 2005 May-Jun;96(3):171-84
Grinchuk O, Kozmik Z, Wu X, Tomarev S. The Optimedin gene is a downstream target of Pax6. J Biol Chem. 2005 Oct 21;280(42):35228-37
Hack MA, Saghatelyan A, de Chevigny A, Pfeifer A, Ashery-Padan R, Lledo PM, Götz M. Neuronal fate determinants of adult olfactory bulb neurogenesis. Nat Neurosci. 2005 Jul;8(7):865-72
Kohwi M, Osumi N, Rubenstein JL, Alvarez-Buylla A. Pax6 is required for making specific subpopulations of granule and periglomerular neurons in the olfactory bulb. J Neurosci. 2005 Jul 27;25(30):6997-7003
Li T, Lu L. Epidermal growth factor-induced proliferation requires down-regulation of Pax6 in corneal epithelial cells. J Biol Chem. 2005 Apr 1;280(13):12988-95
Maekawa M, Takashima N, Arai Y, Nomura T, Inokuchi K, Yuasa S, Osumi N. Pax6 is required for production and maintenance of progenitor cells in postnatal hippocampal neurogenesis. Genes Cells. 2005 Oct;10(10):1001-14
Nacher J, Varea E, Blasco-Ibañez JM, Castillo-Gomez E, Crespo C, Martinez-Guijarro FJ, McEwen BS. Expression of the transcription factor Pax 6 in the adult rat dentate gyrus. J Neurosci Res. 2005 Sep 15;81(6):753-61
Pinson J, Mason JO, Simpson TI, Price DJ. Regulation of the Pax6 : Pax6(5a) mRNA ratio in the developing mammalian brain. BMC Dev Biol. 2005 Jul 19;5:13
Zhou YH, Wu X, Tan F, Shi YX, Glass T, Liu TJ, Wathen K, Hess KR, Gumin J, Lang F, Yung WK. PAX6 suppresses growth of human glioblastoma cells. J Neurooncol. 2005 Feb;71(3):223-9
Kim EA, Noh YT, Ryu MJ, Kim HT, Lee SE, Kim CH, Lee C, Kim YH, Choi CY. Phosphorylation and transactivation of Pax6 by homeodomain-interacting protein kinase 2. J Biol Chem. 2006 Mar 17;281(11):7489-97
Kleinjan DA, Seawright A, Mella S, Carr CB, Tyas DA, Simpson TI, Mason JO, Price DJ, van Heyningen V. Long-range downstream enhancers are essential for Pax6 expression. Dev Biol. 2006 Nov 15;299(2):563-81
Li T, Lu Z, Lu L. Pax6 regulation in retinal cells by CCCTC binding factor. Invest Ophthalmol Vis Sci. 2006 Dec;47(12):5218-26
Mayes DA, Hu Y, Teng Y, Siegel E, Wu X, Panda K, Tan F, Yung WK, Zhou YH. PAX6 suppresses the invasiveness of glioblastoma cells and the expression of the matrix metalloproteinase-2 gene. Cancer Res. 2006 Oct 15;66(20):9809-17
Tyas DA, Simpson TI, Carr CB, Kleinjan DA, van Heyningen V, Mason JO, Price DJ. Functional conservation of Pax6 regulatory elements in humans and mice demonstrated with a novel transgenic reporter mouse. BMC Dev Biol. 2006 May 4;6:21
Wu D, Li T, Lu Z, Dai W, Xu M, Lu L. Effect of CTCF-binding motif on regulation of PAX6 transcription. Invest Ophthalmol Vis Sci. 2006 Jun;47(6):2422-9
Bamiou DE, Campbell NG, Musiek FE, Taylor R, Chong WK, Moore A, van Heyningen V, Free S, Sisodiya S, Luxon LM. Auditory and verbal working memory deficits in a child with congenital aniridia due to a PAX6 mutation. Int J Audiol. 2007 Apr;46(4):196-202
Bamiou DE, Free SL, Sisodiya SM, Chong WK, Musiek F, Williamson KA, van Heyningen V, Moore AT, Gadian D, Luxon LM. Auditory interhemispheric transfer deficits, hearing difficulties, and brain magnetic resonance imaging abnormalities in children with congenital aniridia due to PAX6 mutations. Arch Pediatr Adolesc Med. 2007 May;161(5):463-9
Bel-Vialar S, Medevielle F, Pituello F. The on/off of Pax6 controls the tempo of neuronal differentiation in the developing spinal cord. Dev Biol. 2007 May 15;305(2):659-73
Berger J, Berger S, Tuoc TC, D'Amelio M, Cecconi F, Gorski JA, Jones KR, Gruss P, Stoykova A. Conditional activation of Pax6 in the developing cortex of transgenic mice causes progenitor apoptosis. Development. 2007 Apr;134(7):1311-22
Berkhout M, Nagtegaal ID, Cornelissen SJ, Dekkers MM, van de Molengraft FJ, Peters WH, Nagengast FM, van Krieken JH, Jeuken JW. Chromosomal and methylation alterations in sporadic and familial adenomatous polyposis-related duodenal carcinomas. Mod Pathol. 2007 Dec;20(12):1253-62
Chang JY, Hu Y, Siegel E, Stanley L, Zhou YH. PAX6 increases glioma cell susceptibility to detachment and oxidative stress. J Neurooncol. 2007 Aug;84(1):9-19
Duparc RH, Abdouh M, David J, Lépine M, Tétreault N, Bernier G. Pax6 controls the proliferation rate of neuroepithelial progenitors from the mouse optic vesicle. Dev Biol. 2007 Jan 15;301(2):374-87
Grocott T, Frost V, Maillard M, Johansen T, Wheeler GN, Dawes LJ, Wormstone IM, Chantry A. The MH1 domain of Smad3 interacts with Pax6 and represses autoregulation of the Pax6 P1 promoter. Nucleic Acids Res. 2007;35(3):890-901
Holm PC, Mader MT, Haubst N, Wizenmann A, Sigvardsson M, Götz M. Loss- and gain-of-function analyses reveal targets
PAX6 (paired box 6) Zhou YH
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 651
of Pax6 in the developing mouse telencephalon. Mol Cell Neurosci. 2007 Jan;34(1):99-119
Manuel M, Georgala PA, Carr CB, Chanas S, Kleinjan DA, Martynoga B, Mason JO, Molinek M, Pinson J, Pratt T, Quinn JC, Simpson TI, Tyas DA, van Heyningen V, West JD, Price DJ. Controlled overexpression of Pax6 in vivo negatively autoregulates the Pax6 locus, causing cell-autonomous defects of late cortical progenitor proliferation with little effect on cortical arealization. Development. 2007 Feb;134(3):545-55
Pinto GR, Clara CA, Santos MJ, Almeida JR, Burbano RR, Rey JA, Casartelli C. Mutation analysis of gene PAX6 in human gliomas. Genet Mol Res. 2007 Oct 5;6(4):1019-25
Quinn JC, Molinek M, Martynoga BS, Zaki PA, Faedo A, Bulfone A, Hevner RF, West JD, Price DJ. Pax6 controls cerebral cortical cell number by regulating exit from the cell cycle and specifies cortical cell identity by a cell autonomous mechanism. Dev Biol. 2007 Feb 1;302(1):50-65
Yan Q, Liu WB, Qin J, Liu J, Chen HG, Huang X, Chen L, Sun S, Deng M, Gong L, Li Y, Zhang L, Liu Y, Feng H, Xiao Y, Liu Y, Li DW. Protein phosphatase-1 modulates the function of Pax-6, a transcription factor controlling brain and eye development. J Biol Chem. 2007 May 11;282(19):13954-65
Brill MS, Snapyan M, Wohlfrom H, Ninkovic J, Jawerka M, Mastick GS, Ashery-Padan R, Saghatelyan A, Berninger B, Götz M. A dlx2- and pax6-dependent transcriptional code for periglomerular neuron specification in the adult olfactory bulb. J Neurosci. 2008 Jun 18;28(25):6439-52
Canto-Soler MV, Huang H, Romero MS, Adler R. Transcription factors CTCF and Pax6 are segregated to different cell types during retinal cell differentiation. Dev Dyn. 2008 Mar;237(3):758-67
Davis LK, Meyer KJ, Rudd DS, Librant AL, Epping EA, Sheffield VC, Wassink TH. Pax6 3' deletion results in aniridia, autism and mental retardation. Hum Genet. 2008 May;123(4):371-8
Hellwinkel OJ, Kedia M, Isbarn H, Budäus L, Friedrich MG. Methylation of the TPEF- and PAX6-promoters is increased in early bladder cancer and in normal mucosa adjacent to pTa tumours. BJU Int. 2008 Mar;101(6):753-7
Lang D, Mascarenhas JB, Powell SK, Halegoua J, Nelson M, Ruggeri BA. PAX6 is expressed in pancreatic adenocarcinoma
and is downregulated during induction of terminal differentiation. Mol Carcinog. 2008 Feb;47(2):148-56
Oron-Karni V, Farhy C, Elgart M, Marquardt T, Remizova L, Yaron O, Xie Q, Cvekl A, Ashery-Padan R. Dual requirement for Pax6 in retinal progenitor cells. Development. 2008 Dec;135(24):4037-47
Osumi N, Shinohara H, Numayama-Tsuruta K, Maekawa M. Concise review: Pax6 transcription factor contributes to both embryonic and adult neurogenesis as a multifunctional regulator. Stem Cells. 2008 Jul;26(7):1663-72
Robinson DO, Howarth RJ, Williamson KA, van Heyningen V, Beal SJ, Crolla JA. Genetic analysis of chromosome 11p13 and the PAX6 gene in a series of 125 cases referred with aniridia. Am J Med Genet A. 2008 Mar 1;146A(5):558-69
Tuoc TC, Stoykova A. Er81 is a downstream target of Pax6 in cortical progenitors. BMC Dev Biol. 2008 Feb 28;8:23
Gubert F, Zaverucha-do-Valle C, Pimentel-Coelho PM, Mendez-Otero R, Santiago MF. Radial glia-like cells persist in the adult rat brain. Brain Res. 2009 Mar 3;1258:43-52
Hingorani M, Williamson KA, Moore AT, van Heyningen V. Detailed ophthalmologic evaluation of 43 individuals with PAX6 mutations. Invest Ophthalmol Vis Sci. 2009 Jun;50(6):2581-90
Mascarenhas JB, Young KP, Littlejohn EL, Yoo BK, Salgia R, Lang D. PAX6 is expressed in pancreatic cancer and actively participates in cancer progression through activation of the MET tyrosine kinase receptor gene. J Biol Chem. 2009 Oct 2;284(40):27524-32
Sansom SN, Griffiths DS, Faedo A, Kleinjan DJ, Ruan Y, Smith J, van Heyningen V, Rubenstein JL, Livesey FJ. The level of the transcription factor Pax6 is essential for controlling the balance between neural stem cell self-renewal and neurogenesis. PLoS Genet. 2009 Jun;5(6):e1000511
Zhou YH, Hu Y, Mayes D, Siegel E, Kim JG, Mathews MS, Hsu N, Eskander D, Yu O, Tromberg BJ, Linskey ME. PAX6 suppression of glioma angiogenesis and the expression of vascular endothelial growth factor A. J Neurooncol. 2010 Jan;96(2):191-200
This article should be referenced as such:
Zhou YH. PAX6 (paired box 6). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):645-651.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 652
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
RASSF2 (Ras association (RalGDS/AF-6) domain family member 2) Luke B Hesson, Farida Latif
Lowy Cancer Centre and Prince of Wales Clinical School, Faculty of Medicine, University of New South
Wales, NSW2052, Australia (LBH), School of Clinical and Experimental Medicine, College of Medical and
Dental Sciences, Department of Medical and Molecular Genetics, University of Birmingham, Birmingham
B15 2TT, UK (FL)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/RASSF2ID43461ch20p13.html DOI: 10.4267/2042/44798
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: DKFZp781O1747; KIAA0168;
RASFADIN
HGNC (Hugo): RASSF2
Location: 20p13
Local order:
Telomere-PRNP-PRNT-RASSF2-SLC23A2-
Centromere.
Juxtaposed to the PRNP prion locus conserved in the
syntenic bovine region (Choi et al., 2006).
Note: Brief overview
The RASSF family of tumour suppressor genes (TSG)
encode Ras superfamily effector proteins that, amongst
other functions, mediate some of the growth inhibitory
functions of Ras proteins. Several members of this
family are inactivated by promoter DNA
hypermethylation in a broad range of cancers and
inactivation of RASSF2 has been described in a
growing number of tumour types. RASSF2 functions as
a K-Ras adaptor protein and mediates some of the
growth inhibitory properties of K-Ras. RASSF2
regulates apoptosis and cell cycle progression through
interactions with several downstream effectors
including MST1 and MST2.
DNA/RNA
Description
The RASSF2 gene occupies 43,621bp of genomic
DNA (-ve strand). RASSF2A variant 1
[GenBank:NM_014737] contains 12 exons and is
transcribed from a large (1,850bp) 5' CpG island
encompassing the first two non-coding exons. There is
evidence of multiple splice variants and transcription
initiation sites for the RASSF2 gene. Additional
isoforms of RASSF2 include RASSF2A variant 2
[GenBank:CR627436] that is predicted to produce an
identical protein to RASSF2A variant 1, RASSF2B
[GenBank:AY154471] and RASSF2C
[GenBank:AY154472].
A further isoform [GenBank:CR620887] produces a
non-coding mRNA. RASSF2B and RASSF2C are not
associated with CpG islands (figure 1). Akino et al.,
(2005) investigated promoter activity of the region
upstream of the transcription start site of NM_014737
(RASSF2A variant 1) and found promoter activity was
dependent on a CACCC box and SP1 site just upstream
of exon 1. The authors however did not investigate the
CpG island region of the RASSF2 gene, which is
largely located in intron 1 of the NM_014737
transcript.
RASSF2 (Ras association (RalGDS/AF-6) domain family member 2) Hesson LB, Latif F
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 653
Figure 1: RASSF2 gene structure. Transcription of the RASSF2A isoforms begins within a CpG island that spans exons 1 and 2 (grey box) at -105 to +1745 bp relative to the transcription start site of NM_014737. RASSF2B transcription begins at exon 1beta in intron 5. Transcription of RASSF2C begins at exon 1gamma in intron 2. RASSF2B and RASSF2C do not have 5' CpG islands or predicted promoter regions.
Protein
Description
As mentioned above multiple isoforms are expressed
from the RASSF2 locus. However, RASSF2A variants
1 and 2, as well as RASSF2C (if expressed at all)
contain identical open reading frames encoding a 326
amino acid protein, whilst RASSF2B mRNA is
predicted to encode a truncated protein of 157 amino
acids but is expressed at extremely low levels in all
tissues analysed. Therefore, the protein is simply
referred to as RASSF2 in the literature. The RASSF2
protein (figure 2) contains C-terminal Ras-association
(RA) and Sav/RASSF/Hpo (SARAH) domains that
define the 'classical' RASSF family (RASSF1,
RASSF2, RASSF3, RASSF4, RASSF5, RASSF6). In
addition RASSF2 contains a central bipartite nuclear
localisation signal (NLS) which has been shown to be
essential for tumour suppressor function (Cooper et al.,
2008). The C-terminus of RASSF2 also contains a
sequence shown to be necessary for nuclear export
(Kumari et al., 2009). Detection of endogenous
RASSF2 protein has been described in a variety of cell
lines using an in-house antibody (Vos et al., 2003) or a
commercially available antibody from Santa Cruz
(Cooper et al., 2009).
Expression
Northern blotting shows RASSF2 mRNA is highly
expressed in many normal tissues including brain,
thymus, spleen, liver, small intestines, placenta, lung
and peripheral blood (Vos et al., 2003). The probe used
for northern blotting did not discriminate between
RASSF2 isoforms.
The coding region of RASSF2 has been cloned from a
brain-specific cDNA library (Hesson et al., 2005).
Currently there has been limited analysis of expression
patterns and distribution of the different RASSF2
isoforms. RASSF2A variants 1 and 2 are both
ubiquitously expressed in a range of normal tissues
including colon, stomach, heart, bone marrow, kidney,
ovary, lung, liver, breast, testis and pancreas
(Maruyama et al., 2008). However, expression of the
RASSF2B and RASSF2C isoforms was virtually
undetectable in a range of normal tissues (Maruyama et
al., 2008; L Hesson and F Latif, unpublished
observations). Expression of the RASSF2 gene is
inactivated by DNA methylation of the 5' CpG island
promoter region in a broad spectrum of cancers (see
below).
Localisation
When over expressed RASSF2 is clearly predominantly
nuclear, as demonstrated by immunofluorescence
(Cooper et al., 2008; Kurnari et al., 2007). Some
evidence suggests that the NLS of RASSF2 is an
integral part of the ability of RASSF2 to act as a
tumour suppressor. The localisation of RASSF2 is cell
context specific. Two independent studies indicate that
phosphorylation of RASSF2 appears to be critical for
relocalisation to the cytoplasm, though the critical
phosphorylation sites remain to be determined. Cooper
RASSF2 (Ras association (RalGDS/AF-6) domain family member 2) Hesson LB, Latif F
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 654
Figure 2: RASSF2 transcript and protein structure. RASSF2A [GenBank:NP_055552] is a 326 aa protein containing a central bipartite nuclear localisation signal (NLS), a Ras-association (RA) domain of the RalGDS/AF-6 variety and acidic coiled-coil Sav/RASSF/Hpo (SARAH) domain. RASSF2B [GenBank:AAN59976] is a predicted 157 amino acid protein containing a truncated RA domain. The RASSF2C predicted protein is identical to RASSF2A. The mRNA transcript shown (red bar) represents RASSF2A variant 1 (NM_014737).
Figure 3: RASSF2 is conserved with RASSF paralogues. Schematic representation of the 10 human members of the RASSF family showing the Ras-association, SARAH and predicted diacylglycerol binding domains. The longest isoform for each RASSF gene is represented (GenBank accession numbers: RASSF1A[NP_009113], RASSF2[NP_055552], RASSF3[NP_835463], RASSF4[NP_114412], RASSF5A[NP_872604], RASSF6[NP_958834], RASSF7[NP_003466], RASSF8[BAC98838], RASSF9[NP_005438], RASSF10[NP_001073990]). The RASSF family is subdivided into 'classical' RASSF members and 'N-terminal' RASSF members as indicated. Shown is the percentage amino acid identity of each RASSF members with RASSF2. Protein sequence identity of the 'classical' RASSF members is greatest over the C-terminus. * RASSF10 protein sequence as described in Hesson et al., 2009 (which is N-terminally truncated with respect to GenBank accession number NP_001073990).
et al., (2009) demonstrated that relocalisation of over
expressed RASSF2 from the nucleus to the cytoplasm
is dependent on active MST1 or MST2 and that either
kinase was capable of phosphorylating RASSF2 in
vitro. However, the work of Kumari et al., (2009)
demonstrates that RASSF2 relocalisation is dependent
on the activity of Extracellular signal-Related Kinase 2
(ERK2). Both MSTs and ERK2 can participate in Ras
signalling therefore both studies may be observing the
effects of activation of the same pathway. The presence
of sequences essential for both nuclear import and
export within RASSF2 seems to suggest that the
protein may continuously cycle between cytoplasm and
nucleus in a similar manner to MST1 and MST2 (Lee
and Yonehara, 2002). Given the strong binding of
RASSF2 with MST1 and MST2 (see below) it seems
likely that this would occur in complex with MSTs.
RASSF2 nuclear important may be dependent on
importin-alpha interaction (Kumari et al., 2007), whilst
nuclear export appears to involve the NES (nuclear
export signal)-dependent transport protein CRM-
1/XPO1 (Kumari et al., 2009). What remains to be
determined is the exact conditions under which the
kinetics of nuclear export predominates nuclear import
and vice versa.
Function
Tumour suppressor function of RASSF2
Similar to several other RASSF members RASSF2
suppresses tumour growth when expressed. This has
been demonstrated for colorectal, lung, breast, gastric,
nasopharyngeal and oral squamous cell carcinoma
(OSCC) cell lines in vitro using colony formation,
growth curve and soft agar growth assays (Akino et al.,
2005; Vos et al., 2003; Cooper et al., 2008; Maruyama
et al., 2008; Imai et al., 2008; Zhang et al., 2006).
RASSF2 (Ras association (RalGDS/AF-6) domain family member 2) Hesson LB, Latif F
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 655
Furthermore, RASSF2 re-expression in breast tumour
cells inhibits in vivo tumour growth when cells are
subcutaneously injected into severe combined
immunodeficiency (SCID) mice (Cooper et al., 2008).
Several studies demonstrate that these tumour
suppressive properties are likely to arise from the
ability of RASSF2 to regulate apoptosis and cell cycle
progression (Vos et al., 2003; Maruyama et al., 2008;
Imai et al., 2008; Akino et al., 2005).
In breast cancer cells and Cos-7 cells growth
suppression by RASSF2 is dependent on the nuclear
localisation signal (NLS) located at amino acids 151-
167 (Cooper et al., 2008; Kumari et al., 2009), whilst
other reports have indicated that in OSCC and gastric
cancer cells the C-terminal portion of RASSF2
(RASSF2 [163-326]), containing the RA domain, is
critical for tumour suppressive function (Imai et al.,
2008; Maruyama et al., 2008). Interestingly, in OSCC
this C-terminal portion exhibited enhanced growth
suppression relative to full length RASSF2 (Imai et al.,
2008). In fact, RASSF2 [163-326] also disrupts the
NLS yet leaves the sequence required for nuclear
export intact. In a separate study of colorectal cancer
cells both RASSF2 truncations (RASSF2 [1-163] and
RASSF2 [163-326]) exhibited reduced growth
suppression compared to full length RASSF2 (Akino et
al., 2005). Whilst in gastric cancer transfection of
RASSF2 with deletion of the NLS [RASSF2deltaNLS]
actually increased the percentage of apoptotic cells
relative to full length RASSF2 (Maruyama et al.,
2008). These studies indicate the growth suppressive
properties of RASSF2 are likely cell background
specific but more importantly that nuclear import,
nuclear export and the Ras-association domain are
required for correctly regulated RASSF2 growth
suppression.
RASSF2 interaction with Ras
RASSF2 contains a functional RA domain that displays
a strong binding to K-Ras, but only weak binding to H-
Ras (Vos et al., 2003). RASSF2 associates with the K-
Ras effector domain in a GTP-dependent manner thus
displaying the basic properties of a genuine Ras
effector. RASSF2 growth inhibition is enhanced in the
presence of K-RasG12V. Furthermore, siRNA-
mediated knock-down of RASSF2 in K-Ras
transformed cells enhanced anchorage-independent
growth. However, in the absence of K-Ras
transformation knock-down of RASSF2 inhibited
growth (Akino et al., 2005). These data indicate that
RASSF2 mediates some of the growth inhibitory
properties of K-Ras and that inactivation of RASSF2
enhances K-Ras-induced transformation.
RASSF2 interaction with the proapoptotic kinases
MST1 and MST2.How the interaction of RASSF
proteins with Ras results in growth suppression has
been the subject of intense investigation. The
proapoptotic mammalian Serine/Threonine kinases
MST1 and MST2 were identified as RASSF2
interacting partners by yeast two-hybrid (Y2-H)
(Khokhlatchev et al., 2002). RASSF1 and RASSF5
were also identified as MST binding partners as part of
a novel Ras-regulated signalling pathway. Recently the
interaction of RASSF2 and MST1/2 was formally
demonstrated in human cells at the endogenous level.
Interaction occurs between the SARAH domains found
within RASSF2 and MST1/2 (Cooper et al., 2009).
RASSF2 appears to have a distinct role in regulating
MST2 function. Activation of MST2 is followed by a
rapid proteasome-dependent loss of MST2 stability
(that is not associated with MST2 cleavage).
Interestingly, over expression of RASSF2 results in
increased levels of MST2 and provides protection of
MST2 from degradation following its activation. In
agreement with this loss of RASSF2 protein in
colorectal tumours, or in colorectal tumour cell lines in
which RASSF2 levels are decreased by shRNAi, also
leads to decreases in MST2 levels (Cooper et al., 2009).
RASSF2 appears to be a substrate for MST1 and MST2
and co-expression of either kinase with RASSF2
relocalises RASSF2 from the nucleus to the cytoplasm
in a manner dependent on kinase activity (Cooper et al.,
2009). Since MST2 remains in complex with RASSF2
following its activation these data collectively suggest
RASSF2 stabilises active MST2 allowing (or perhaps
even targeting) MST2 substrate phosphorylation. This
RASSF2-mediated stabilisation also appears to be true
for MST1. Thus loss of RASSF2, as is frequently
observed in cancer, leads to loss of MST1 and MST2
leading to a decrease in apoptotic potential. That
RASSF2 appears to be capable of influencing MST
stability so drastically is likely to be due to the
observation that the majority of both MST1 and MST2
are in complex with RASSF2 in at least some cell types
(Cooper et al., 2009). The interaction of RASSF2 with
MST1/2 poses an interesting question with regards to
the regulation of RASSF2 localisation. Both RASSF2
and MST1/2 have been shown to contain sequences
essential for nuclear import and export (Lee and
Yonehara, 2002; Kumari et al., 2009). Both the NLS
and NES sequences within MST1/2 and RASSF2
respectively are located very close to or within the
SARAH domains and neither are canonical NLS/NES
sequences. Mapping of both these sequences were
determined by deletion mapping, which would most
likely also affect RASSF2-MST1/2 interaction thus it
now seems likely that the RASSF2-MST1/2 complex
constantly cycles between the nucleus (by virtue of
RASSF2 NLS) and cytoplasm (by virture of MST1/2
NES) and disruption of the interaction between
RASSF2 and MST1/2 would likely affect the
localisation of both proteins. Also, the fact that
RASSF2 translocation to the cytoplasm is dependent on
ERK2 activity (Kumari and Mahalingam, 2009)
suggests the Ras-MEK-ERK pathway may serve to
phosphorylate MST1/2, which then phosphorylates
RASSF2, translocating it to the cytoplasm and allowing
RASSF2 to interact with Ras (figure 4). That nuclear
RASSF2 is required for full tumour suppressor activity
RASSF2 (Ras association (RalGDS/AF-6) domain family member 2) Hesson LB, Latif F
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 656
(Cooper et al., 2008; Kumari et al., 2009) may be
explained by the fact that ERK2 translocates to the
nucleus upon its activation (Khokhlatchev et al., 1998).
Other functions of RASSF2
Other functions and interacting partners of RASSF2 are
extremely likely. Y2-H using RASSF2 as bait
implicates NORE1A and RASSF3 in RASSF2
function, although these have not yet been confirmed in
mammalian cells (Hesson et al., 2005). These
interactions may implicate other RASSF members in
modulating RASSF2 function and suggests a complex
network of cross-talk between signalling pathways
involving RASSF proteins. Also, the exact mechanisms
of apoptotic and cell cycle regulation of RASSF2 have
yet to be completely defined. Microarray analysis of
gene expression before and after exogenous expression
of RASSF2 in gastric and OSCC cancer cell lines
showed RASSF2 downregulates expression of several
inflammatory response genes including the cytokines
IL-8, LCN2, CXCL1, CXCL2, CXCL3, CXCL5 and
CXCL6, CCL20 and CCL21 and genes involved in
immune-cell chemotaxis (Maruyama et al., 2008; Imai
et al., 2008). A possible pathway influenced by
RASSF2 is the NF-kB pathway since over expression
of RASSF2 significantly downregulated NF-kB
transcriptional activity (Maruyama et al., 2008; Imai et
al., 2008). Of note is the recent observation that pigs
experimentally infected with Porcine Circovirus Type 2
(PCV2) show upregulation of several CXCL family
cytokines as well as RASSF2 (Fernandes et al., 2009)
therefore it is likely a role for RASSF2 in regulating
immune response pathways remains to be discovered.
There is also evidence that RASSF2 may regulate the
actin cytoskeleton since re-expression of RASSF2 leads
to loss of stress fibres, cell rounding and the
suppression of RhoGTPase activation (Maruyama et
al., 2008; Akino et al., 2005). Additionally, RASSF2
upregulation appears to be a cellular response to
ionising radiation (Sakamoto-Hojo et al., 2003).
Homology
Human RASSF2 has highly conserved orthologues
across many species (table 1). The main features of the
RASSF2 protein are conserved across these species
including the RA and SARAH domains as well as the
NLS and the sequence important for nuclear export.
RASSF2 is one of 10 members of the Ras-association
domain family (RASSF) comprising RASSF1-10.
RASSF1-6 are termed the 'classical' RASSF family and
contain C-terminal RA and SARAH domains.
Consequently, RASSF1-6 are most similar in sequence
within their C-termini. RASSF7-10 (RASSF7,
RASSF8, RASSF9, RASSF10) represent evolutionarily
conserved but structurally distinct RASSF members
that lack the SARAH domains and contain N-terminal
RA domains. RASSF7-10 are termed the 'N-terminal'
RASSF family. RASSF2 is most similar to
Figure 4: One possible RASSF2 pathway. Recent evidence suggests a RASSF2-MST1/2 complex may continuously cycle through the nucleus and that nuclear localisation of RASSF2 is essential for tumour suppressor function. There are also reports demonstrating that the activity of the kinases ERK2 and MST1/2 is crucial for cytoplasmic relocalisation of RASSF2. Therefore activation of the RASSF2 tumour suppressor pathway may emanate from the nucleus following ERK2 and MST1/2 activation allowing RASSF2 to accumulate in the cytoplasm where it may encounter another interacting partner K-RasGTP.
RASSF2 (Ras association (RalGDS/AF-6) domain family member 2) Hesson LB, Latif F
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 657
Table 1: RASSF2 has highly conserved orthologues in several species.
RASSF4 and RASSF6 (figure 3), both of which are
also epigenetically inactivated in cancer, and
participate in K-Ras signalling to inhibit tumour cell
growth and induce apoptosis (Hesson et al., 2009;
Ikeda et al., 2006; Allen et al., 2006; Eckfeld et al.,
2005; Chow et al., 2004).
Mutations
Note
Similar to all other RASSF members, perhaps with the
exception of RASSF1A (Kashuba et al., 2009; Pan et
al., 2005), mutation of RASSF2 is a rare event and to
date no inactivating mutations have been described.
Analysis of ovarian primary tumours failed to identify a
single amino acid changing or truncating point
mutation (Cooper et al., 2008). However, more
thorough investigations of larger cohorts of different
tumour types may be required to determine this
definitively.
Implicated in
Colorectal carcinoma (CRC)
Note
Colorectal carcinoma (CRC) including colon
adenomas.
Prognosis
In early colorectal cancers RASSF2 methylation with
oncogenic activation of either K-Ras, B-Raf or
PIK3CA presented significantly more frequently in
cases of venous invasion (Nosho et al., 2007).
Oncogenesis
Similar to several other RASSF members, RASSF2 is
frequently inactivated by CpG island DNA
hypermethylation (Hesson et al., 2007). RASSF2
inactivation has been most extensively investigated in
colorectal cancer in which inactivation of other RASSF
members is relatively rare. Several studies now
RASSF2 (Ras association (RalGDS/AF-6) domain family member 2) Hesson LB, Latif F
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 658
strongly suggest that RASSF2 inactivation is a frequent
and early event in colorectal cancer formation being
present in colon adenomas, particularly those with a
villous component (Kakar et al., 2008; Hesson et al.,
2005; Akino et al., 2005; Harada et al., 2007). The
frequencies of RASSF2 methylation in CRCs vary
between 42% (Akino et al., 2005) and 70% (Hesson et
al., 2005) whilst for adenomas methylation occurs
between 25% (Harada et al., 2007) and 94% (Kakar et
al., 2008). This most likely reflects the differences in
histopathological subtypes and the CpG island region
analysed as well differences in colorectal cancer
aetiology in different populations.
Some reports describe variable frequencies of RASSF2
methylation depending on tumour location within the
colon (Harada et al., 2007). Interestingly, cells from
apparently normal colonic epithelium from patients
with hyperplastic polyposis (HPP) also frequently
demonstrate methylation of several TSGs including
RASSF2 (Minoo et al., 2006). This may indicate an
early role for RASSF2 inactivation in colonic
hyperplasia. RASSF2 methylation was found to be
associated with K-Ras or BRAF mutation (Harada et
al., 2007; Akino et al., 2005) however, in another study
K-Ras mutation and RASSF2 methylation were
mutually exclusive (Hesson et al., 2005). Methylation
of the RASSF2 promoter and loss of expression
occurred in conjunction with loss of histone H3
acetylation, a marker of transcriptional activity.
Reduced RASSF2A expression also correlated with
methylation in primary CRCs (Akino et al., 2005). In
colorectal tumour cell lines re-expression of RASSF2
resulted in inhibition of anchorage-independent growth
in soft agar, which was associated with morphological
changes, cell detachment, disruption of the actin stress
fibre network, decreased Rho activity, increased
apoptosis and inhibition of cell cycle progression.
Deregulation of the actin cytoskeletal network and
morphological changes that result in cellular
detachment may therefore be a mechanism by which
RASSF2 induces anoikis, a form of suspension-
dependent apoptosis.
Non-small cell lung carcinoma (NSCLC)
Oncogenesis
Investigation of NSCLC primary tumours found
methylation of the RASSF2 CpG island in 44%
(22/50). Methylation was found at an equal frequency
in all grades (I/II = 44% (7/16); IIIA = 44% (4/9) and
IV = 44% (10/23)) suggesting RASSF2 became
hypermethylated early in tumour formation and was not
associated with development to higher grades (Cooper
et al., 2008). The incidence of RASSF2 methylation
appears much more frequent in NSCLC than SCLC
(small cell lung cancer) as shown by an earlier study by
Kaira et al., (2007), in which only 18% (4/22) SCLC
but 62% (16/26) NSCLC cell lines demonstrated
RASSF2 methylation with concomitant loss of
RASSF2A expression. RASSF2A expression was
restored following treatment with the DNA
demethylating agent 5-aza-2'deoxycytidine and/or
trichostatin A. In primary NSCLC tumours 31%
(33/106) were methylated and methylation was more
frequent in specimens from non-smokers than from
smokers (45%, 18/40 vs 23%, 15/66 respectively;
p=0.014).
Nasopharyngeal carcinoma
Prognosis
RASSF2 methylation correlated with lymph node
metastasis in nasopharyngeal carcinoma (Zhang et al.,
2006).
Oncogenesis
Fifty one percent (27/53) of primary nasopharyngeal
carcinomas (NPCs) showed cancer-specific RASSF2
methylation, which correlated with loss of RASSF2A
expression in both NPC cell lines and primary tumours
(Zhang et al., 2006). This study also provided evidence
that RASSF2 re-expression suppressed colony
formation ability in NPC cell lines (with concomitant
inhibition of cell cycle progression) and decreased cell
motility and migration as determined by wound healing
assay.
Gastric cancer
Prognosis
Both Maruyama et al., (2008) and Endoh et al., (2005)
found DNA methylation of the region around the
transcription start site of RASSF2A variant 1
significantly correlated with an absence of lymphatic
invasion. Whilst Maruyama et al., (2009) found further
associations with methylation and the absence of
venous invasion or lymph node metastasis, less
advanced stage, presence of EBV infection, the absence
of TP53 mutations and the presence of a CpG-island
methylator phenotype (CIMP).
Oncogenesis
The RASSF2 gene contains a 1.8kb CpG island that
encompasses the first two non-coding exons (figure 1).
The majority of this CpG island was interrogated for
hypermethylation in a series of gastric cancers (Endoh
et al., 2005). The study found varying frequencies of
methylation throughout the CpG island ranging from
29% (23/78) at the region encompassing the
transcription start site, to 79% (62/78) at a region of the
CpG island within intron 1 (though this intronic region
also exhibited a frequency of 60% (47/78) methylation
in corresponding normal gastric epithelia). Methylation
was mostly cancer specific at and around the
transcription start site and silencing of RASSF2A
expression most closely correlated with methylation at
this region (Endoh et al., 2005). Similar findings were
described by Maruyama et al., (2008) who examined
the methylation status of the CpG island regions
encompassing the transcriptional start sites of
RASSF2A variants 1 and 2. Methylation of RASSF2A
variant 1 was detected in 29.5% (23/78), whilst
RASSF2 (Ras association (RalGDS/AF-6) domain family member 2) Hesson LB, Latif F
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 659
RASSF2A variant 2 was methylated in 25.6% (23/78)
of gastric cancer cases.
This may be significant since the expression of
RASSF2A variants 1 and 2 appear to be differentially
regulated by DNA methylation from within the same
CpG island indicating multiple promoters and possibly
accounting for the differences in methylation densities
throughout the region. RASSF2A re-expression
inhibited the growth of gastric cancer cell lines as
shown by reduced colony formation ability. This was a
result of inhibition of cell cycle progression and
induction of apoptosis (Maruyama et al., 2008).
Prostate cancer
Prognosis
A prospective study of a large cohort of patients
referred for prostate biopsy determined that detection
of RASSF2 methylation in patient urine shows
promising clinical utility as an early detection
biomarker for prostate cancer (Payne et al., 2009).
Though primary prostate tumour tissues were not
investigated the study nevertheless provided
information independent of the extensively used pre-
existing prostate cancer biomarker PSA (prostate
specific antigen). Detection of RASSF2 methylation
was significantly more frequent in patients with non-
organ-confined prostate cancer (Payne et al., 2009).
Thus RASSF2 methylation may represent an interesting
biomarker for early prostate cancer detection and
predicting invasive potential but requires further
validation.
Breast cancer
Oncogenesis
RASSF2 was frequently hypermethylated in primary
breast cancers (38%, 15/40) and re-expression in breast
cancer cell lines inhibited colony formation ability,
anchorage-independent growth in soft agar and in vivo
tumour formation in SCID mice (Cooper et al., 2008).
RASSF2 growth suppression was dependent on a
functional NLS (located at amino acids 151-167) since
its mutation prevented anchorage-independent growth
inhibition.
Hepatocellular carcinoma (HCC)
Oncogenesis
In an extensive DNA hypermethylation analysis of
cancerous and non-cancerous liver tissues (including
normal liver tissues from non-cancer patients) Nishida
et al., (2008) assessed the methylation status of 19 gene
loci in hepatitis B virus (HBV) and hepatitis C virus
(HCV)-related HCCs. This study found that normal
ageing within liver tissues is associated with a gradual
increase in aberrant methylation and that HCV
infection in particular may accelerate age-related
methylation. RASSF2 methylation was identified as a
cancer-specific event that is completely absent in
normal liver (0/22), infrequent in non-cancerous liver
from HCC patients (2.6%, 2/77), yet frequent in HCV-
related HCC (48%, 21/44) vs virus-negative HCC
(5.6%, 1/18; p=0.0029). Though this suggests loss of
RASSF2 expression may play a role in HCC the
potential importance and clinical implications of these
findings require further investigation.
Oral squamous cell carcinoma (OSCC)
Oncogenesis
Analysis of the expression of RASSF1-6 in OSCC cell
lines identified RASSF2 as the most frequently
downregulated RASSF gene analysed. This loss of
expression was caused by RASSF2 CpG island
methylation, which was found in 26% (12/46) of
primary OSCCs (Imai et al., 2008). In OSCC cell lines
re-expression of RASSF2 inhibited colony formation
ability by inducing apoptosis and inhibiting cell cycle
progression. Investigation of 482 OSCCs identified
RASSF2 methylation in 28% (134/482) cases. The
combination of RASSF1A and RASSF2 methylation
was significantly associated with poor disease-free
survival (p=0.009, Huang et al., 2009). Furthermore,
methylation of RASSF1A and RASSF2 increased in
patients undergoing post-surgical radiotherapy when
compared with surgery-only patients possibly
indicating that hypermethylation of RASSF1A and
RASSF2 is associated with the radioresistance
commonly observed in OSCC patients. It also indicates
the potential of using combined epigenetic and
radiotherapy as an adjuvant to surgery.
Endometrial carcinoma
Oncogenesis
Liao et al., (2008) investigated endometrial carcinomas
for RASSF2 CpG island methylation and found 25/76
(33%) were methylated. RASSF2 methylation was
found more frequently in tumour samples from older
patients. Similar findings were observed in colorectal
carcinomas (Hesson et al., 2005) and in OSCC (Imai et
al., 2008) suggesting loss of RASSF2 expression may
be a gradual age-related process.
Ovarian cancer
Oncogenesis
Although methylation of the RASSF2 promoter is not
an event associated with ovarian cancer (Cooper et al.,
2008) the gene does localise to one of the regions
deleted in ovarian tumour cell lines as indicated by
array-based genomic hybridisation (Lambros et al.,
2005).
Leukaemia
Oncogenesis
Recent evidence suggests that RASSF2 expression may
be downregulated in leukaemias with MLL
rearrangement by overexpression of one or more of the
miR-17-92 polycistronic miRNA oncogene cluster (Li
et al., 2009) that may target a region within the 3'UTR
of the RASSF2 mRNA.
RASSF2 (Ras association (RalGDS/AF-6) domain family member 2) Hesson LB, Latif F
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 660
References Khokhlatchev AV, Canagarajah B, Wilsbacher J, Robinson M, Atkinson M, Goldsmith E, Cobb MH. Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation. Cell. 1998 May 15;93(4):605-15
Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T, Zhang XF, Seed B, Avruch J. Identification of a novel Ras-regulated proapoptotic pathway. Curr Biol. 2002 Feb 19;12(4):253-65
Lee KK, Yonehara S. Phosphorylation and dimerization regulate nucleocytoplasmic shuttling of mammalian STE20-like kinase (MST). J Biol Chem. 2002 Apr 5;277(14):12351-8
Sakamoto-Hojo ET, Mello SS, Pereira E, Fachin AL, Cardoso RS, Junta CM, Sandrin-Garcia P, Donadi EA, Passos GA. Gene expression profiles in human cells submitted to genotoxic stress. Mutat Res. 2003 Nov;544(2-3):403-13
Vos MD, Ellis CA, Elam C, Ulku AS, Taylor BJ, Clark GJ. RASSF2 is a novel K-Ras-specific effector and potential tumor suppressor. J Biol Chem. 2003 Jul 25;278(30):28045-51
Chow LS, Lo KW, Kwong J, Wong AY, Huang DP. Aberrant methylation of RASSF4/AD037 in nasopharyngeal carcinoma. Oncol Rep. 2004 Oct;12(4):781-7
Eckfeld K, Hesson L, Vos MD, Bieche I, Latif F, Clark GJ. RASSF4/AD037 is a potential ras effector/tumor suppressor of the RASSF family. Cancer Res. 2004 Dec 1;64(23):8688-93
Akino K, Toyota M, Suzuki H, Mita H, Sasaki Y, Ohe-Toyota M, Issa JP, Hinoda Y, Imai K, Tokino T. The Ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer. Gastroenterology. 2005 Jul;129(1):156-69
Endoh M, Tamura G, Honda T, Homma N, Terashima M, Nishizuka S, Motoyama T. RASSF2, a potential tumour suppressor, is silenced by CpG island hypermethylation in gastric cancer. Br J Cancer. 2005 Dec 12;93(12):1395-9
Hesson LB, Wilson R, Morton D, Adams C, Walker M, Maher ER, Latif F. CpG island promoter hypermethylation of a novel Ras-effector gene RASSF2A is an early event in colon carcinogenesis and correlates inversely with K-ras mutations. Oncogene. 2005 Jun 2;24(24):3987-94
Lambros MB, Fiegler H, Jones A, Gorman P, Roylance RR, Carter NP, Tomlinson IP. Analysis of ovarian cancer cell lines using array-based comparative genomic hybridization. J Pathol. 2005 Jan;205(1):29-40
Pan ZG, Kashuba VI, Liu XQ, Shao JY, Zhang RH, Jiang JH, Guo C, Zabarovsky E, Ernberg I, Zeng YX. High frequency somatic mutations in RASSF1A in nasopharyngeal carcinoma. Cancer Biol Ther. 2005 Oct;4(10):1116-22
Choi SH, Kim IC, Kim DS, Kim DW, Chae SH, Choi HH, Choi I, Yeo JS, Song MN, Park HS. Comparative genomic organization of the human and bovine PRNP locus. Genomics. 2006 May;87(5):598-607
Minoo P, Baker K, Goswami R, Chong G, Foulkes WD, Ruszkiewicz AR, Barker M, Buchanan D, Young J, Jass JR. Extensive DNA methylation in normal colorectal mucosa in hyperplastic polyposis. Gut. 2006 Oct;55(10):1467-74
Vos MD, Dallol A, Eckfeld K, Allen NP, Donninger H, Hesson LB, Calvisi D, Latif F, Clark GJ. The RASSF1A tumor suppressor activates Bax via MOAP-1. J Biol Chem. 2006 Feb 24;281(8):4557-63
Allen NP, Donninger H, Vos MD, Eckfeld K, Hesson L, Gordon L, Birrer MJ, Latif F, Clark GJ. RASSF6 is a novel member of the RASSF family of tumor suppressors. Oncogene. 2007 Sep 13;26(42):6203-11
Harada K, Hiraoka S, Kato J, Horii J, Fujita H, Sakaguchi K, Shiratori Y. Genetic and epigenetic alterations of Ras signalling pathway in colorectal neoplasia: analysis based on tumour clinicopathological features. Br J Cancer. 2007 Nov 19;97(10):1425-31
Hesson LB, Cooper WN, Latif F. Evaluation of the 3p21.3 tumour-suppressor gene cluster. Oncogene. 2007 Nov 15;26(52):7283-301
Hesson LB, Cooper WN, Latif F. The role of RASSF1A methylation in cancer. Dis Markers. 2007;23(1-2):73-87
Ikeda M, Hirabayashi S, Fujiwara N, Mori H, Kawata A, Iida J, Bao Y, Sato Y, Iida T, Sugimura H, Hata Y. Ras-association domain family protein 6 induces apoptosis via both caspase-dependent and caspase-independent pathways. Exp Cell Res. 2007 Apr 15;313(7):1484-95
Kaira K, Sunaga N, Tomizawa Y, Yanagitani N, Ishizuka T, Saito R, Nakajima T, Mori M. Epigenetic inactivation of the RAS-effector gene RASSF2 in lung cancers. Int J Oncol. 2007 Jul;31(1):169-73
Kumari G, Singhal PK, Rao MR, Mahalingam S. Nuclear transport of Ras-associated tumor suppressor proteins: different transport receptor binding specificities for arginine-rich nuclear targeting signals. J Mol Biol. 2007 Apr 13;367(5):1294-311
Nosho K, Yamamoto H, Takahashi T, Mikami M, Taniguchi H, Miyamoto N, Adachi Y, Arimura Y, Itoh F, Imai K, Shinomura Y. Genetic and epigenetic profiling in early colorectal tumors and prediction of invasive potential in pT1 (early invasive) colorectal cancers. Carcinogenesis. 2007 Jun;28(6):1364-70
Zhang Z, Sun D, Van do N, Tang A, Hu L, Huang G. Inactivation of RASSF2A by promoter methylation correlates with lymph node metastasis in nasopharyngeal carcinoma. Int J Cancer. 2007 Jan 1;120(1):32-8
Cooper WN, Dickinson RE, Dallol A, Grigorieva EV, Pavlova TV, Hesson LB, Bieche I, Broggini M, Maher ER, Zabarovsky ER, Clark GJ, Latif F. Epigenetic regulation of the ras effector/tumour suppressor RASSF2 in breast and lung cancer. Oncogene. 2008 Mar 13;27(12):1805-11
Imai T, Toyota M, Suzuki H, Akino K, Ogi K, Sogabe Y, Kashima L, Maruyama R, Nojima M, Mita H, Sasaki Y, Itoh F, Imai K, Shinomura Y, Hiratsuka H, Tokino T. Epigenetic inactivation of RASSF2 in oral squamous cell carcinoma. Cancer Sci. 2008 May;99(5):958-66
Kakar S, Deng G, Cun L, Sahai V, Kim YS. CpG island methylation is frequently present in tubulovillous and villous adenomas and correlates with size, site, and villous component. Hum Pathol. 2008 Jan;39(1):30-6
Liao X, Siu MK, Chan KY, Wong ES, Ngan HY, Chan QK, Li AS, Khoo US, Cheung AN. Hypermethylation of RAS effector related genes and DNA methyltransferase 1 expression in endometrial carcinogenesis. Int J Cancer. 2008 Jul 15;123(2):296-302
Maruyama R, Akino K, Toyota M, Suzuki H, Imai T, Ohe-Toyota M, Yamamoto E, Nojima M, Fujikane T, Sasaki Y, Yamashita T, Watanabe Y, Hiratsuka H, Hirata K, Itoh F, Imai K, Shinomura Y, Tokino T. Cytoplasmic RASSF2A is a proapoptotic mediator whose expression is epigenetically silenced in gastric cancer. Carcinogenesis. 2008 Jul;29(7):1312-8
Nishida N, Nagasaka T, Nishimura T, Ikai I, Boland CR, Goel A. Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma. Hepatology. 2008 Mar;47(3):908-18
RASSF2 (Ras association (RalGDS/AF-6) domain family member 2) Hesson LB, Latif F
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 661
Cooper WN, Hesson LB, Matallanas D, Dallol A, von Kriegsheim A, Ward R, Kolch W, Latif F. RASSF2 associates with and stabilizes the proapoptotic kinase MST2. Oncogene. 2009 Aug 20;28(33):2988-98
Fernandes LT, Tomás A, Bensaid A, Pérez-Enciso M, Sibila M, Sánchez A, Segalés J. Exploratory study on the transcriptional profile of pigs subclinically infected with porcine circovirus type 2. Anim Biotechnol. 2009;20(3):96-109
Hesson LB, Dunwell TL, Cooper WN, Catchpoole D, Brini AT, Chiaramonte R, Griffiths M, Chalmers AD, Maher ER, Latif F. The novel RASSF6 and RASSF10 candidate tumour suppressor genes are frequently epigenetically inactivated in childhood leukaemias. Mol Cancer. 2009 Jul 1;8:42
Huang KH, Huang SF, Chen IH, Liao CT, Wang HM, Hsieh LL. Methylation of RASSF1A, RASSF2A, and HIN-1 is associated with poor outcome after radiotherapy, but not surgery, in oral squamous cell carcinoma. Clin Cancer Res. 2009 Jun 15;15(12):4174-80
Kashuba VI, Pavlova TV, Grigorieva EV, Kutsenko A, Yenamandra SP, Li J, Wang F, Protopopov AI, Zabarovska VI, Senchenko V, Haraldson K, Eshchenko T, Kobliakova J, Vorontsova O, Kuzmin I, Braga E, Blinov VM, Kisselev LL, Zeng YX, Ernberg I, Lerman MI, Klein G, Zabarovsky ER. High mutability of the tumor suppressor genes RASSF1 and RBSP3 (CTDSPL) in cancer. PLoS One. 2009 May 29;4(5):e5231
Kumari G, Mahalingam S. Extracellular signal-regulated kinase 2 (ERK-2) mediated phosphorylation regulates nucleo-cytoplasmic shuttling and cell growth control of Ras-associated tumor suppressor protein, RASSF2. Exp Cell Res. 2009 Oct 1;315(16):2775-90
Li Z, Luo RT, Mi S, Sun M, Chen P, Bao J, Neilly MB, Jayathilaka N, Johnson DS, Wang L, Lavau C, Zhang Y, Tseng C, Zhang X, Wang J, Yu J, Yang H, Wang SM, Rowley JD, Chen J, Thirman MJ. Consistent deregulation of gene expression between human and murine MLL rearrangement leukemias. Cancer Res. 2009 Feb 1;69(3):1109-16
Payne SR, Serth J, Schostak M, Kamradt J, Strauss A, Thelen P, Model F, Day JK, Liebenberg V, Morotti A, Yamamura S, Lograsso J, Sledziewski A, Semjonow A. DNA methylation biomarkers of prostate cancer: confirmation of candidates and evidence urine is the most sensitive body fluid for non-invasive detection. Prostate. 2009 Sep 1;69(12):1257-69
This article should be referenced as such:
Hesson LB, Latif F. RASSF2 (Ras association (RalGDS/AF-6) domain family member 2). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):652-661.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 662
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
SEMA3B (sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3B) Munmi Bhattacharyya, Ranjan Tamuli
Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati-781 039, Assam, India
(MB, RT)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/SEMA3BID42252ch3p21.html DOI: 10.4267/2042/44799
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: FLJ34863; LUCA-1; SEMA5; SEMAA;
SemA; semaV
HGNC (Hugo): SEMA3B
Location: 3p21.31
DNA/RNA
Note
SEMA3B was first discovered as a secreted member of
the semaphorin/collapsing family (contains a highly
conserved semaphorin domain) and it has a role in
axonal guidance.
Description
DNA size 11.53kb; mRNA size 9534 bp 18 exons.
Protein
Description
749 amino acids; region 1-24 (24) is a signal peptide,
30-513 (484) is the sema domain and 573-659 (87) is
the Ig-like C2-type domain.
Isoforms: two isoforms have been identified.
- Isoform 1 (identifier: Q13214-1): this isoform has
been chosen as the 'canonical' sequence.
- Isoform 2 (identifier: Q13214-2): the sequence of this
isoform differs from the 'canonical' sequence, amino
acid residues from 332-332 are missing.
Expression
It is expressed abundantly, but expressed differentially
in neural and non-neural tissues.
Localisation
Secreted.
Function
SEMA3B belongs to the semaphorin/collapsing group
of family (contains a highly conserved 749 amino acid
semaphoring domain at NH2-terminal). SEMA3B
involves in diverse processes such as immune
modulation, organogenesis, neuronal apoptosis and
drug resistance. SEM3B also plays a critical role in
axonal guidance during neuronal development.
SEMA3B can act as a tumour suppressor by inducing
apoptosis either by its expression in tumour cells or
when applied as a soluble ligand. SEM3B induced
apoptosis is associated with increase in cytochrome c
release and caspase-3 cleavage, as well as increased
phosphorylation of several proapoptotic proteins,
including glycogen synthase kinase-3beta, FKHR and
SEMA3B (sema domain, immunoglobulin domain (Ig), short basic domain, secreted, Bhattacharyya M, Tamuli R (semaphorin) 3B)
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 663
MDM-2. The common method of inactivation of
SEMA3B is by allelic loss and gene inactivation via
promoter methylation and consequently, expression
level of SEM3B is reduced in tumor cells.
Homology
The percent identity below represents identity of
SEMA3B over an aligned region in UniGene.
Pan troglodytes 98.54%, Bos taurus 90.24%, Rattus
norvegicus 89.19%, Canis lupus familiaris 88.72%,
Mus musculus 88.65%.
Mutations
Note
A missense mutation in SEMA3B is reported in
African-American and Latino-American population.
Implicated in
Gallbladder carcinoma (GBC)
Note
SEMA3B believes to play a role in gallbladder
carcinoma (GBC), which is a highly malignant
neoplasm in the Chilean females. A very high
frequency (46/50, 92%) of abnormal promoter
methylation that causes epigenetic inactivation of
SEMA3B and the loss of heterozygosity at 3p21.3
(14/32, 44%) region (that contains SEMA3B gene) was
detected among the Chilean females with GBC.
Therefore, SEMA3B gene alterations may play a role
in GBC pathogenesis via a two-hit mechanism,
including allelic loss and abnormal promoter
methylation.
Nasopharyngeal carcinoma
Note
SEMA3B is associated with nasopharyngeal carcinoma
(NPC), as evident from both loss of heterozygosity
analysis and functional studies. 21 primary NPC tumors
and 2 NPC cell lines (CNE2 and SUNE1) screened for
mutations by PCR-sequencing and two missense
polymorphisms including Thr415Ile and lle242Met
were found in SEMA3B. For the Thr415Ile
polymorphism, the Ile allele type which leads to
SEMA3B function defects was predominant in NPC
with the allele frequency of 64% (27/42). SEMA3B
mRNA is expressed in non-neoplastic nasopharyngeal
epithelia, but found absent or down-regulated in 76%
(16/21) of primary NPC tumors. Thus, high frequency
of SEMA3B expression alterations suggests that the
inactivation of this gene was strongly associated with
NPC.
Neuroblastoma
Note
In neuroblastoma, significantly higher percentage of
methylated CpG sites in the SEMA3B promoter was
detected in tumors exhibiting 3p loss (95%), relative to
tumors without loss (52%), suggesting a two-hit
mechanism of allele inactivation. Additionally, low
levels of SEMA3B expression were also seen in tumors
with unmethylated SEMA3B promoters (n = 4).
However, SEMA3B was upregulated in the SK-N-BE
neuroblastoma cell line following induction of
differentiation with retinoic acid and interestingly,
higher levels of SEMA3B expression was found in
differentiated tumors with favorable histopathology (n
= 19) than in tumors with unfavorable histology (n =
22). The association of SEMA3B expression with
neuroblastoma differentiation suggests that this TSG
may play a role in neuroblastoma pathobiology and
SEMA3B expression profile suggests that
transcriptional regulation of this locus is complex.
Colorectal carcinoma
Disease
SEMA3B was also found frequently downregulated in
colorectal cancer, which suggests that SEMA3B is
involved in the suppression of colon tumor growth.
However, the molecular mechanism through which
SEM3B suppresses colorectal cancer is not clear.
Breast cancer
Disease
Expression of SEMA3B induces apoptosis in breast
cancer cells. SEMA3B induces apoptosis through the
neuropilin-1 (Np-1) receptor by inactivating the Akt
signaling pathway.
Ovarian cancer
Note
Decreased expression of SEMA3B and loss of
heterozygosity (LOH) at SEMA gene loci also account
for ovarian cancer progression. Patients with a high
vascular endothelial growth factor/SEMA
(VEGF/SEMA) ratio showed poor survival than those
with a low VEGF/SEMA ratio.
Lung cancer
Note
A single nucleotide alteration in the SEMA3B leads to
amino acid substitution T415I and this variant protein
has a reduced ability to act as a tumour suppressor. Thr
to Ile substitution alters the structure of protein by
altering its conformation and affects binding of
SEMA3B with neuropilin receptors-1 (NRP-1) and
NRP-2. The variant Ile allele occurs at an allele
frequency of 0.18 in African-American and 0.39 in
Latino-American population.
References Püschel AW, Adams RH, Betz H. Murine semaphorin D/collapsin is a member of a diverse gene family and creates domains inhibitory for axonal extension. Neuron. 1995 May;14(5):941-8
Sekido Y, Bader S, Latif F, Chen JY, Duh FM, Wei MH, Albanesi JP, Lee CC, Lerman MI, Minna JD. Human
SEMA3B (sema domain, immunoglobulin domain (Ig), short basic domain, secreted, Bhattacharyya M, Tamuli R (semaphorin) 3B)
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 664
semaphorins A(V) and IV reside in the 3p21.3 small cell lung cancer deletion region and demonstrate distinct expression patterns. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4120-5
Lerman MI, Minna JD. The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium. Cancer Res. 2000 Nov 1;60(21):6116-33
Tse C, Xiang RH, Bracht T, Naylor SL. Human Semaphorin 3B (SEMA3B) located at chromosome 3p21.3 suppresses tumor formation in an adenocarcinoma cell line. Cancer Res. 2002 Jan 15;62(2):542-6
Kuroki T, Trapasso F, Yendamuri S, Matsuyama A, Alder H, Williams NN, Kaiser LR, Croce CM. Allelic loss on chromosome 3p21.3 and promoter hypermethylation of semaphorin 3B in non-small cell lung cancer. Cancer Res. 2003 Jun 15;63(12):3352-5
Liu XQ, Sun M, Chen HK, Li JX, Pan ZG, Long QX, Wang XZ, Zeng YX. [Mutation and expression of SEMA3B and SEMA3F gene in nasopharyngeal carcinoma]. Ai Zheng. 2003 Jan;22(1):16-20
Castro-Rivera E, Ran S, Thorpe P, Minna JD. Semaphorin 3B (SEMA3B) induces apoptosis in lung and breast cancer, whereas VEGF165 antagonizes this effect. Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11432-7
Marsit CJ, Wiencke JK, Liu M, Kelsey KT. The race associated allele of Semaphorin 3B (SEMA3B) T415I and its role in lung cancer in African-Americans and Latino-Americans. Carcinogenesis. 2005 Aug;26(8):1446-9
Osada R, Horiuchi A, Kikuchi N, Ohira S, Ota M, Katsuyama Y, Konishi I. Expression of semaphorins, vascular endothelial
growth factor, and their common receptor neuropilins and alleic loss of semaphorin locus in epithelial ovarian neoplasms: increased ratio of vascular endothelial growth factor to semaphorin is a poor prognostic factor in ovarian carcinomas. Hum Pathol. 2006 Nov;37(11):1414-25
Nair PN, McArdle L, Cornell J, Cohn SL, Stallings RL. High-resolution analysis of 3p deletion in neuroblastoma and differential methylation of the SEMA3B tumor suppressor gene. Cancer Genet Cytogenet. 2007 Apr 15;174(2):100-10
Riquelme E, Tang M, Baez S, Diaz A, Pruyas M, Wistuba II, Corvalan A. Frequent epigenetic inactivation of chromosome 3p candidate tumor suppressor genes in gallbladder carcinoma. Cancer Lett. 2007 May 18;250(1):100-6
Castro-Rivera E, Ran S, Brekken RA, Minna JD. Semaphorin 3B inhibits the phosphatidylinositol 3-kinase/Akt pathway through neuropilin-1 in lung and breast cancer cells. Cancer Res. 2008 Oct 15;68(20):8295-303
Rolny C, Capparuccia L, Casazza A, Mazzone M, Vallario A, Cignetti A, Medico E, Carmeliet P, Comoglio PM, Tamagnone L. The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment. J Exp Med. 2008 May 12;205(5):1155-71
Pronina IV, Loginov VI, Prasolov VS, Klimov EA, Khodyrev DS, Kazubskaia TP, Gar'kavtseva RF, Sulimova GE, Braga EA. [Alteration of SEMA3B gene expression levels in epithelial tumors]. Mol Biol (Mosk). 2009 May-Jun;43(3):439-45
This article should be referenced as such:
Bhattacharyya M, Tamuli R. SEMA3B (sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3B). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):662-664.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 665
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TNFSF15 (tumor necrosis factor (ligand) superfamily, member 15) Gui-Li Yang, Jian-Wei Qi, Zhi-Song Zhang, Lu-Yuan Li
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA (LYL);
College of Pharmacy and College of Life Sciences, Nankai University, 94 Wei Jin Road, 300071 Tianjin,
China (LYL, GLY, JWQ, ZSZ)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/TNFSF15ID42638ch9q32.html DOI: 10.4267/2042/44800
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: MGC129934; MGC129935; TL1;
TL1A; VEGI; VEGI192A
HGNC (Hugo): TNFSF15
Location: 9q32
Local order: TNFSF15 gene at 9q32, near the CD30L
gene at 9q33.
DNA/RNA
Description
The human VEGI gene spans about 17 kb and consists
of four exons.
Transcription
The size of VEGI mRNA is approximately 6.5 kb.
Boxes with roman numerals above represent exons and horizontal lines represent intronic sequence. The putative transcription start site is indicated by a double arrowhead. R denotes the 5' untranslated sequence unique to each respective transcript, and stippled boxe represents the common 3' untranslated region.
Figure A. All three isoforms.
TNFSF15 (tumor necrosis factor (ligand) superfamily, member 15) Yang GL, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 666
Figure B. A ribbon diagram of the TL1A trimer. (Jin et al. BBRC 364:1, 2007).
It is unusual for a human gene of 6.5 kb to contain only
a small open reading frame of 522 nucleotides.
Multiple VEGI transcripts generated by the use of
cryptic splice sites and alternate exons.
Pseudogene
Not known.
Protein
Description
Hydrophobicity analysis of VEGI predicts a 13 amino
acid hydrophobic region that follows the amino
terminal segment of 12 amino acids, suggesting a
structure characteristic of a type II transmembrane
protein, with residues 26-174 constituting an
extracellular domain analogous to domains found in
other TNF family members.
VEGI isoforms exhibit a carboxyl terminal domain of
151 amino acid residues, which is encoded by part of
the fourth exon, termed IVb. The initially characterized
VEGI isoform, designated VEGI-174, is encoded by
the fourth exon (parts IVa and IVb) alone, which
includes both the putative transmembrane domain and
the conserved extracellular domain. There are two
additional endothelial-specific transcripts of 7.5 and 2.0
kb, which encode peptides of 251 (VEGI-251) and 192
(VEGI-192) residues, respectively. The VEGI-251 and
-192 isoforms differ in their amino terminal regions,
but share the conserved 151-amino acid residue
carboxy terminal domain. VEGI-251 possesses a
putative secretory signal peptide and its overexpression
causes apoptosis of endothelial cells and inhibition of
tumor growth.
Expression
VEGI is specifically expressed in endothelial cells.
Analysis of total RNA preparations from many cell
lines and primary cell cultures by Northern blot
analysis confirmed the specificity of VEGI expression,
with only HUVEC and human venous endothelial cells
demonstrating detectable levels of expression. Using
multiple tissue Northern blots, the VEGI transcript was
found in many adult human tissues, including placenta,
lung, skeletal muscle, kidney, pancreas, spleen,
prostate, small intestine, and colon, suggesting that the
gene product may play a role in the function of a
normal vasculature.The failure to detect the transcripts
of this new gene in some of the human tissues probably
is due to relatively small proportion of endothelial cells
in these tissues. Using isoform-specific probes, we
have determined that the distribution profiles of VEGI
isoforms in human organs and tissues appear to be
different. The 7.5 kb transcript encoding VEGI-251
was expressed at high levels in the placenta, kidney,
lung and liver, whereas the 2 kb transcript
corresponding to VEGI-174 was observed in liver,
kidney, skeletal muscle and heart. VEGI-174 mRNA
was more abundant in heart, skeletal muscle, pancreas,
adrenal gland, and liver, while VEGI-251 was more
abundant in fetal kidney and fetal lung. Overlapping
expression of VEGI-251 and VEGI-174 mRNA was
detected in prostate, salivary gland and placenta,
whereas VEGI-192 mRNA was not readily detected by
Northern blot. These expression patterns suggest the
possibility of tissue or developmentally specific
functions for VEGI isoforms.
TNFSF15 (tumor necrosis factor (ligand) superfamily, member 15) Yang GL, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 667
Amino acid sequence alignment of three VEGI isoforms. The putative hydrophobic regions of VEGI-251 and VEGI-174 are underlined. Asterisk denotes the start of shared sequences for all three isoforms.
Alternatively, this expression pattern also supports the
view that one VEGI isoform is the functional cytokine,
while the others act in regulatory roles to modulate the
activity of the active isoform. In this case, it is possible
that the non-functional isoforms do not exist at the
protein level. VEGI isoform expression has also been
examined in cultured cells by RNase protection assay.
All three known VEGI isoforms were detected in
human endothelial cells, including coronary artery
endothelial (HCAE), HUVE cells, and human
microvascular endothelial (HMVE) cells. Very low
levels are sometimes detected in adult bovine aortic
endothelial (ABAE) cells. Little VEGI expression was
detectable in human coronary artery smooth muscle
(CASM) and mouse endothelioma bEND.3 cells. More
than one isoform is detectable simultaneously, with
VEGI-251 being the most abundant. The expression of
this protein is inducible by TNF and IL-1 alpha, but not
by gamma-interferon.
Localisation
Endothelial cells and monocytes. However, VEGI was
not expressed in either B or T cells.
Function
VEGI is an endogenous inhibitor of angiogenesis
produced largely by vascular endothelial cells and
exerts a specific inhibitory activity on the proliferation
of endothelial cells. VEGI enforces growth arrest of
endothelial cells in G0 and early G1 phases of the cell
cycle but induces apoptosis in proliferating endothelial
cells. The MAPKs p38 and jun N-terminal kinase
(JNK) are required for VEGI-mediated endothelial
inhibition. Engineered overexpression of secreted
VEGI by cancer cells or systemic administration of
recombinant VEGI to tumor-bearing mice inhibits
tumor growth in numerous tumor models. Recent
studies show that VEGI helps modulate the immune
system by activating T cells and stimulating dendritic
cell maturation, suggesting that VEGI is directly
involved in modulating the interaction between the
endothelium and the immune system. Recombinant
VEGI has an inhibitory activity on mouse bone
marrow-derived EPCs in culture, preventing their
differentiation toward endothelial cells.
Interaction of TL1A with DR3 promotes T cell
expansion during an immune response (Migone et al.,
2002).
Homology
VEGI exhibits 20-30% sequence homology to human
TNF-alpha, TNF-beta, and the Fas ligand, similar to
that among other TNF family members.
Implicated in
Colon carcinoma
Note
Local production of a secreted form of VEGI via gene
transfer caused complete suppression of the growth of
MC-38 murine colon cancers in syngeneic
C57BL/6mice. Histological examination showed
marked reduction of vascularization in MC-38 tumors
that expressed soluble but not membrane-bound VEGI
or were transfected with control vector. The
conditioned media from soluble VEGI-expressing cells
showed marked inhibitory effect on in vitro
proliferation of adult bovine aortic endothelial cells.
TNFSF15 (tumor necrosis factor (ligand) superfamily, member 15) Yang GL, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 668
Breast cancer
Note
The anticancer potential of VEGI was examined in a
breast cancer xenograft tumor model in which the
cancer cells were co-injected with Chinese hamster
ovary cells overexpressing a secreted form of the
protein. The co-injection resulted in potent inhibition of
xenograft tumor growth. Our findings are consistent
with the view that VEGI is an endothelial cell-specific
negative regulator of angiogenesis.
Mucosal vaccine adjuvant
Note
Kayamuro et al., (2009) reported that TL1A induced
the strongest immune response and augmented OVA-
specific IgG and IgA responses in serum and mucosal
compartments, respectively. The OVA-specific
immune response of TL1A was characterized by high
levels of serum IgG1 and increased production of IL-4
and IL-5 from splenocytes of immunized mice,
suggesting that TL1A might induce Th2-type
responses. These findings indicate that TL1A has the
most potential as a mucosal adjuvant among the TNFS
cytokines.
Inflammatory bowel disease
Note
Bamias et al., (2003) provided evidence that the novel
cytokine TL1A may play an important role in a Th1-
mediated disease such as Crohn's disease. Takedatsu et
al., (2008) revealed that TL1A is an important
modulator in the development of chronic mucosal
inflammation by enhancing T(H)1 and T(H)17 effector
functions. The central role of TL1A represents an
attractive, novel therapeutic target for the treatment of
Crohn's disease patients.
Inflammatory arthritis
Note
Bull et al., (2008) demonstrated that the DR3-TL1A
pathway regulates joint destruction in two murine
models of arthritis and represents a potential novel
target for therapeutic intervention in inflammatory joint
disease. Bamias et al., (2008) concluded that TL1A
may serve as an inflammatory marker in rheumatoid
arthritis. Interactions between TL1A and its receptors
may be important in the pathogenesis of rheumatoid
arthritis.
Renal inflammation and injury
Note
Al-Lamki et al., (2008) suggested that TL1A may
contribute to renal inflammation and injury through
DR3-mediated activation of NF-kappaB and caspase-3,
respectively, but that an unidentified receptor may
mediate the NF-kappaB-independent induction of
TNFR2 in tubular epithelial cells.
References Tan KB, Harrop J, Reddy M, Young P, Terrett J, Emery J, Moore G, Truneh A. Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and non-hematopoietic cells. Gene. 1997 Dec 19;204(1-2):35-46
Yue TL, Ni J, Romanic AM, Gu JL, Keller P, Wang C, Kumar S, Yu GL, Hart TK, Wang X, Xia Z, DeWolf WE Jr, Feuerstein GZ. TL1, a novel tumor necrosis factor-like cytokine, induces apoptosis in endothelial cells. Involvement of activation of stress protein kinases (stress-activated protein kinase and p38 mitogen-activated protein kinase) and caspase-3-like protease. J Biol Chem. 1999 Jan 15;274(3):1479-86
Zhai Y, Ni J, Jiang GW, Lu J, Xing L, Lincoln C, Carter KC, Janat F, Kozak D, Xu S, Rojas L, Aggarwal BB, Ruben S, Li LY, Gentz R, Yu GL. VEGI, a novel cytokine of the tumor necrosis factor family, is an angiogenesis inhibitor that suppresses the growth of colon carcinomas in vivo. FASEB J. 1999 Jan;13(1):181-9
Zhai Y, Yu J, Iruela-Arispe L, Huang WQ, Wang Z, Hayes AJ, Lu J, Jiang G, Rojas L, Lippman ME, Ni J, Yu GL, Li LY. Inhibition of angiogenesis and breast cancer xenograft tumor growth by VEGI, a novel cytokine of the TNF superfamily. Int J Cancer. 1999 Jul 2;82(1):131-6
Yu J, Tian S, Metheny-Barlow L, Chew LJ, Hayes AJ, Pan H, Yu GL, Li LY. Modulation of endothelial cell growth arrest and apoptosis by vascular endothelial growth inhibitor. Circ Res. 2001 Dec 7;89(12):1161-7
Chew LJ, Pan H, Yu J, Tian S, Huang WQ, Zhang JY, Pang S, Li LY. A novel secreted splice variant of vascular endothelial cell growth inhibitor. FASEB J. 2002 May;16(7):742-4
Migone TS, Zhang J, Luo X, Zhuang L, Chen C, Hu B, Hong JS, Perry JW, Chen SF, Zhou JX, Cho YH, Ullrich S, Kanakaraj P, Carrell J, Boyd E, Olsen HS, Hu G, Pukac L, Liu D, Ni J, Kim S, Gentz R, Feng P, Moore PA, Ruben SM, Wei P. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity. 2002 Mar;16(3):479-92
Bamias G, Martin C 3rd, Marini M, Hoang S, Mishina M, Ross WG, Sachedina MA, Friel CM, Mize J, Bickston SJ, Pizarro TT, Wei P, Cominelli F. Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease. J Immunol. 2003 Nov 1;171(9):4868-74
Zilberberg L, Shinkaruk S, Lequin O, Rousseau B, Hagedorn M, Costa F, Caronzolo D, Balke M, Canron X, Convert O, Laïn G, Gionnet K, Goncalvès M, Bayle M, Bello L, Chassaing G, Deleris G, Bikfalvi A. Structure and inhibitory effects on angiogenesis and tumor development of a new vascular endothelial growth inhibitor. J Biol Chem. 2003 Sep 12;278(37):35564-73
Asahara T, Kawamoto A. Endothelial progenitor cells for postnatal vasculogenesis. Am J Physiol Cell Physiol. 2004 Sep;287(3):C572-9
Hou W, Medynski D, Wu S, Lin X, Li LY. VEGI-192, a new isoform of TNFSF15, specifically eliminates tumor vascular endothelial cells and suppresses tumor growth. Clin Cancer Res. 2005 Aug 1;11(15):5595-602
Bamias G, Mishina M, Nyce M, Ross WG, Kollias G, Rivera-Nieves J, Pizarro TT, Cominelli F. Role of TL1A and its receptor DR3 in two models of chronic murine ileitis. Proc Natl Acad Sci U S A. 2006 May 30;103(22):8441-6
TNFSF15 (tumor necrosis factor (ligand) superfamily, member 15) Yang GL, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 669
Metheny-Barlow LJ, Li LY. Vascular endothelial growth inhibitor (VEGI), an endogenous negative regulator of angiogenesis. Semin Ophthalmol. 2006 Jan-Mar;21(1):49-58
Jin T, Kim S, Guo F, Howard A, Zhang YZ. Purification and crystallization of recombinant human TNF-like ligand TL1A. Cytokine. 2007 Nov;40(2):115-22
Tian F, Grimaldo S, Fujita M, Cutts J, Vujanovic NL, Li LY. The endothelial cell-produced antiangiogenic cytokine vascular endothelial growth inhibitor induces dendritic cell maturation. J Immunol. 2007 Sep 15;179(6):3742-51
Al-Lamki RS, Wang J, Tolkovsky AM, Bradley JA, Griffin JL, Thiru S, Wang EC, Bolton E, Min W, Moore P, Pober JS, Bradley JR. TL1A both promotes and protects from renal inflammation and injury. J Am Soc Nephrol. 2008 May;19(5):953-60
Bamias G, Siakavellas SI, Stamatelopoulos KS, Chryssochoou E, Papamichael C, Sfikakis PP. Circulating levels of TNF-like cytokine 1A (TL1A) and its decoy receptor 3 (DcR3) in rheumatoid arthritis. Clin Immunol. 2008 Nov;129(2):249-55
Bull MJ, Williams AS, Mecklenburgh Z, Calder CJ, Twohig JP, Elford C, Evans BA, Rowley TF, Slebioda TJ, Taraban VY, Al-Shamkhani A, Wang EC. The Death Receptor 3-TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis. J Exp Med. 2008 Oct 27;205(11):2457-64
Cai J, Wei R, Cheng J. Preparation and characterization of a novel chimeric protein VEGI-CTT in Escherichia coli. J Biomed Biotechnol. 2008;2008:564969
Gao D, Nolan DJ, Mellick AS, Bambino K, McDonnell K, Mittal V. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science. 2008 Jan 11;319(5860):195-8
Takedatsu H, Michelsen KS, Wei B, Landers CJ, Thomas LS, Dhall D, Braun J, Targan SR. TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 activation. Gastroenterology. 2008 Aug;135(2):552-67
Kayamuro H, Yoshioka Y, Abe Y, Katayama K, Yoshida T, Yamashita K, Yoshikawa T, Hiroi T, Itoh N, Kawai Y, Mayumi T, Kamada H, Tsunoda S, Tsutsumi Y. TNF superfamily member, TL1A, is a potential mucosal vaccine adjuvant. Biochem Biophys Res Commun. 2009 Jul 3;384(3):296-300
Tian F, Liang PH, Li LY. Inhibition of endothelial progenitor cell differentiation by VEGI. Blood. 2009 May 21;113(21):5352-60
This article should be referenced as such:
Yang GL, Qi JW, Zhang ZS, Li LY. TNFSF15 (tumor necrosis factor (ligand) superfamily, member 15). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):665-669.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 670
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BAP1 (BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase)) Frédéric Guénard, Francine Durocher
Cancer Genomics Laboratory, Oncology and Molecular Endocrinology Research Centre, CRCHUL, CHUQ
and Laval University, Québec, G1V 4G2, Canada (FG, FD)
Published in Atlas Database: September 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/BAP1ID755ch3p21.html DOI: 10.4267/2042/44801
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: DKFZp686N04275; FLJ35406;
FLJ37180; HUCEP-13; KIAA0272; UCHL2; hucep-6
HGNC (Hugo): BAP1
Location : 3p21.1
DNA/RNA
Description
The gene spans 9.0 kb and is composed of 17 exons.
Transcription
Transcription start is 115 bp upstream of first ATG of
the BAP1 ORF.
Pseudogene
No pseudogene reported.
Protein
Description
Human BAP1 is 729 amino acids with a molecular
weight of 90 kDa. The amino-terminal 240 amino acids
show homology to ubiquitin C-terminal hydrolases
(UCH).
BAP1 also contains a region of extreme acidity (amino
acids 396 to 408), multiple potential phosphorylation
sites and N-linked glycosylation sites. The C-terminal
region contains two putative nuclear localization
signals.
BAP1 binds to the RING finger domain of BRCA1
through its carboxyl-terminal region (594-657 amino
acids). Domain comprised by residues 182-365 of
BAP1 interacts with the RING finger domain of
BARD1. Interaction of BAP1 with HCF-1 (host cell
factor 1; HCFC1) is dependent on the NHNY sequence
resembling the HCF-binding motif (HBM).
Expression
BAP1 is expressed in a variety of human adult tissues.
High expression was detected in testis, placenta and
ovary, with varying levels detected in other tissues.
Expression of BAP1 in normal human breast tissue was
also detected.
Analysis conducted in mice revealed that Bap1
expression is up-regulated in the breast during puberty,
pregnancy and as a result of parity.
Structure of BAP1. BAP1 is a 729 aa protein. UCH, Ubiquitin C-terminal hydrolase; HBM, HCF-binding motif (NHNY sequence); NLS, Nuclear localization signal.
BAP1 (BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase)) Guénard F, Durocher F
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 671
BAP1 mRNA level is significantly increased in
MCF10a cell line following genistein treatment, an
isoflavone found in soya and proposed to prevent breast
cancer.
Localisation
BAP1 is a nuclear-localized ubiquitin carboxy-terminal
hydrolase.
Function
BAP1 enhances BRCA1-mediated inhibition of breast
cancer cell growth and may serve as a
regulator/effector of BRCA1 growth
control/differentiation pathways. BAP1 interacts with
HCF-1, a transcriptional cofactor found in a number of
important regulatory complexes. Bap1 may help to
control cell proliferation by regulating HCF-1 protein
levels and by associating with genes involved in the
G1-S transition.
The BRCA1/BARD1 complex possess a dual E3
ubiquitin ligase activity, promotes its own
ubiquitination and targets other proteins. Although
BAP1 associates with BRCA1, it does not appear to
function in the deubiquitylation of the BRCA1/BARD1
complex. BAP1 inhibits the E3 ligase activity of
BRCA1/BARD1 by binding the RING finger domain
of BARD1 and possesses deubiquitination activity
toward ubiquitin chains catalyzed by BRCA1/BARD1.
BAP1 and BRCA1/BARD1 may coordinately regulate
ubiquitination during the DNA damage response and
the cell cycle, BAP1 being phosphorylated by ATM
and ATR in response to DNA damage and BAP1
inhibition causing S-phase retardation.
It was also proposed that specific regions and UCH
activity of BAP1 play an essential role in TCR.
Homology
The amino-terminal 240 amino acids show significant
homology to a class of thiol proteases, designated
UCH, which are implicated in the proteolytic
processing of ubiquitin.
Mutations
Note
The mutation of a residue predicted to disrupt the
helical nature of the extreme C-terminal region of
BAP1 abolishes the BAP1/BRCA1 interaction.
BAP1 can suppress tumorigenicity of lung cancer cells
in athymic nude mice.
Deubiquitinating activity and nuclear localization are
both required for BAP1-mediated tumor suppression.
Moreover, BAP1-mediated growth suppression is
independent of wild-type BRCA1.
Squamous-cell carcinomas and large-cell
undifferentiated carcinomas showed LOH for a 3p21-
22 locus.
Large rearrangements, deletions, and missense
mutations of the BAP1 locus have been found in lung
and sporadic breast tumors and in lung cancer cell
lines.
Implicated in
Breast cancer
Note
A study conducted on high-risk breast cancer families
from the French population revealed that the BAP1
gene does not appear to be commonly involved in high-
risk breast cancer predisposition. These results were
thereafter confirmed in a larger study conducted on
families with high risk of breast cancer from the French
Canadian population. These studies do not rule out the
possibility that BAP1 alleles might be associated with
moderate or low breast cancer risk.
Selected variations of the BAP1 gene were also
excluded as low penetrance risk alleles in sporadic
breast cancer carried from the Spanish population.
Medulloblastoma
Note
Medulloblastoma is a highly malignant tumor of the
cerebellum. This disease with poor prognosis occurs
mostly in children. A screen of cDNA libraries with
autologous sera to identify antigen-specific immune
responses associated with this agressive tumor type
pointed to the BAP1 gene as a possible target of
immune response.
Schizophrenia
Note
The BAP1 gene was excluded as a promizing candidate
gene for schizophrenia in a fine mapping association
study carried out on chromosome 3p, one of the regions
showing strong evidence of linkage with schizophrenia.
References Buchhagen DL, Qiu L, Etkind P. Homozygous deletion, rearrangement and hypermethylation implicate chromosome region 3p14.3-3p21.3 in sporadic breast-cancer development. Int J Cancer. 1994 May 15;57(4):473-9
Jensen DE, Proctor M, Marquis ST, Gardner HP, Ha SI, Chodosh LA, Ishov AM, Tommerup N, Vissing H, Sekido Y, Minna J, Borodovsky A, Schultz DC, Wilkinson KD, Maul GG, Barlev N, Berger SL, Prendergast GC, Rauscher FJ 3rd. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene. 1998 Mar 5;16(9):1097-112
Jensen DE, Rauscher FJ 3rd. BAP1, a candidate tumor suppressor protein that interacts with BRCA1. Ann N Y Acad Sci. 1999;886:191-4
Hu JJ, Mohrenweiser HW, Bell DA, Leadon SA, Miller MS. Symposium overview: genetic polymorphisms in DNA repair and cancer risk. Toxicol Appl Pharmacol. 2002 Nov 15;185(1):64-73
Mallery DL, Vandenberg CJ, Hiom K. Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains. EMBO J. 2002 Dec 16;21(24):6755-62
BAP1 (BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase)) Guénard F, Durocher F
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 672
Behrends U, Schneider I, Rössler S, Frauenknecht H, Golbeck A, Lechner B, Eigenstetter G, Zobywalski C, Müller-Weihrich S, Graubner U, Schmid I, Sackerer D, Späth M, Goetz C, Prantl F, Asmuss HP, Bise K, Mautner J. Novel tumor antigens identified by autologous antibody screening of childhood medulloblastoma cDNA libraries. Int J Cancer. 2003 Aug 20;106(2):244-51
Coupier I, Cousin PY, Hughes D, Legoix-Né P, Trehin A, Sinilnikova OM, Stoppa-Lyonnet D. BAP1 and breast cancer risk. Fam Cancer. 2005;4(4):273-7
Caëtano B, Le Corre L, Chalabi N, Delort L, Bignon YJ, Bernard-Gallon DJ. Soya phytonutrients act on a panel of genes implicated with BRCA1 and BRCA2 oncosuppressors in human breast cell lines. Br J Nutr. 2006 Feb;95(2):406-13
Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 2007 May 25;316(5828):1160-6
Ventii KH, Devi NS, Friedrich KL, Chernova TA, Tighiouart M, Van Meir EG, Wilkinson KD. BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization. Cancer Res. 2008 Sep 1;68(17):6953-62
Guénard F, Labrie Y, Ouellette G, Beauparlant CJ, Durocher F. Genetic sequence variations of BRCA1-interacting genes AURKA, BAP1, BARD1 and DHX9 in French Canadian families with high risk of breast cancer. J Hum Genet. 2009 Mar;54(3):152-61
Misaghi S, Ottosen S, Izrael-Tomasevic A, Arnott D, Lamkanfi M, Lee J, Liu J, O'Rourke K, Dixit VM, Wilson AC. Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1. Mol Cell Biol. 2009 Apr;29(8):2181-92
Nishikawa H, Wu W, Koike A, Kojima R, Gomi H, Fukuda M, Ohta T. BRCA1-associated protein 1 interferes with BRCA1/BARD1 RING heterodimer activity. Cancer Res. 2009 Jan 1;69(1):111-9
Vega A, Salas A, Milne RL, Carracedo B, Ribas G, Ruibal A, de León AC, González-Hernández A, Benítez J, Carracedo A. Evaluating new candidate SNPs as low penetrance risk factors in sporadic breast cancer: a two-stage Spanish case-control study. Gynecol Oncol. 2009 Jan;112(1):210-4
So HC, Fong PY, Chen RY, Hui TC, Ng MY, Cherny SS, Mak WW, Cheung EF, Chan RC, Chen EY, Li T, Sham PC. Identification of neuroglycan C and interacting partners as potential susceptibility genes for schizophrenia in a Southern Chinese population. Am J Med Genet B Neuropsychiatr Genet. 2010 Jan 5;153B(1):103-13
This article should be referenced as such:
Guénard F, Durocher F. BAP1 (BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):670-672.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 673
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
CDA (Cytidine Deaminase) Yoshiro Saito
Division of Medicinal Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku,
Tokyo 158-8501, Japan (YS)
Published in Atlas Database: September 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/CDAID998ch1p36.html DOI: 10.4267/2042/44802
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: CDD
HGNC (Hugo): CDA
Location: 1p36.12
Note: CDA catalyzes hydrolytic deamination of
cytidine and deoxycytidine into uridine and
deoxyuridine, respectively.
DNA/RNA
Description
The human CDA spans approximately 30 kB and
consists of 4 exons. No splice variant was reported.
Transcription
The full length CDA mRNA is 985 bp with an open
reading frame of 441 bp.
Pseudogene
No pseudogene was reported.
Protein
Note
X-ray crystal structures of CDA from Yeast (1R5T)
and Bacillus Subtilis (1JTK, 1UX0, 1UX1 and 1UWZ)
are publicized in the PDB.
Description
The human CDA protein consists of 146 amino acids
and has a molecular weight of 16,184. This is a soluble
cytoplasmic protein and it is involved in pyrimidine
salvaging.
Expression
Although the protein expression profile in tissues has
not been revealed, its mRNA expression determined by
Nothern blotting was observed in high levels in liver
and placenta, low in lung and kidney, but not in heart,
brain and muscle (Laliberte and Momparler, 1994).
High CDA activity was reported in liver and spleen,
and moderate in lung, kidney, large intestine mucosa
and colon mucosa (Ho, 1973).
CDA (Cytidine Deaminase) Saito Y
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 674
Localisation
This protein is localized in cytoplasm.
Function
CDA catalyzes hydrolytic deamination of cytidine and
deoxycytidine into uridine and deoxyuridine,
respectively. This protein also inactivate
chemotherapeutic nucleoside analogs 2,2-
difluorodeoxycytidine (gemcitabine) and cytosine
arabinoside (cytarabine, Ara-C).
Mutations
Germinal
Two nonsynonymous genetic varitions, 79A>C
(Lys27Gln) and 208G>A (Ala70Thr), have been found
in the human CDA gene (Yue et al., 2003). Ethnic
differences in the minor allele frequencies of these
variations have been reported. The 79A>C (Lys27Gln)
was found at 0.30-0.36 frequencies in Caucasians, at
0.20-0.21 in Japanese and at 0.04-0.10 in Africans
(Ueno et al., 2007). In contrast, the 208G>A
(Ala70Thr) was found at 0.13 in Africans and 0.04 in
Japanese, but not in Caucasians. Interestingly, the
208G>A (Ala70Thr) has not been detected in African-
Americans. The mutant protein with 70Thr was
reported to have remarkably reduced activities in vitro
(Yue et al., 2003) and in vivo (Sugiyama et al., 2007).
On the other hand, controvertial results on the effects of
activities have been obtained for 79A>C (Lys27Gln).
The recombinant enzyme with Gln27 retained its
catalytic activities for cytidine and ara-C as substrates
(Yue et al., 2003), while showing reduced activity with
increased Km value in the case of gemcitabine (Gilbert
et al., 2006). However, the minor allele of this SNP was
reported to be associated with higher enzymatic
activities for gemcitbine based on tests using lysates of
red blood cells taken from Caucasian cancer patients
(Giovannetti et al., 2008; Tibaldi et al., 2008). In line
with this, the minor allele was associated with
decreased response, shorter time to progression and
overall survival, and lower frequencies of grade 3 and 4
neutropenia in Caucasian non-small cell lung cancer
patients treated with gemcitabine and cisplatin (Tibaldi
et al., 2008).
Implicated in
Adverse reactions by anti-cancer drugs
Note
CDA is involved in the metabolic inactivation of anti-
cancer drug gemcitabine and cytosine arabinoside (ara-
C). CDA polymorphisms 208G>A (Ala70Thr) has been
associated with adverse reactions including neutropenia
by gemcitabine. Reduced clearance of gemcitabine and
plasma CDA activities significantly depended on the
number of minor allele 208A (70Thr) in 256 Japanese
patients with cancer (Sugiyama et al., 2007). This
polymorphism was also associated with increased
incidences of grade 3/4 neutropenia in the patients
coadministered with other anti-cancer drugs (Sugiyama
et al., 2007). Notably, one patient with homozygous
208A (70Thr) showed severe hematologic and
nonhematologic toxicities during chemotherapy with
gemcitabine and cisplatin, and had 1/5 value of
gemcitabine clearance and 12% of plasma CDA
activity compared to those of the patients without CDA
nonsynonymous polymorphisms (Yonemori et al.,
2005, Sugiyama et al., 2007). Among the other panels
of Japanese pancreatic cancer patients, three patients
encountered life-threatening toxicities after
chemotherapies including gemcitabine (Ueno et al.,
2009). Two of them had homozygous CDA 208A
(70Thr), and showed extremely low plasma CDA
activity and gemcitabine clearance. Together with the
previous one patient, homozygous 208A (70Thr) was
suggested to be a key factor causing gemcitabine-
induced severe adverse reactions in the Japanese (Ueno
et al., 2009). With regard to another nonsynonymous
polymorphism, the minor allele of CDA 79A>C
(Lys27Gln) was associated with decreased response,
shorter time to progression and overall survival, and
lower frequencies of grade 3 and 4 neutropenia in
Caucasian non-small cell lung cancer patients treated
with gemcitabine and cisplatin (Tibaldi et al., 2008).
Homozygous 79C (27Gln) was also associated with
increased postinduction treatment-related motality with
ara-C in patients with acute myeloid leukemia (Bhatla
et al., 2008).
Acute myeloid leukemia
Disease
CDA genetic polymorphisms (79A>C, Lys27Gln;
208G>A, Ala70Thr; 435T>C, silent) were not
associated with susceptibility to acute myeloid
leukemia in Chinese children (Yue et al., 2007).
Colorectal cancer
Note
Combination of the five gene expression levels (CDA,
MGC20553, BANK1, BCNP1 and MS4A1) in
peripheral white blood cells could be used as a
biomarker for diagnosis of colorectal cancer (Han et al.,
2008).
References Ho DH. Distribution of kinase and deaminase of 1-beta-D-arabinofuranosylcytosine in tissues of man and mouse. Cancer Res. 1973 Nov;33(11):2816-20
Laliberté J, Momparler RL. Human cytidine deaminase: purification of enzyme, cloning, and expression of its complementary DNA. Cancer Res. 1994 Oct 15;54(20):5401-7
Yue L, Saikawa Y, Ota K, Tanaka M, Nishimura R, Uehara T, Maeba H, Ito T, Sasaki T, Koizumi S. A functional single-nucleotide polymorphism in the human cytidine deaminase gene contributing to ara-C sensitivity. Pharmacogenetics. 2003 Jan;13(1):29-38
CDA (Cytidine Deaminase) Saito Y
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 675
Yonemori K, Ueno H, Okusaka T, Yamamoto N, Ikeda M, Saijo N, Yoshida T, Ishii H, Furuse J, Sugiyama E, Kim SR, Kikura-Hanajiri R, Hasegawa R, Saito Y, Ozawa S, Kaniwa N, Sawada J. Severe drug toxicity associated with a single-nucleotide polymorphism of the cytidine deaminase gene in a Japanese cancer patient treated with gemcitabine plus cisplatin. Clin Cancer Res. 2005 Apr 1;11(7):2620-4
Gilbert JA, Salavaggione OE, Ji Y, Pelleymounter LL, Eckloff BW, Wieben ED, Ames MM, Weinshilboum RM. Gemcitabine pharmacogenomics: cytidine deaminase and deoxycytidylate deaminase gene resequencing and functional genomics. Clin Cancer Res. 2006 Mar 15;12(6):1794-803
Sugiyama E, Kaniwa N, Kim SR, Kikura-Hanajiri R, Hasegawa R, Maekawa K, Saito Y, Ozawa S, Sawada J, Kamatani N, Furuse J, Ishii H, Yoshida T, Ueno H, Okusaka T, Saijo N. Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism. J Clin Oncol. 2007 Jan 1;25(1):32-42
Ueno H, Kiyosawa K, Kaniwa N. Pharmacogenomics of gemcitabine: can genetic studies lead to tailor-made therapy? Br J Cancer. 2007 Jul 16;97(2):145-51
Yue LJ, Chen XW, Li CR, Li CG, Shi HS, Zhang M. [Single-nucleotide polymorphisms of the cytidine deaminase gene in childhood with acute leukemia and normal Chinese children]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2007 Dec;24(6):699-702
Giovannetti E, Laan AC, Vasile E, Tibaldi C, Nannizzi S, Ricciardi S, Falcone A, Danesi R, Peters GJ. Correlation between cytidine deaminase genotype and gemcitabine
deamination in blood samples. Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):720-5
Han M, Liew CT, Zhang HW, Chao S, Zheng R, Yip KT, Song ZY, Li HM, Geng XP, Zhu LX, Lin JJ, Marshall KW, Liew CC. Novel blood-based, five-gene biomarker set for the detection of colorectal cancer. Clin Cancer Res. 2008 Jan 15;14(2):455-60
Tibaldi C, Giovannetti E, Vasile E, Mey V, Laan AC, Nannizzi S, Di Marsico R, Antonuzzo A, Orlandini C, Ricciardi S, Del Tacca M, Peters GJ, Falcone A, Danesi R. Correlation of CDA, ERCC1, and XPD polymorphisms with response and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Clin Cancer Res. 2008 Mar 15;14(6):1797-803
Bhatla D, Gerbing RB, Alonzo TA, Conner H, Ross JA, Meshinchi S, Zhai X, Zamzow T, Mehta PA, Geiger H, Perentesis J, Davies SM. Cytidine deaminase genotype and toxicity of cytosine arabinoside therapy in children with acute myeloid leukemia. Br J Haematol. 2009 Feb;144(3):388-94
Ueno H, Kaniwa N, Okusaka T, Ikeda M, Morizane C, Kondo S, Sugiyama E, Kim SR, Hasegawa R, Saito Y, Yoshida T, Saijo N, Sawada J. Homozygous CDA*3 is a major cause of life-threatening toxicities in gemcitabine-treated Japanese cancer patients. Br J Cancer. 2009 Mar 24;100(6):870-3
This article should be referenced as such:
Saito Y. CDA (Cytidine Deaminase). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):673-675.
Gene Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 676
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
CKS1B (CDC28 protein kinase regulatory subunit 1B) Yongyou Zhang
Case Western Reserve University, 2103 Cornell Rd, WRB-3101, Cleveland, Ohio 44106, USA (YZ)
Published in Atlas Database: September 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/CKS1BID40092ch1q21.html DOI: 10.4267/2042/44803
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: CKS-1; CKS1; PNAS-143; PNAS-16;
PNAS-18; ckshs1
HGNC (Hugo): CKS1B
Location: 1q21.3
DNA/RNA
Genomic organization of the CKS1B gene.
Description
Three exons, spans approximately 4.61 kb of genomic
DNA in the centromere-to-telomere orientation. The
translation initiation codon ATG is located in exon 1,
and the stop codon in exon 3.
Transcription
mRNA of approximately 1.8 kb. There are two
transcript variants for CKS1B gene. The variant 2 uses
a different splice site at the 3' end of the first exon
compared to variant 1. There is no evidence that variant
2 encodes a protein.
Pseudogene
4 processed, non-expressed, pseudogenes in human
genome.
Protein
Description
The open reading frame encodes a 79 amino acid
protein, with an estimated molecular weight of
approximately 9660 Da.
The side chains of residues of CKS1b in the binding sites for Cdk2, Skp2 and phosphorylated substrate are shown, with residues in the Cdk2-binding site in green, in the phosphate-binding site in blue, and the Skp2-binding site in red. (The structure figure modified from the origin paper: Markus A. Seeliger et al, Role of Conformational Heterogeneity in Domain Swapping and Adapter Function of the Cks Proteins. J. Biol. Chem., Vol. 280, Issue 34, 30448-30459, August 26, 2005).
CKS1B (CDC28 protein kinase regulatory subunit 1B) Zhang Y
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 677
Expression
Basical level expression in all mammalian cell and
aberrant expression in cancer cell.
Localisation
Cytoplasm and nucleus.
Function
CKS1B protein binds to the catalytic subunit of the
cyclin dependent kinases and is essential for their
biological function of cell cycle control.
Schematic of the regulation of cell cycle by the CKS1B. CKS1B associates with the p27kip1-Cdk/cyclin complex, induces the formation of the p27kip1-SCF ubiquitin ligase complex, triggers degradation of p27kip1, and signals cells to undergo the G1/S transition by releasing and activating the Cdk/cyclin A/E complexes. CycE/A, cyclin E or Cyclin A; Ub, ubiquitin.
Homology
The CKS1B proteins are evolutionary conserved.
Mammalian cells express two well-conserved
members, like the human CKS1B and CKS2 proteins.
The CKSB1B protein is highly conserved across
species.
Implicated in
Cancer
Note
The expression of CKS1B is elevaled in multiple
cancer, including breast cancer, lymphoma, myeloma,
colon cancer, prostate cancer, lung cancer, renal
carcinoma, oesophageal squamous cell carcinoma,
salivary cancer, serous ovarian cancer, bladder cancer,
urothelial carcinoma et al.
Prognosis
Overexpression of CKS1B is associated with poor
prognosis in multiple cancer, including myeloma,
breast cancer, lymphoma, renal carcinoma, ovarian
cancer et al.
Oncogenesis
Amplification and overexpression of CKS1B were
strongly associated with lymph node metastasis and
poor prognosis in breast, salivary cancer and
oesophageal squamous cell carcinoma. Generally,
CKS1B is an essential factor in facilitating Skp2-
dependent degradation of p27. In breast cancer cell,
overexpression of CKS1B may inhibit the apoptosis
through the MEK-Erk pathway. All of these suggest
that CKS1B alterations may have a significant
biological role in the tumorigenesis in different tissue
and the novel therapeutic strategy for cancer through
inhibiting the CKS1B activity. Therefore, disruption of
Skp2-CKS1B assembly or down-regulation of CKS1B
expression may be used for cancer therapy.
References Richardson HE, Stueland CS, Thomas J, Russell P, Reed SI. Human cDNAs encoding homologs of the small p34Cdc28/Cdc2-associated protein of Saccharomyces cerevisiae and Schizosaccharomyces pombe. Genes Dev. 1990 Aug;4(8):1332-44
Bourne Y, Watson MH, Hickey MJ, Holmes W, Rocque W, Reed SI, Tainer JA. Crystal structure and mutational analysis of the human CDK2 kinase complex with cell cycle-regulatory protein CksHs1. Cell. 1996 Mar 22;84(6):863-74
Demetrick DJ, Zhang H, Beach DH. Chromosomal mapping of the human genes CKS1 to 8q21 and CKS2 to 9q22. Cytogenet Cell Genet. 1996;73(3):250-4
Spruck C, Strohmaier H, Watson M, Smith AP, Ryan A, Krek TW, Reed SI. A CDK-independent function of mammalian Cks1: targeting of SCF(Skp2) to the CDK inhibitor p27Kip1. Mol Cell. 2001 Mar;7(3):639-50
Morris MC, Kaiser P, Rudyak S, Baskerville C, Watson MH, Reed SI. Cks1-dependent proteasome recruitment and activation of CDC20 transcription in budding yeast. Nature. 2003 Jun 26;423(6943):1009-13
Bashir T, Dorrello NV, Amador V, Guardavaccaro D, Pagano M. Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. Nature. 2004 Mar 11;428(6979):190-3
Kitajima S, Kudo Y, Ogawa I, Bashir T, Kitagawa M, Miyauchi M, Pagano M, Takata T. Role of Cks1 overexpression in oral squamous cell carcinomas: cooperation with Skp2 in promoting p27 degradation. Am J Pathol. 2004 Dec;165(6):2147-55
Zhang Y, Lin Y, Bowles C, Wang F. Direct cell cycle regulation by the fibroblast growth factor receptor (FGFR) kinase through phosphorylation-dependent release of Cks1 from FGFR substrate 2. J Biol Chem. 2004 Dec 31;279(53):55348-54
Shapira M, Ben-Izhak O, Linn S, Futerman B, Minkov I, Hershko DD. The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma. Cancer. 2005 Apr 1;103(7):1336-46
Slotky M, Shapira M, Ben-Izhak O, Linn S, Futerman B, Tsalic M, Hershko DD. The expression of the ubiquitin ligase subunit Cks1 in human breast cancer. Breast Cancer Res. 2005;7(5):R737-44
Ouellet V, Guyot MC, Le Page C, Filali-Mouhim A, Lussier C, Tonin PN, Provencher DM, Mes-Masson AM. Tissue array analysis of expression microarray candidates identifies markers associated with tumor grade and outcome in serous epithelial ovarian cancer. Int J Cancer. 2006 Aug 1;119(3):599-607
Kawakami K, Enokida H, Tachiwada T, Nishiyama K, Seki N, Nakagawa M. Increased SKP2 and CKS1 gene expression contributes to the progression of human urothelial carcinoma. J Urol. 2007 Jul;178(1):301-7
Westbrook L, Manuvakhova M, Kern FG, Estes NR 2nd, Ramanathan HN, Thottassery JV. Cks1 regulates cdk1
CKS1B (CDC28 protein kinase regulatory subunit 1B) Zhang Y
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 678
expression: a novel role during mitotic entry in breast cancer cells. Cancer Res. 2007 Dec 1;67(23):11393-401
Krishnan A, Hariharan R, Nair SA, Pillai MR. Fluoxetine mediates G0/G1 arrest by inducing functional inhibition of cyclin dependent kinase subunit (CKS)1. Biochem Pharmacol. 2008 May 15;75(10):1924-34
Lan Y, Zhang Y, Wang J, Lin C, Ittmann MM, Wang F. Aberrant expression of Cks1 and Cks2 contributes to prostate tumorigenesis by promoting proliferation and inhibiting programmed cell death. Int J Cancer. 2008 Aug 1;123(3):543-51
Liu Z, Fu Q, Lv J, Wang F, Ding K. Prognostic implication of p27Kip1, Skp2 and Cks1 expression in renal cell carcinoma: a tissue microarray study. J Exp Clin Cancer Res. 2008 Oct 15;27:51
Martinsson-Ahlzén HS, Liberal V, Grünenfelder B, Chaves SR, Spruck CH, Reed SI. Cyclin-dependent kinase-associated proteins Cks1 and Cks2 are essential during early embryogenesis and for cell cycle progression in somatic cells. Mol Cell Biol. 2008 Sep;28(18):5698-709
Nagler RM, Ben-Izhak O, Ostrovsky D, Golz A, Hershko DD. The expression and prognostic significance of Cks1 in salivary cancer. Cancer Invest. 2009 Jun;27(5):512-20
Wang XC, Tian J, Tian LL, Wu HL, Meng AM, Ma TH, Xiao J, Xiao XL, Li CH. Role of Cks1 amplification and overexpression in breast cancer. Biochem Biophys Res Commun. 2009 Feb 20;379(4):1107-13
Calvisi DF, Pinna F, Ladu S, Muroni MR, Frau M, Demartis I, Tomasi ML, Sini M, Simile MM, Seddaiu MA, Feo F, Pascale RM. The degradation of cell cycle regulators by SKP2/CKS1 ubiquitin ligase is genetically controlled in rodent liver cancer and contributes to determine the susceptibility to the disease. Int J Cancer. 2010 Mar 1;126(5):1275-81
This article should be referenced as such:
Zhang Y. CKS1B (CDC28 protein kinase regulatory subunit 1B). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):676-678.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 679
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
COL16A1 (collagen, type XVI, alpha 1) Susanne Grässel, Sabine Ratzinger
Orthopaedic Surgery, University of Regensburg, Abt. Experimentelle Orthopadie, ZMB im BioPark 1, Josef-
Engert-Strasse 9, D-93053 Regensburg, Germany (SG); Centre for Medical Biotechnology, BioPark 1,
Regensburg, Germany (SR)
Published in Atlas Database: September 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/COL16A1ID44542ch1p35.html DOI: 10.4267/2042/44804
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: 447AA; FP1572
HGNC (Hugo): COL16A1
Location: 1p35.2
DNA/RNA
Description
In 1992 the cDNA sequence of COL16A1 has been
discovered in a screening for collagen-like sequences in
cDNA banks of a human fibroblast cell line and human
placenta tissue. Two laboratories published
independently the human COL16A1 cDNA sequence
(Pan et al., 1992; Yamaguchi et al., 1992). The coding
sequence of authentic collagen type XVI comprises of
1604 amino acids including a 21 amino acid signal
peptide, whereas the recombinant version of collagen
type XVI contains 1597 amino acids (Kassner et al.,
2004). The nucleotide sequences published by Pan et
al., and Yamaguchi et al., were completed by Kassner
et al., with respect to a missing codon for one amino
acid (Kassner et al., 2004). Two predicted
imperfections in the collagenous region could not be
confirmed (unpublished data).
Transcription
The cDNA of 5.4 kb comprises a 4809 bp coding
sequence, framed by non-translated parts, including a
425 bp 3'-non-coding sequence which contains
polyadenylating signals. COL16A1 has been localized
to chromosome 1, 1p35-p34 (Pan et al., 1992). No
splice variants have been described up to
now. COL16A1 gene expression and transcription
varies in various phases of cell growth in cultured skin
fibroblasts. Gene expression was increased in
stationary phases (G0/G1) of cell growth when cell
proliferation was inhibited by serum deprivation or
suspension arrest (Tajima et al., 2000). Transcription
activity of the COL16A1 gene appears to be
mechanosensitive. It is downregulated in HCS2/8
human chondrosarcoma cells after application of
continuous hydrostatic pressure (Sironen et al., 2002).
Pseudogene
No pseudogenes are described up to now.
Protein
Description
Collagen type XVI, by structural analogy a member of
the FACIT - (fibril-associated collagens with
interrupted triple helices) family of collagens, contains
10 collagenous (COL) domains interspersed with 11
non-collagenous (NC) regions (Fig. 1A-C). It is a
homotrimeric molecule of about 210 kDa for each
native alpha1 chain. 32 cysteine residues, which are
almost all located in the non-collagenous domains at
the junction to the preceding collagenous regions,
contribute to a high thermal stability of the homotrimer
in form of disulfide bonds (Pan et al., 1992; Yamaguchi
et al., 1992). The prominent non-collagenous NC11
domain consists mainly of a 200-residue motif referred
to as proline-arginine-rich protein (PARP) in several
other collagen types or as tsp-1 in thrombospondin
(Fig. 1A).
COL16A1 (collagen, type XVI, alpha 1) Grässel S, Ratzinger S
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 680
Figure 1: Collagen type XVI, domain and molecular structure. Collagen type XVI affinity- purified from culture medium of over expressing HEK 293 EBNA cells elutes in full- length chains and proteolytically processed fragments with following molecular weight as (213 kDa) (A), (182 kDa) (B) and (78 kDa) (C). One alpha 1 chain of intact collagen XVI consists of 10 collagenous domains (COL1-COL10) and 11 non-collagenous domains (NC1-NC11). Atomic Force Microscopy (AFM) of affinity-purified recombinant full-length collagen type XVI trimers allows measurement of molecular size (D). Rotary shadowed TEM image of purified recombinant full-length collagen type XVI trimers corroborates the AFM data (E). Length of intact collagen XVI comes to about 240 nm. COL = collagenous domains, NC = non-collagenous domains.
COL16A1 (collagen, type XVI, alpha 1) Grässel S, Ratzinger S
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 681
It has been recombinantly expressed and used for
generation of specific anti-NC11 antibodies (Tillet et
al., 1995). 24% of the total number of proline residues
and 48% of the total number of lysine residues were
hydroxylated in recombinant collagen type XVI.
Because only lysine and proline in the Y position of X-
Y-Gly amino acid triplets and additionally some lysine
residues in the Y position of X-Y-Ser and X-Y-Ala in
collagens are subject to hydroxylation, the amino acid
sequence of authentic human collagen type XVI would
imply that 54% of the available prolines and a
maximum of 92% of the available lysines could
potentially be hydroxylated in recombinant collagen
type XVI. Two of the three potential N-glycosylation
sites reside in the N-terminal NC11 region and are
glycosylated. One has been assigned to the NC1
domain whereas here, no evidence has been found for
the attachment of a glycosaminoglycan chain (Kassner
et al., 2004).
Atomic force images of individual trimeric molecules
exhibited a total length of 168 ± 3 nm including the N-
terminal NC11 globular domains and the flexible
threadlike tail comprising all collagenous regions plus
the remaining non-collagenous domains. The height of
the NC11 domain constituted 0.94 ± 0.06 nm and the
radius at half height (r0.5h) was calculated as 9.48 ± 0.47
nm. The threadlike section of the remaining molecule
C-terminal of the NC11 domain appeared to be a thin
flat structure with a height between 0.5 and 0.7 nm.
Notably, at a distance of 94.8 ± 4.6 nm from the NC11
terminus the molecular measurements increased either
in height or diameter. The extension of this section
contributed with 73.1 ± 1.6 nm to the total length of the
protein (Fig. 1D). Rotary shadowing images of purified
recombinant collagen type XVI exhibited extended rod-
like molecules with a globular domain at one end,
probably constituting the large N-terminal NC11
domain (Fig. 1E). The shape of the molecules revealed
highly flexible regions, in some molecules even two or
more kinks. The length of the molecules varied
between 100-240 nm, with the majority being close to
150 nm.
The N-terminal half of human fibrillin-1/fibrillin-2
binds dose-dependent to collagen type XVI at low salt
concentrations of 50-100 mM NaCl, while interaction
between collagen type XVI and the C-terminal half of
fibrillin-1/-2 under these conditions were considerably
lower. These results indicate that monomeric fibrillin-
1/-2 can interact with collagen type XVI with low
affinity. Both, fibrillin-1 and -2 did not interact with the
recombinant NC11 domain. Soluble recombinant
fibronectin interacted strongly with collagen type XVI
at 150 mM NaCl
with half maximal binding at about 12 µg/ml (about 55
nM fibronectin), indicating that fibronectin can bind to
collagen XVI with high affinity (Kassner et al., 2004).
Collagen XVI co-localizes with alpha2 integrin at the
dermal epidermal junction (DEJ) (Fig. 2A-C) and with
alpha1 integrin and around fat cells in subdermal layers
(Fig. 2D-F). Cells bearing the integrins alpha1beta1
and alpha2beta1 attach and spread on recombinant
collagen type XVI. Collagen type XVI induces the
recruitment of these integrins into focal adhesion
plaques, a principal step in integrin signaling. In cell-
free binding assays, collagen type XVI is more avidly
bound by alpha1beta1 integrin than by alpha2beta1
integrin. Both integrins interact with collagen type XVI
via the A-domain of their alpha-subunits. A tryptic
collagen type XVI fragment comprising the
collagenous domains 1-3 is recognized by alpha1beta1
integrin. Electron microscopy of complexes of
alpha1beta1 integrin with this tryptic collagen XVI
fragment or with full-length collagen type XVI
revealed a unique alpha1beta1 integrin binding site
within collagen type XVI located in the COL 1-3
domains (Eble et al., 2006).
Expression
Collagen type XVI is expressed in various cells and
tissues. It is synthezised by dermal fibroblasts, smooth
muscle cells (Grassel et al., 1996), dermal dendrocytes
and dendritic cells in the skin (Akagi et al., 2002),
articular and costal chondrocytes (Kassner et al., 2003),
endometrial stromal cells (Tierney et al., 2003), basal
dermal and oral keratinocytes (Grassel et al., 1999),
bone marrow derived mesenchymal stem cells (Grassel
et al., 2009), neurons from the dorsal root ganglion
(Hubert et al., 2007), glioblastoma/astrocytoma cells
(Senner et al., 2008) and intestinal myofibroblasts
(Ratzinger et al., Matrix Biol., in revision). Collagen
type XVI is further expressed in the limbal
stem/progenitor niche which comprises clusters of cells
in the basal epithelium. There it is associated with the
corneal-limbal transition zone (Schlotzer-Schrehardt et
al., 2007). During early mouse development, collagen
type XVI occurs in many tissues and is co-distributed
with the major fibrillar collagens. In particular, it is
strongly expressed in differentiating chondrocytes and
dermal fibroblasts, smooth muscle cells of the heart and
dorsal root neural fibers, whereas in adult mice no
signal appears in brain tissue. Additional expression is
found in the cortical areas of the kidney and ovaries
(Lai et al., 1996). In adults it is found in skin, cartilage,
gastrointestinal tract and glioma tissues.
COL16A1 (collagen, type XVI, alpha 1) Grässel S, Ratzinger S
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 682
Figure 2: Distribution of collagen XVI and integrins alpha1beta1 and alpha2beta1 in adult murine skin. Cryosections from murine skin were stained with purified anti-collagen XVI-antibodies (red fluorescence, A, B, D, E), and with mAb JA221 directed against the integrin alpha2 subunit (green fluorescence, A, C) and with mAb AGF-1 directed against the integrin alpha1 subunit (green fluorescence, D, F), Panels A and D show combined staining for collagen XVI and the integrin subunits. The same sections are shown either in panel B, E stained for collagen XVI together with DAPI, or in panel C, F stained for integrin subunits and DAPI. E = epidermis, F = fatty tissue, D = dermis, DEJ = dermal epidermal junction zone. All pictures were taken at 400 x magnification.
Figure 3: Ultrastructural localization of collagen XVI in fibrillar extracts from skin and cartilage by immunogold electron microscopy. Double labeling of collagen XVI (18 nm gold particles, light arrow) and fibrillin-1 (12 nm gold particles, dark arrow) demonstrate co-localization on "bead on the string" microfibrils with collagen XVI bound at one distinct bead of the microfibrils. The large D-periodically banded collagen I fibrils lack collagen XVI labeling (light arrowhead). Bar = 0.12 µm. (A). In cartilage a special subpopulation of thin D-periodically banded cartilage fibrils were labeled with collagen XVI (black arrow, 18 nm gold particles), other fibril populations lack collagen XVI association, Bar = 0.09 µm. (B).
COL16A1 (collagen, type XVI, alpha 1) Grässel S, Ratzinger S
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 683
Localisation
Extracellular matrix of tissues. For skin and cartilage
tissue its suprastructure is known. It is associated to the
fibrillin containing microfibrillar apparatus in the
dermal-epidermal junction zone in skin and to collagen
II containing D-banded cartilage fibrils in costal
cartilage (Grassel et al., 1999; Kassner et al., 2003). It
is deposited pericellular around fibroblasts and smooth
muscle cells (Grassel et al., 1996) and in the territorial
region of chondrocytes (Kassner et al., 2003).
Function
Morphogenesis and assembly of distinct
suprastructures in different tissues, i.e. microfibrillar
apparatus in the dermis and fibrillar networks in
various connective tissues (Fig. 3A, B). Presumably, it
is an adaptor protein such as collagen type IX and
connects and organizes large fibrillar networks and thus
regulates integrity and stability of ECMs (Eble et al.,
2006; Grassel et al., 1999; Kassner et al., 2003). It is a
substrate for adhesion and invasion of tumor cells, i.e.
glioblastomas (Senner et al., 2008) and regeneration of
connective tissues after neural injury (Hubert et al.,
2007).
Homology
Based on conserved structural features with other
FACIT - collagens, namely: collagen type IX, collagen
type XII, collagen type XIV, collagen type XIX,
collagen type XX, collagen type XXI and collagen type
XXII. These structural features are: the presence of two
highly conserved cysteine residues separated by four
amino acids at the NC1-COL1 junctions and the
existence of two G-X-Y triplet imperfections within the
COL2 domain. A succession of triple-helical domains
connected by short non collagneous domains and the
presence of a large N-terminal domain that always
exhibits a TSPN subdomain next to the collagenous
domain. Besides from these common criteria, the
FACITs display remarkable divergence in the size and
composition of their N-terminal domains and in the
number of their collagenous domains (Ricard-Blum et
al., 2005).
Mutations
Note
There are no reports about mutations in the COL16A1
gene published as yet.
Germinal
None yet described.
Somatic
None yet described.
Implicated in
Glioblastoma tumorigenesis
Note
The progression of glioblastoma growth is
characterized by diffuse invasion of tumor cells into the
brain tissue. COL16A1 was upregulated on mRNA
level in glioblastoma tissues compared to normal cortex
(Fig. 4). Collagen type XVI protein was detected in
glioblastoma tissue and was secreted by glioblastoma
cell lines. A siRNA mediated knockdown of collagen
type XVI resulted in decreased cell adhesion of
glioblastoma cell lines whereas adhesion was
augmented on culture surfaces coated with recombinant
collagen type XVI. However, the migration potential of
glioblastoma cells on collagen type XVI remained
unaffected. Collagen type XVI appears to play a
supportive role for tumour specific remodelling of
extracellular matrix indicated through de novo
expression by glioblastoma cells (Senner et al., 2008).
Disease
Gliomas are the most frequent intrinsic brain tumors
and comprise astrocytic gliomas (grades II, III, IV)
including fibrillary astrocytoma (WHO grade II),
anaplastic astrocytoma (WHO grade III), and
glioblastoma (WHO grade IV). They are characterized
by diffuse invasion of tumour cells into the brain
parenchyma. The fatal outcome of this disease results
from single-tumour cells that have already invaded
distant brain regions at the time of diagnosis.
Glioblastoma behave highly invasive which cause the
high morbidity and mortality rates of these tumours
(Claes et al., 2007; Louis et al., 2007).
Prognosis
The 5-year survival rate of glioblastoma (WHO grade
IV) is 3%.
Neuronal development and regeneration
Note
In the nervous system, low collagen type XVI
expression was reported in the brain, however, in spinal
root fibres high gene expression levels were detected
during development (Lai et al., 1996). A SAGE banks
analysis showed an induction of Col16A1 gene
expression during development and after nerve injury
in dorsal root ganglia (DRG) of mice which contain the
cell bodies of neurons (Mechaly et al., 2006). Their
axons transmit sensory information from the periphery
to the central nervous system. During development and
regeneration, neurites require extracellular matrix for
growth and guidance (Hari et al., 2004),
COL16A1 (collagen, type XVI, alpha 1) Grässel S, Ratzinger S
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 684
Figure 4: Immunohistochemical staining of collagen type XVI and collagen type IV in brain sections. Immunofluorescence staining on cryo-sections for collagen XVI (red, white arrows) and collagen IV (green, light blue arrow heads) reveals an expression of collagen XVI around blood vessels, however not in the parenchyma of normal brain (A), whereas in glioblastoma (B) and pilocystic astrocytoma (C) collagen XVI is highly expressed throughout the tumour tissue.
however, the composition of the ECM is yet unknown.
In cell culture, satellite cells express collagen type XVI
indicating secretion and deposition by neuronal and
glia cells. Collagen type XVI participates in final steps
of DRG structural and functional maturation. So far,
collagen type XVI is the only FACIT collagen, whose
expression is regulated by nerve injury, taking
presumably part in remodelling events like
inflammation, cell proliferation, and neuronal death
(Hubert et al., 2007).
Fibrotic skin diseases
Note
In skin, COL16A1 transcripts were detected in cultured
dermal fibroblasts and keratinocytes (Pan et al., 1992).
Gene expression in fibroblasts varied according to the
horizontal layers in skin. Fibroblasts explanted from the
upper dermis displayed higher COL16A1 gene
expression than those from the middle and lower
dermis. In cultured skin fibroblasts an increase of
COL16A1 mRNA level was observed in stationary
phases of the cell cycle (non-adherent and confluent
phases) (Tajima et al., 2000). In localized scleroderma
and in systemic scleroderma COL16A1 gene
expression was upregulated 2.3 fold and 3.6 fold,
respectively, compared with keloid and normal controls
(Akagi et al., 1999).
Disease
Systemic and localized scleroderma are characterized
by systemic and localized deposition of highly
overproduced collagens in the skin. This collagen
accumulation is a result of overproduction of collagens
type I, II, and VI (Graves et al., 1983; Krieg et al.,
1985).
Crohn's disease
Note
Collagen type XVI is produced by myofibroblasts in
the normal intestine and its synthesis is increased in the
inflamed bowel wall (Fig. 5). Collagen type XVI
promotes cell spreading, formation and maturation of
focal adhesion contacts. Myofibroblasts develop
increased numbers of focal adhesion contacts on
collagen type XVI with increased recruitment of alpha1
integrin into the focal adhesions at the tip of the cells.
Focal adhesions on myofibroblasts from inflamed colon
tissue also display an increase in length on collagen
type XVI compared to collagen type I. As a result,
larger forces can be transmitted which then promote
and augment contraction of the ECM and ultimately
result in elevated stricture formation. Increased cell
spreading on collagen type XVI presumably adds to the
maintenance of cells in the inflamed intestinal regions
and thus promotes fibrotic responses of the
COL16A1 (collagen, type XVI, alpha 1) Grässel S, Ratzinger S
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 685
tissue and prolongs further disturbances of the delicate
hoemostasis between cells and surrounding ECM
(Ratzinger et al., Matrix Biol., in revision).
Disease
Crohn's disease is characterized by chronic
inflammation of the gastrointestinal tract, accompanied
by other systemic abnormalities. Inflammatory lesions
progress to intestinal fibrotic processes. A
pathologically overshooting healing response to
inflammation-induced disintegration of mucosal tissue
leads to excessive tissue repair.
An altered cytoarchitecture of the bowel wall with
disruption of the muscularis mucosa, thickening of the
muscularis propria, and deposition of collagens
contributes to the inflammation process (Burke et al.,
2007). Fibrillar and non-fibrillar collagens are up-
regulated in CD (type I, II, IV, V, VI) (Graham et al.,
1988; Matthes et al., 1992; Pucilowska et al.,
2000; Stallmach et al., 1992). Mesenchymal cells like
fibroblasts, myofibroblasts and smooth-muscle cells are
the main producers of extracellular matrix components
and play an important part in tissue growth and
development (Powell et al., 1999; Simon-Assmann et
al., 1995). Myofibroblasts are considered as central
player in tissue repair contributing to fibrosis, stricture
formation and stenosis by reconstituting a collagen-rich
extracellular matrix (ECM) and promoting wound
closure by contraction (Pucilowska et al., 2000;
Tomasek et al., 2002). Myofibroblasts motility, their
ability to contract wounds and the production of ECM
is altered in chronic inflammation. Normal wound
healing would terminate the contractile and
synthesizing activity of myofibroblasts by apoptotic
reduction of the cell number (Desmouliere et al., 1995).
COL16A1 (collagen, type XVI, alpha 1) Grässel S, Ratzinger S
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 686
Figure 5: Morphological distribution of collagen type XVI in health and disease. Morphological distribution of collagen XVI (green fluorescence) and alpha-smooth muscle actin (red fluorescence) is demonstrated for the bowel wall of healthy tissue (A-D) and CD tissue (E-H). Arrow heads indicate positive staining for collagen XVI. A negative control is displayed as inlet in D. c: crypts, m: muscle layer, s: submucosa, bv: blood vessel, e: erythrocytes, ep: epithelial cells, lp: lamina propria.
References Graves PN, Weiss IK, Perlish JS, Fleischmajer R. Increased procollagen mRNA levels in scleroderma skin fibroblasts. J Invest Dermatol. 1983 Feb;80(2):130-2
Krieg T, Perlish JS, Mauch C, Fleischmajer R. Collagen synthesis by scleroderma fibroblasts. Ann N Y Acad Sci. 1985;460:375-86
Graham MF, Diegelmann RF, Elson CO, Lindblad WJ, Gotschalk N, Gay S, Gay R. Collagen content and types in the intestinal strictures of Crohn's disease. Gastroenterology. 1988 Feb;94(2):257-65
Matthes H, Herbst H, Schuppan D, Stallmach A, Milani S, Stein H, Riecken EO. Cellular localization of procollagen gene transcripts in inflammatory bowel diseases. Gastroenterology. 1992 Feb;102(2):431-42
Pan TC, Zhang RZ, Mattei MG, Timpl R, Chu ML. Cloning and chromosomal location of human alpha 1(XVI) collagen. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6565-9
Stallmach A, Schuppan D, Riese HH, Matthes H, Riecken EO. Increased collagen type III synthesis by fibroblasts isolated from strictures of patients with Crohn's disease. Gastroenterology. 1992 Jun;102(6):1920-9
Yamaguchi N, Kimura S, McBride OW, Hori H, Yamada Y, Kanamori T, Yamakoshi H, Nagai Y. Molecular cloning and partial characterization of a novel collagen chain, alpha 1(XVI), consisting of repetitive collagenous domains and cysteine-containing non-collagenous segments. J Biochem. 1992 Dec;112(6):856-63
Desmoulière A, Redard M, Darby I, Gabbiani G. Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. Am J Pathol. 1995 Jan;146(1):56-66
Simon-Assmann P, Kedinger M, De Arcangelis A, Rousseau V, Simo P. Extracellular matrix components in intestinal development. Experientia. 1995 Sep 29;51(9-10):883-900
Tillet E, Mann K, Nischt R, Pan TC, Chu ML, Timpl R. Recombinant analysis of human alpha 1 (XVI) collagen. Evidence for processing of the N-terminal globular domain. Eur J Biochem. 1995 Feb 15;228(1):160-8
Grässel S, Timpl R, Tan EM, Chu ML. Biosynthesis and processing of type XVI collagen in human fibroblasts and smooth muscle cells. Eur J Biochem. 1996 Dec 15;242(3):576-84
Lai CH, Chu ML. Tissue distribution and developmental expression of type XVI collagen in the mouse. Tissue Cell. 1996 Apr;28(2):155-64
Akagi A, Tajima S, Ishibashi A, Yamaguchi N, Nagai Y. Expression of type XVI collagen in human skin fibroblasts: enhanced expression in fibrotic skin diseases. J Invest Dermatol. 1999 Aug;113(2):246-50
Grässel S, Unsöld C, Schäcke H, Bruckner-Tuderman L, Bruckner P. Collagen XVI is expressed by human dermal fibroblasts and keratinocytes and is associated with the microfibrillar apparatus in the upper papillary dermis. Matrix Biol. 1999 Jun;18(3):309-17
Powell DW, Mifflin RC, Valentich JD, Crowe SE, Saada JI, West AB. Myofibroblasts. II. Intestinal subepithelial myofibroblasts. Am J Physiol. 1999 Aug;277(2 Pt 1):C183-201
Pucilowska JB, Williams KL, Lund PK. Fibrogenesis. IV. Fibrosis and inflammatory bowel disease: cellular mediators and animal models. Am J Physiol Gastrointest Liver Physiol. 2000 Oct;279(4):G653-9
Tajima S, Akagi A, Tanaka N, Ishibashi A, Kawada A, Yamaguchi N. Expression of type XVI collagen in cultured skin fibroblasts is related to cell growth arrest. FEBS Lett. 2000 Mar 3;469(1):1-4
Akagi A, Tajima S, Ishibashi A, Matsubara Y, Takehana M, Kobayashi S, Yamaguchi N. Type XVI collagen is expressed in factor XIIIa+ monocyte-derived dermal dendrocytes and constitutes a potential substrate for factor XIIIa. J Invest Dermatol. 2002 Feb;118(2):267-74
Sironen RK, Karjalainen HM, Törrönen K, Elo MA, Kaarniranta K, Takigawa M, Helminen HJ, Lammi MJ. High pressure effects on cellular expression profile and mRNA stability. A cDNA array analysis. Biorheology. 2002;39(1-2):111-7
Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002 May;3(5):349-63
Kassner A, Hansen U, Miosge N, Reinhardt DP, Aigner T, Bruckner-Tuderman L, Bruckner P, Grässel S. Discrete
COL16A1 (collagen, type XVI, alpha 1) Grässel S, Ratzinger S
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 687
integration of collagen XVI into tissue-specific collagen fibrils or beaded microfibrils. Matrix Biol. 2003 Apr;22(2):131-43
Tierney EP, Tulac S, Huang ST, Giudice LC. Activation of the protein kinase A pathway in human endometrial stromal cells reveals sequential categorical gene regulation. Physiol Genomics. 2003 Dec 16;16(1):47-66
Hari A, Djohar B, Skutella T, Montazeri S. Neurotrophins and extracellular matrix molecules modulate sensory axon outgrowth. Int J Dev Neurosci. 2004 Apr;22(2):113-7
Kassner A, Tiedemann K, Notbohm H, Ludwig T, Mörgelin M, Reinhardt DP, Chu ML, Bruckner P, Grässel S. Molecular structure and interaction of recombinant human type XVI collagen. J Mol Biol. 2004 Jun 11;339(4):835-53
Ricard-Blum S, Ruggiero F. The collagen superfamily: from the extracellular matrix to the cell membrane. Pathol Biol (Paris). 2005 Sep;53(7):430-42
Eble JA, Kassner A, Niland S, Mörgelin M, Grifka J, Grässel S. Collagen XVI harbors an integrin alpha1 beta1 recognition site in its C-terminal domains. J Biol Chem. 2006 Sep 1;281(35):25745-56
Méchaly I, Bourane S, Piquemal D, Al-Jumaily M, Ventéo S, Puech S, Scamps F, Valmier J, Carroll P. Gene profiling during development and after a peripheral nerve traumatism reveals genes specifically induced by injury in dorsal root ganglia. Mol Cell Neurosci. 2006 Jul;32(3):217-29
Burke JP, Mulsow JJ, O'Keane C, Docherty NG, Watson RW, O'Connell PR. Fibrogenesis in Crohn's disease. Am J Gastroenterol. 2007 Feb;102(2):439-48
Claes A, Idema AJ, Wesseling P. Diffuse glioma growth: a guerilla war. Acta Neuropathol. 2007 Nov;114(5):443-58
Hubert T, Grimal S, Ratzinger S, Mechaly I, Grassel S, Fichard-Carroll A. Collagen XVI is a neural component of the developing and regenerating dorsal root ganglia extracellular matrix. Matrix Biol. 2007 Apr;26(3):206-10
Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007 Aug;114(2):97-109
Schlötzer-Schrehardt U, Dietrich T, Saito K, Sorokin L, Sasaki T, Paulsson M, Kruse FE. Characterization of extracellular matrix components in the limbal epithelial stem cell compartment. Exp Eye Res. 2007 Dec;85(6):845-60
Senner V, Ratzinger S, Mertsch S, Grässel S, Paulus W. Collagen XVI expression is upregulated in glioblastomas and promotes tumor cell adhesion. FEBS Lett. 2008 Oct 15;582(23-24):3293-300
Grässel S, Ahmed N, Göttl C, Grifka J. Gene and protein expression profile of naive and osteo-chondrogenically differentiated rat bone marrow-derived mesenchymal progenitor cells. Int J Mol Med. 2009 Jun;23(6):745-55
This article should be referenced as such:
Grässel S, Ratzinger S. COL16A1 (collagen, type XVI, alpha 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):679-687.
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 688
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
COPS2 (COP9 constitutive photomorphogenic homolog subunit 2 (Arabidopsis)) Susanne Jennek, Florian Kraft, Aria Baniahmad
Institute of Human Genetics and Anthropology, Jena University Hospital, Kollegiengasse 10, 07743 Jena,
Germany (SJ, FK, AB)
Published in Atlas Database: September 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/COPS2ID47362ch15q21.html DOI: 10.4267/2042/44805
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: ALIEN; CSN2; SGN2; TRIP15
HGNC (Hugo): COPS2
Location: 15q21.1
Note:
The beta casein is also abbreviated as CSN2.
DNA/RNA
Transcription
The promoter region of CSN2 contains 4 NF-kB
binding sites. Binding to these sites activates the
transcription of CSN2 gene. Deletion of the C terminus
of NF-kB abrogates the ability to induce CSN2 gene
expression (Wu et al., 2009).
Furthermore, CSN2/Alien gene expression in vivo is
activated by thyroid hormone receptor (TR) and thyroid
hormone suggesting a regulatory feedback mechanism
between TR and CSN2/Alien expression (Tenbaum et
al., 2003).
The CSN2 gene is localized on chromosome 15q21.2 (top panel). A homologous sequence is located on chromosome 9q33.2 (not shown).The gene structure highlights intron/exon arrangement, whereas red boxes display coding sequence (CDS) and grey the untranslated regions. The lower panel exhibits the CSN2/Alien cDNA. The green boxes indicate the 13 exons and the black line below illustrates the coding sequences CDS. The grey box in isoform 2 highlights the additional inserted 21bp stretch which is specific for this splice variant. Differential functions of these isoforms are not yet known. The italic numbers illustrate the base pairs.
COPS2 (COP9 constitutive photomorphogenic homolog subunit 2 (Arabidopsis)) Jennek S, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 689
Schematic structure of the CSN2 protein (modified according to Akiyama et al., 2003). The N-terminal region contains a region for interaction with DAX-1/NiF3l1 (aa 1-275). The central part of the protein includes the nuclear localization signal (NLS), a leucine zipper (LZ) domain and a corepressor region (CR) which contains an I/LXXI/VI motif. The C-terminal region contains a PCI domain, might be used for interaction between CSN subunits (reviewed in: Wei and Deng, 2003). The numbers represent the amino acids (aa).
Protein
Description
Three isoforms are known:
CSN2 short/Alien a: 305 amino acids (aa); 36 kDa
protein.
CSN2 long 1/Alien b1: 443 aa; 51.6 kDa protein.
CSN2 long 2/Alien b2: 450 aa; 52.4 kDa protein.
CSN2 activity can be regulated through
phosphorylation and dephosphorylation (Kapelari et al.,
2000).
Expression
Mouse Csn2 is widely expressed in embryonic, fetal
and adult tissues (Schaefer et al., 1998). Several mRNA
levels have been described in mice: 1,8 kb ; 2,2 kb ; 4
kb and 6 kb (Schaefer et al.,1998; Altincicek et al.,
2000; Tenbaum et al., 2003).
Localisation
CSN2 is localized in both the cytoplasm and the
nucleus, predominantly being localized in the nucleus
(Schaefer et al., 1998; Dressel et al., 1999; Tenbaum et
al., 2003).
Function
CSN2 short/Alien a acts as a corepressor for nuclear
hormone receptors (NHR). Originally in mammalians,
Alien was identified as an interacting protein of the
thyroid hormone receptor (TR) in a ligand-sensitive
manner (Lee et al., 1995). Moreover, Alien enhances
TR-mediated gene silencing through its autonomous
silencing function (Dressel et al., 1999). Additionally,
the vitamin D receptor (VDR), the androgen receptor
(AR) and the orphan receptor DAX-1 can also interact
with Alien. Functionally Alien enhances gene silencing
mediated by these nuclear receptors (Altincicek et al.,
2000; Polly et al., 2000; Moehren et al., 2007).
Notably, Alien seems to lack interaction with retinoid
X receptor (RXR), retinoid acid receptor (RAR),
estrogen receptor (ER), glucocorticoid receptor (GR)
and germ cell nuclear factor (GCNF) (Dressel et al.,
1999; Fuhrmann et al., 2000; reviewed in: Papaioannou
et al., 2007).
Also, corepression function was identified by CSN2
short/Alien a for transcription factors involved in cell
cycle regulation and DNA repair such as several
members of the E2F transcription factor family (Escher
et al., 2007; reviewed in: Papaioannou et al., 2007).
Alien is recruited to the E2F1 gene promoter repressing
endogenous E2F1 gene expression in vivo. The data
also suggest that Alien inhibits transactivation of E2F1,
a positive regulator of cell cycle progression. In line
with this, Alien represses cell cycle progression.
Remarkably, the inhibition of E2F1-mediated
transactivation is independent of retinoblastoma protein
pRB (Tenbaum et al., 2007). pRB represses E2F1
transcriptional activation. It is not yet known whether
Alien is able to substitute pRB function during cell
cycle progression (Tenbaum et al., 2007). Furthermore,
a direct interaction between Alien and pRB is detected.
Interestingly, a pRB-mutant lacking silencing function
also lacks interaction with CSN2 short/Alien (Escher et
al., 2007).
In addition, Alien interacts with the highly conserved
chromatin associated tumor suppressor proteins
Inhibitor of growth 1 (ING1b) and 2 (ING2) in vivo
and both p33ING1b and p33ING2 are known to induce
premature cellular senescence. It is shown that p33ING
proteins enhance Alien-mediated gene silencing
(Fegers et al., 2007).
The recruitment of HDAC-activity is one mechanism
by which Alien realizes its corepression functions
(Dressel et al., 1999). However, it is suggested that
Alien exhibits both HDAC-dependent and -independent
options for gene repression (reviewed in: Papaioannou
et al., 2007). Moreover, CSN2 short/Alien a interacts
with nucleosome assembly protein 1 (NAP1) in vivo
and in vitro regulating its activity through enhancing
NAP1-mediated nucleosome assembly on DNA and
thereby leading to gene repression (Eckey et al., 2007).
The CSN2 long/Alien b isoform is an essential part of
the COP9 signalosome (CSN) complex which is highly
conserved in eukaryotes and consists of eight subunits
(reviewed in: Wie et al., 2008). The CSN complex
plays a central role in the regulation of degradation of
multiple proteins through the ability to de-neddylate
cullin, which enables the association of cullin with
CAND1, a negative regulator of the cullin-based E3
ubiquitin ligases (reviewed in: von Arnim, 2003;
reviewed in: Wolf et al., 2003; Chamovitz, 2009; Wu et
al., 2009). A role for CSN2 long/Alien b is suggested
by the interaction between CSN2 and subunits of the
26S proteasome was already shown (Huang et al.,
2005). The promoter region of the Csn2 gene contains
NF-kB binding sites like other CSN subunits.
COPS2 (COP9 constitutive photomorphogenic homolog subunit 2 (Arabidopsis)) Jennek S, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 690
Accordingly, these members of the CSN complex are
regulated by NF-kB. Snail, a transcription factor, which
is a part of the TGF-b pathway and is involved in
inflammatory-triggered migration, invasiveness and
metastasis of tumor cells, is stabilized by the induction
of the CSN complex via NF-kB (Wu et al., 2009).
There are also COP9 subcomplexes with yet unknown
functions (reviewed in: Wei et al, 2008).
Interaction of COP9 via CSN2 with p53 in tumors can
raise the stability of p53, the most important protein
involving in a variety of essential tumor suppressive
functions and induction of cellular senescence. But in
contrast to Snail, the lower turnover does not lead to an
increase in transcription activity and therefore neither
to an increased p21 expression nor to cell cycle arrest
(Leal et al., 2008).
Moreover, CSN2 protein interacts physically with the
anaphase-promoting complex (APC/C), a major
regulator of the cell cycle and affects specifically its
stability (Kob et al., 2008).
Homology
CSN2 is a highly conserved protein from humans to
Drosophila (Dressel et al., 1999). CSN2 has
homologies in any multicellular organism including
plants. It is over 60% identical between animal and
plant counterparts (Wei and Deng, 2003;
Schwechheimer, 2004).
Originally, the name Alien was given to a gene in the
Drosophila genome with an unknown function
(Goubeaud et al., 1996). It shares high homologies with
Thyroid hormone receptor-interacting protein 15
(TRIP15), a mammalian protein (Lee et al., 1995;
Dressel et al., 1999).
Mutations
Note
So far natural occurring point mutations of CSN2 in
association with cancer and other disease were not yet
described.
Implicated in
Human tumors
Oncogenesis
Aberrant expression of CNS2/Alien seems to be
associated with human tumors. CSN2 expression is lost
in several human tumors. In thyroid tumors the loss of
CSN2 is at least 50% (Leal et al., 2008). Moreover,
high percentages of reduction (15-30%) of CSN2
mRNA level were observed in tumors of pancreas,
breast, ovary, kidney, uterus und rectum (Leal et al.,
2008).
It was shown by quantitative analysis that the CSN2
expression is reduced up to 50% in tumors of prostate,
lung and colon (Leal et al., 2008).
References Lee JW, Choi HS, Gyuris J, Brent R, Moore DD. Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. Mol Endocrinol. 1995 Feb;9(2):243-54
Goubeaud A, Knirr S, Renkawitz-Pohl R, Paululat A. The Drosophila gene alien is expressed in the muscle attachment sites during embryogenesis and encodes a protein highly conserved between plants, Drosophila and vertebrates. Mech Dev. 1996 Jun;57(1):59-68
Dressel U, Thormeyer D, Altincicek B, Paululat A, Eggert M, Schneider S, Tenbaum SP, Renkawitz R, Baniahmad A. Alien, a highly conserved protein with characteristics of a corepressor for members of the nuclear hormone receptor superfamily. Mol Cell Biol. 1999 May;19(5):3383-94
Altincicek B, Tenbaum SP, Dressel U, Thormeyer D, Renkawitz R, Baniahmad A. Interaction of the corepressor Alien with DAX-1 is abrogated by mutations of DAX-1 involved in adrenal hypoplasia congenita. J Biol Chem. 2000 Mar 17;275(11):7662-7
Kapelari B, Bech-Otschir D, Hegerl R, Schade R, Dumdey R, Dubiel W. Electron microscopy and subunit-subunit interaction studies reveal a first architecture of COP9 signalosome. J Mol Biol. 2000 Jul 28;300(5):1169-78
Polly P, Herdick M, Moehren U, Baniahmad A, Heinzel T, Carlberg C. VDR-Alien: a novel, DNA-selective vitamin D(3) receptor-corepressor partnership. FASEB J. 2000 Jul;14(10):1455-63
Fuhrmann G, Chung AC, Jackson KJ, Hummelke G, Baniahmad A, Sutter J, Sylvester I, Schöler HR, Cooney AJ. Mouse germline restriction of Oct4 expression by germ cell nuclear factor. Dev Cell. 2001 Sep;1(3):377-87
Akiyama H, Fujisawa N, Tashiro Y, Takanabe N, Sugiyama A, Tashiro F. The role of transcriptional corepressor Nif3l1 in early stage of neural differentiation via cooperation with Trip15/CSN2. J Biol Chem. 2003 Mar 21;278(12):10752-62
Tenbaum SP, Juenemann S, Schlitt T, Bernal J, Renkawitz R, Muñoz A, Baniahmad A. Alien/CSN2 gene expression is regulated by thyroid hormone in rat brain. Dev Biol. 2003 Feb 1;254(1):149-60
von Arnim AG. On again-off again: COP9 signalosome turns the key on protein degradation. Curr Opin Plant Biol. 2003 Dec;6(6):520-9
Wei N, Deng XW. The COP9 signalosome. Annu Rev Cell Dev Biol. 2003;19:261-86
Wolf DA, Zhou C, Wee S. The COP9 signalosome: an assembly and maintenance platform for cullin ubiquitin ligases? Nat Cell Biol. 2003 Dec;5(12):1029-33
Schwechheimer C. The COP9 signalosome (CSN): an evolutionary conserved proteolysis regulator in eukaryotic development. Biochim Biophys Acta. 2004 Nov 29;1695(1-3):45-54
Huang X, Hetfeld BK, Seifert U, Kähne T, Kloetzel PM, Naumann M, Bech-Otschir D, Dubiel W. Consequences of COP9 signalosome and 26S proteasome interaction. FEBS J. 2005 Aug;272(15):3909-17
Eckey M, Hong W, Papaioannou M, Baniahmad A. The nucleosome assembly activity of NAP1 is enhanced by Alien. Mol Cell Biol. 2007 May;27(10):3557-68
COPS2 (COP9 constitutive photomorphogenic homolog subunit 2 (Arabidopsis)) Jennek S, et al.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 691
Escher N, Kob R, Tenbaum SP, Eisold M, Baniahmad A, von Eggeling F, Melle C. Various members of the E2F transcription factor family interact in vivo with the corepressor alien. J Proteome Res. 2007 Mar;6(3):1158-64
Fegers I, Kob R, Eckey M, Schmidt O, Goeman F, Papaioannou M, Escher N, von Eggeling F, Melle C, Baniahmad A. The tumor suppressors p33ING1 and p33ING2 interact with alien in vivo and enhance alien-mediated gene silencing. J Proteome Res. 2007 Nov;6(11):4182-8
Papaioannou M, Melle C, Baniahmad A. The coregulator Alien. Nucl Recept Signal. 2007 Nov 30;5:e008
Tenbaum SP, Papaioannou M, Reeb CA, Goeman F, Escher N, Kob R, von Eggeling F, Melle C, Baniahmad A. Alien inhibits E2F1 gene expression and cell proliferation. Biochim Biophys Acta. 2007 Sep;1773(9):1447-54
Leal JF, Fominaya J, Cascón A, Guijarro MV, Blanco-Aparicio C, Lleonart M, Castro ME, Ramon Y Cajal S, Robledo M,
Beach DH, Carnero A. Cellular senescence bypass screen identifies new putative tumor suppressor genes. Oncogene. 2008 Mar 27;27(14):1961-70
Chamovitz DA. Revisiting the COP9 signalosome as a transcriptional regulator. EMBO Rep. 2009 Apr;10(4):352-8
Kob R, Kelm J, Posorski N, Baniahmad A, von Eggeling F, Melle C. Regulation of the anaphase-promoting complex by the COP9 signalosome. Cell Cycle. 2009 Jul 1;8(13):2041-9
Wu Y, Deng J, Rychahou PG, Qiu S, Evers BM, Zhou BP. Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell. 2009 May 5;15(5):416-28
This article should be referenced as such:
Jennek S, Kraft F, Baniahmad A. COPS2 (COP9 constitutive photomorphogenic homolog subunit 2 (Arabidopsis)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):688-691.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 692
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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t(3;6)(q27;p21) Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0306q27p21ID2155.html DOI: 10.4267/2042/44806
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: In only two cases were the hybrid genes
uncovered: a PIM1/BCL6 was found in one case
(Yoshida et al., 1999), and a SFRS3/BCL6 in another
case (Chen et al., 2001). These cases will also be
described separately.
Clinics and pathology
Disease
Non Hodgkin lymphoma (NHL).
Epidemiology
Seven cases available: 3 cases of follicular lymphoma
(FL), 3 cases of diffuse large B-cell lymphoma
(DLBCL), and one NHL not otherwise specified. Very
few data available: 4 male / 2 female patients, aged 49-
79 years (Ohno et al., 1994; Miura et al., 1996; Yoshida
et al., 1999; Chen et al., 2001; Varga et al., 2001;
Keller et al., 2006).
Cytogenetics
Cytogenetics morphological
The t(3;6) was the sole anomaly in one case (a FL
case), accompanied with +X in a subclone and +21 in
another in the other FL case, found within a complex
karyotype in the 4 remainind cases with cytogenetic
data. Other additional anomalies of note were: del(7q),
t(14;18)(q32;q21) (2 cases each) and t(1;14)(q21;q32),
del(1q), del(5q) (1 case each).
Genes involved and proteins
BCL6
Location
3q27
Protein
706 amino acids; composed of a NH2-term BTB/POZ
domain (amino acids 1-130 (32-99 according to Swiss-
Prot)) which mediates homodimerization and protein-
protein interactions with other corepressors (including
HDAC1 and NCOR2/SMRT) to constitute a large
repressing complex, another transcription repression
domain (191-386), PEST sequences (300-417) with a
KKYK motif (375-379), and six zinc finger at the C-
term (518-541, 546-568, 574-596, 602-624, 630-652,
658-681), responsible for sequence specific DNA
binding. Transcription repressor; recognizes the
consensus sequence: TTCCT(A/C)GAA (Albagli-
Curiel, 2003).
References Ohno H, Kerckaert JP, Bastard C, Fukuhara S. Heterogeneity in B-cell neoplasms associated with rearrangement of the LAZ3 gene on chromosome band 3q27. Jpn J Cancer Res. 1994 Jun;85(6):592-600
Miura I, Ohshima A, Takahashi N, Hashimoto K, Nimura T, Utsumi S, Saito M, Miki T, Hirosawa S, Miura AB. A new non-random chromosomal translocation t(3;6)(q27;p21.3) associated with BCL6 rearrangement in two patients with non-Hodgkin's lymphoma. Int J Hematol. 1996 Oct;64(3-4):249-56
Yoshida S, Kaneita Y, Aoki Y, Seto M, Mori S, Moriyama M. Identification of heterologous translocation partner genes fused to the BCL6 gene in diffuse large B-cell lymphomas: 5'-RACE and LA - PCR analyses of biopsy samples. Oncogene. 1999 Dec 23;18(56):7994-9
Chen W, Itoyama T, Chaganti RS. Splicing factor SRP20 is a novel partner of BCL6 in a t(3;6)(q27;p21) translocation in transformed follicular lymphoma. Genes Chromosomes Cancer. 2001 Nov;32(3):281-4
Varga AE, Dobrovic A, Webb GC, Hutchinson R. Clustering of 1p36 breakpoints distal to 1p36.2 in hematological malignancies. Cancer Genet Cytogenet. 2001 Feb;125(1):78-9
Albagli-Curiel O. Ambivalent role of BCL6 in cell survival and transformation. Oncogene. 2003 Jan 30;22(4):507-16
t(3;6)(q27;p21) Huret JL
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 693
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
This article should be referenced as such:
Huret JL. t(3;6)(q27;p21). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):692-693.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 694
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
t(3;6)(q27;p21) PIM1/BCL6 Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0306q27p21ID2088.html DOI: 10.4267/2042/44807
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: t(3;6)(q27;p21) has been described in a few cases
were PIM1/BCL6 rearrangement has not been
ascertained, or were another hybrid gene has been
uncovered.
Clinics and pathology
Disease
Non Hodgkin lymphoma (NHL).
Epidemiology
Only one case available: a case of diffuse large B-cell
lymphoma (DLBCL) (Yoshida et al., 1999).
Genes involved and proteins
BCL6
Location
3q27
Protein
706 amino acids; composed of a NH2-term BTB/POZ
domain (amino acids 1-130 (32-99 according to Swiss-
Prot)) which mediates homodimerization and protein-
protein interactions with other corepressors (including
HDAC1 and NCOR2/SMRT) to constitute a large
repressing complex, another transcription repression
domain (191-386), PEST sequences (300-417) with a
KKYK motif (375-379), and six zinc finger at the C-
term (518-541, 546-568, 574-596, 602-624, 630-652,
658-681), responsible for sequence specific DNA
binding.
Transcription repressor; recognizes the consensus
sequence: TTCCT(A/C)GAA (Albagli-Curiel, 2003).
PIM1
Location
6p21.2
Protein
404 amino acids; serine/threonine-protein kinase;
regulated by hematopoietic cytokine receptors; synergy
with c-MYC in cell proliferation and in apoptosis
induction through an enhancement of the activation of
caspase-3-like proteases; Cdc25A (cell cycle
phosphatase) is a substrate for Pim-1.
Result of the chromosomal anomaly
Hybrid gene
Description
5' PIM1 - 3' BCL6, but also 5' BCL6 - 3' PIM1;
breakpoint in BCL6 between exon 1 and 2.
References Yoshida S, Kaneita Y, Aoki Y, Seto M, Mori S, Moriyama M. Identification of heterologous translocation partner genes fused to the BCL6 gene in diffuse large B-cell lymphomas: 5'-RACE and LA - PCR analyses of biopsy samples. Oncogene. 1999 Dec 23;18(56):7994-9
Albagli-Curiel O. Ambivalent role of BCL6 in cell survival and transformation. Oncogene. 2003 Jan 30;22(4):507-16
This article should be referenced as such:
Huret JL. t(3;6)(q27;p21) PIM1/BCL6. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):694.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 695
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
t(3;6)(q27;p21) SFRS3/BCL6 Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0306q27p21ID1336.html DOI: 10.4267/2042/44808
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: t(3;6)(q27;p21) has been described in a few cases
where SFRS3/BCL6 rearrangement has not been
ascertained, or where another hybrid gene has been
uncovered.
Clinics and pathology
Disease
Non Hodgkin lymphoma (NHL).
Epidemiology
Only one case available: a case of follicular lymphoma
(FL) (Chen et al., 2001).
Cytogenetics
Cytogenetics morphological
The t(3;6) was accompanied with del(1q), del(7q),
t(14;18)(q32;q21) and other anomalies.
Genes involved and proteins
BCL6
Location
3q27
Protein
706 amino acids; composed of a NH2-term BTB/POZ
domain (amino acids 1-130 (32-99 according to Swiss-
Prot)) which mediates homodimerization and protein-
protein interactions
with other corepressors (including HDAC1 and
NCOR2/SMRT) to constitute a large repressing
complex, another transcription repression domain (191-
386), PEST sequences (300-417) with a KKYK motif
(375-379), and six zinc finger at the C-term (518-541,
546-568, 574-596, 602-624, 630-652, 658-681),
responsible for sequence specific DNA binding.
Transcription repressor; recognizes the consensus
sequence: TTCCT(A/C)GAA (Albagli-Curiel, 2003).
SFRS3
Location
6p21.3
Protein
164 amino acids (alternate splicing 124 aa); SFRS3 is a
member of the serine- and arginine-rich (SR) protein
family; comprise a RNA recognition motifs (RRM)
(amino acids 10-83) and an SR domain (aa 86-164)
according to Swiss-Prot; role in splicing of mRNA
precursors; promote the export of some cellular
mRNAs; possible role in cell cycle.
References Chen W, Itoyama T, Chaganti RS. Splicing factor SRP20 is a novel partner of BCL6 in a t(3;6)(q27;p21) translocation in transformed follicular lymphoma. Genes Chromosomes Cancer. 2001 Nov;32(3):281-4
Albagli-Curiel O. Ambivalent role of BCL6 in cell survival and transformation. Oncogene. 2003 Jan 30;22(4):507-16
This article should be referenced as such:
Huret JL. t(3;6)(q27;p21) SFRS3/BCL6. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):695.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 696
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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t(8;20)(p11;q13) Marie-Joëlle Mozziconacci, Christine Pérot
Institut Paoli-Calmettes, 232 Bd de Sainte-Marguerite, 13009 Marseille, France (MJM); Hôpital Saint-
Antoine, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France (CP)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t820p11q13ID1507.html DOI: 10.4267/2042/44809
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
Top. GTG and R-banded partial karyotypes. Bottom. FISH of metaphase chromosomes of t(8;20)(p11;q13) with digoxigenin-labeled RP11-313J18 (MYST3 at 8p11) and biotinylated RP11-1151C1 (5' and main part of NCOA3 region at 20q13) and RP11-122N8 (3' part of NCOA3 and SULF2 region at 20q13). Fused RP11-313J18 / RP11-1151C1+RP11-122N8 (red/green) signals are observed on der(8) and der(20) chromosomes. Courtesy of Christine Pérot and Marie-Joëlle Mozziconacci.
t(8;20)(p11;q13) Mozziconacci MJ, Pérot C
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 697
Clinics and pathology
Disease
Acute myeloid leukemia AML-M5 without features of
erythrophagocytosis.
Note
Only one case reported (a 75-year old woman). t(8;20)
as a sole abnormality.
Clinics
Splenomegaly, DIVC. Hyperleucocytosis, anemia and
thrombopenia.
Treatment
Hydroxyurea and low-dose cytosine-arabinoside.
Evolution
Death 2 months after diagnosis. No remission obtained.
Genes involved and proteins
MYST3 (MYST histone acetyltransferase (monocytic leukemia) 3)
Location
8p11
Note
MYST3 is a histone acetyltransferase (HAT) belonging
to the MYST family of HATs, that includes proteins
involved in cell cycle regulation, chromatin remodeling
and dosage compensation. MYST3 plays an important
role during hematopoiesis with his transcriptional
coregulator activity.
DNA/RNA
Breakpoint in intron 17.
Protein
MYST3 contains a LAP (Leukemia associated protein)
zinc finger domain, a HAT domain (Histone
acetyltransferase) and a acidic domain. 2004 amino
acids; 225 kDa.
NCOA3 (Nuclear Receptor Coactivator 3)
Location
20q13.1
Note
NCOA3 is a transcriptional coactivator that interacts
with nuclear hormone receptors and with other
transcription factors including TP52, NfkB and ER81.
It has intrinsic histone acetyltransferase activity and
recruits CREB Binding Protein (CBP)/p300 co-
integrators into multisubunit coactivator complexes.
DNA/RNA
Breakpoint in exon 13 (Δ45 bp).
Protein
Member of the p160/steroid receptor coactivator
family. 1424 amino acids; 155 kDa (130 kDa encoded
by isoform b).
Result of the chromosomal anomaly
Hybrid gene
Note
Both MYST3-NCOA3 and NCOA3-MYST3 are
expressed. Only the MYST3-NCOA3 fusion transcript
has an open reading frame that may generate a
functional chimeric protein.
Fusion protein
Note
The CREB-interacting domain in NCOA3 (1046-
1092aa) is conserved in the putative MYST3-NCOA3
fusion protein (at positions 1246-1292aa).
References Esteyries S, Perot C, Adelaide J, Imbert M, Lagarde A, Pautas C, Olschwang S, Birnbaum D, Chaffanet M, Mozziconacci MJ. NCOA3, a new fusion partner for MOZ/MYST3 in M5 acute myeloid leukemia. Leukemia. 2008 Mar;22(3):663-5
This article should be referenced as such:
Mozziconacci MJ, Pérot C. t(8;20)(p11;q13). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):696-697.
Solid Tumour Section Mini Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 698
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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Esophagus: Barrett's esophagus, dysplasia and adenocarcinoma DunFa Peng, Wael El-Rifai
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA (DP, WER)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Tumors/BarrettsEsophagID5591.html DOI: 10.4267/2042/44810
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: Barrett's adenocarcinoma is one of malignancies
with the most rapid increase in incidence during past
decades in the Western countries. It is defined as
adenocarcinoma of the lower esophagus and
gastroesophageal junction associated with Barrett's
esophagus. Barrett's esophagus is the only known
precursor for Barrett's adenocarcinoma through
Barrett's dysplasia (also called metaplasia-dysplasia-
adenocarcinoma sequence).
Clinics and pathology
Disease
Barrett's Esophagus
Note
Barrett's esophagus is defined as the normal esophageal
squamous epithelium that is replaced by intestinalized
metaplastic columnar epithelia.
Phenotype / cell stem origin
The progenitor cell from which Barrett's oesophagus
develops is still unclear. Progenitor cells resident in the
submucosal glands or the interbasal layer of the
epithelium, bone-marrow-derived stem cells, or
transdifferentiated squamous cells are included in the
candidate cells.
Etiology
Gastroesophageal reflux disease (GERD) is considered
the major risk factor for Barrett's esophagus. About 1 in
10 patients with GERD are found to have Barrett's
esophagus. GERD generates reactive oxygen species
that produce oxidative stress and subsequent oxidative
DNA damage. Some DNA damage may cause DNA
mutations that accumulate and cause tumor formation.
Epidemiology
Barrett's esophagus is more common in men than in
women, with a male:female ratio of about 2:1. The risk
factors of Barrett's esophagus include Age (increasing
with age), Race (more common in Caucasians),
smoking (not clear), alcohol consumption (not clear),
gastroesophageal reflux disease (GERD, major factor),
and obesity. On the other hand, some controversial
reports indicate that H. pylori infection and the virulent
cagA strains in particular, may protect against the
development of Barrett's oesophagus and progression
to adenocarcinoma.
Clinics
Heartburn is the most common symptom of GERD and
Barrett's esophagus.
Esophagus: Barrett's esophagus, dysplasia and adenocarcinoma Peng D, El-Rifai W
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 699
Normal esophagus is covered by squamous epithelia (A). However, in Barrett's esophagus (B), the squamous epithelia are replaced by intestinalized metaplastic columnar epithelia.
Disease
Barrett's dysplasia
Note
Barrett's dysplasia is defined morphologically as
unequivocal neoplastic epithelium that remains
confined within the basement membrane of the
epithelium from which it developed. In patients with
Barrett's esophagus, dysplasia is graded as either low or
high, depending on its cytological and architectural
features.
Epidemiology
Most Barrett's esophagus never progress to dysplasia
and carcinoma. It has been reported that the male
gender, longstanding gastroesophageal reflux disease,
hiatal hernia size, and segment length are strongly
associated with Barrett's dysplasia. On the other hand,
successful antireflux surgery protects the Barrett's
mucosa from developing high-grade dysplasia and
esophageal adenocarcinoma.
Disease
Barrett's adenocarcinoma
Note
Adenocarcinoma of lower esophagus and
gastroesophageal junction associated with Barrett's
esophagus through metaplasia-dysplasia-
adenocarcinoma sequence.
Classification: Tumor classification is based on UICC
TNM classification for esophageal cancers.
Etiology
Barrett's esophagus with dysplasia
Epidemiology
Barrett's esophagus is the only known precursor for
Barrett's adenocarcinoma. The patients with Barrett's
esophagus have 20 folds more risk for developing
esophageal adenocarcinoma. However, only 1-5% of
Barrett's esophagus progress to Barrett's
adenocarcinoma. Although longstanding
gastroesophageal reflux disease, hiatal hernia size,
Esophagus: Barrett's esophagus, dysplasia and adenocarcinoma Peng D, El-Rifai W
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 700
A representative image of a Barrett's adenocarcinoma with moderate to poor differentiation. Atypic tumor cells form quite irregular tubules and some form solid cord.
and segment length are strongly associated with
adenocarcinoma, Barrett's esophagus with dysplasia is
likely the true precursor for developing to
adenocarcinoma.
Clinics
Heartburn is the most common symptom of GERD and
Barrett's esophagus. As for Barrett's adenocarcinoma, it
shares the symptoms with other esophageal type
cancers, such as difficulty swallowing, unexplained
weight loss, pain in the throat or mid-chest, etc.
Pathology
There is no difference in the term of histology of
Barrett's adenocarcinoma from that in the stomach and
colon. It can be graded into well-, moderately- and
poorly-differentiated adenocarcinoma based on their
cytologic and architectural atypia. The Lauren
classification for gastric cancer has also been used by
some pathologists and physicians to divide into either
intestinal or diffuse histological type.
Treatment
Esophagectomy is still the most common primary
treatment. Other treatment modalities include
chemotherapy, radiation therapy, stents, photodynamic
therapy, and endoscopic therapy with an Nd:YAG
laser. Combined modality therapy (i.e., chemotherapy
plus surgery or chemotherapy and radiation therapy
plus surgery) is under clinical evaluation.
Prognosis
The prognosis of Barrett's adenocarcinoma depends on
the stage at diagnosis, treatment and the patients'
general condition. The overall 5-year survival rate in
patients amenable to definitive treatment ranges from 5
to 30%.
Cytogenetics
Note
The chromosomal alterations most frequently identified
in Barrett's adenocarcinoma by CGH were: gains in 8q
(80%), 20q (60%); 2p, 7p and 10q (47% each), 6p
(37%), 15q (33%), and 17q (30%). Losses were
observed predominantly in the 4q (50%); 5q and 9p
(43% each), 18q (40%), 7q (33%), and 14q (30%).
Genes involved and proteins
Note
There are many genes that have been reported to be
genetically and/or epigenetically dysregulated, such as
gene mutation, amplification, and LOH and DNA
methylation that involved cell cycle control, apoptosis,
cell adhesion and antioxidative stress, etc. Some
representative genes are described below.
ERBB2 (HER2/neu)
Location
17q21
Note
ERBB2 protein over-expression and/or DNA
amplification have been reported in 10-70% of
esophageal adenocarcinomas. The present literature
data suggest that ERBB2 overexpression may be a late
event in the dysplasia-carcinoma sequence, as it
occurred predominantly in high-grade dysplasia and
adenocarcinomas.
Esophagus: Barrett's esophagus, dysplasia and adenocarcinoma Peng D, El-Rifai W
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 701
CGH analysis of a case of Barrett's esophageal adenocarcinoma. Tumor DNA was labeled with FITC (Green) and reference DNA was labeled with TRITC (red). The hybridizations were analyzed using an Olympus fluorescence microscope and the ISIS digital image analysis system (Metasystems GmbH, Altlussheim, Germany) based on integrated high-sensitivity monochrome CCD camera and automated CGH analysis software. The green colon indicates areas of DNA gains whereas the red color indicates DNA losses in the tumor sample.
It has been reported that ERBB2 over-
expression/amplification in carcinoma correlated
significantly with tumor invasion, lymph node
metastasis, and poor prognosis in patients with Barrett's
related adenocarcinoma.
Protein
The ERBB2 (also called HER2 or NEU) gene encodes
an integral type I protein of 185 kDa, 1255 amino
acids, with a cysteine-rich extracellular ligand-binding
domain, a transmembrane domain and an intracellular
region endowed with a tyrosine kinase activity.
C-MYC
Location
8q24
Note
Frequent high-level chromosomal amplification of
8q21 has been reported in Barrett's adenocarcinoma
and c-myc is the potential target gene for this
amplification.
It has been reported that amplification of c-myc was
detected in 25% of high-grade dysplasia and 44% of
adenocarcinomas, but in none of Barrett's metaplasia
and low-grade dysplasia.
Protein
DNA binding protein with 439 amino acids and 48 kDa
(p64); 454 amino acids (p67, 15 additional amino acids
in N-term), contains a transactivation domain, an acidic
domain, a nuclear localization signal, a basic domain, a
helix-loop-helix motif, and a leucin zipper.
CDX1
Location
5q33.1
Note
CDX1 is predominantly expressed in the small intestine
and colon, but not in normal esophageal squamous
epithelia or gastric epithelia.
CDX1 was over-expressed in Barrett's esophagus and
adenocarcinomas, most likely through promoter DNA
hypomethylation.
Protein
Member of the caudal-related homeobox transcription
factor gene family. The encoded protein regulates
intestine-specific gene expression and differentiation of
intestine.
CDX2
Location
13q12.2
Note
CDX2 is predominantly expressed in the small intestine
and colon, but not in normal esophageal squamous
epithelia or gastric epithelia.
CDX2 expression is observed in the intestinal
metastasis area.
Esophagus: Barrett's esophagus, dysplasia and adenocarcinoma Peng D, El-Rifai W
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 702
Protein
Member of the caudal-related homeobox transcription
factor gene family.
The encoded protein regulates intestine-specific gene
expression and differentiation of intestine. It is
suggested that CDX2 is a "master switch" gene whose
normal expression determines the proximal and distal
specialization of the gut in embryogenesis.
CDKN2A (p16)
Location
9p21.3
Note
Tumor suppressor gene controls the G1/S transition of
the cell cycle. Inactivation of CDKN2A is among the
most common genetic/epigenetic alterations through
Barrett's carcinogenesis and is an early event. LOH,
promoter hypermethylation, or sequence mutations
have been reported in over 85% of Barrett's esophagus
that were associated with p16 inactivation.
DNA / RNA
7288 bp.
Exon Count: 3.
Protein
Tumor suppressor protein having 156 aa, functions as
an inhibitor of CDK4 kinase in cell cycle G1 control.
TP53
Location
17p13
Note
Loss of p53 occurs through either LOH, sequence
mutation, or both. Loss of p53 has been reported in
Barrett's esophagus and likely correlates with
progression to adenocarcinoma, as patients with LOH
in TP53 are 16 times more likely to progress to
adenocarcinoma than patients without TP53 LOH.
DNA / RNA
Exon Count: 11.
Protein
A tumor suppressor protein essential in cell cycle
regulation and in DNA damage repair. p53
transcriptionally regulates multiple genes functioning
as an inhibitor of cell growth and proliferation and
inducer of apoptosis. Loss of TP53 functions promotes
tumor progression, most likely by preventing cell cycle
arrest, suppressing apoptosis and permitting genetic
instability for subsequent genetic alterations.
CDKN1B (p27)
Location
12p13
Note
It has been reported that in 83% of Barrett's
adenocarcinomas, p27 protein was down-regulated by
an immunohistochemical study. And for p27 to arrest
cell cycle, it must localize in the nucleus. However, in
approximately 50% of high-grade dysplasia, p27 was
observed in cytoplasmic localization, which renders it
inactive.
Protein
A tumor suppressor protein essential in cell cycle
regulation, a CDK inhibitor.
GPX3
Location
5q33.1
Note
GPX3 is one of the glutathione peroxidase family
members, which functions in the detoxification of
hydrogen peroxide. Frequent GPX3 gene promoter
hypermethylation has recently been demonstrated in
Barrett's adenocarcinomas and its precancerous lesions,
Barrett's esophagus and dysplasia, and was
significantly associated with gene down-regulation. It
is noted that GPX3 has been recently reported as a
potential tumor suppressor in prostatic carcinomas.
Protein
GPX3 is a secretory protein.
GPX7
Location
1p32.3
Note
GPX7 is one of the glutathione peroxidase family
members which function in the detoxification of
hydrogen peroxide. Unlike other glutathione peroxidase
family members, GPX7 incorporates cysteine instead
of selenocysteine in the conserved catalytic motif.
Frequent GPX7 gene promoter hypermethylation has
recently been demonstrated in Barrett's
adenocarcinomas and its precancerous lesion, Barrett's
dysplasia, and was significantly associated with gene
down-regulation. Recent research indicates that GPX7
may have dual functions, antioxidative activity and
tumor suppressor function in Barrett's adenocarcinoma.
DNA / RNA
Genomic Size: 6679.
Exon Count: 3.
Coding Exon Count: 3.
MGMT
Location
10q26.3
Note
It is recently reported that hypermethylation was
detected in 78.9% of esophageal adenocarcinomas, in
100% of Barrett's intraepithelial neoplasia, in 88.9% of
Barrett's metaplasia, in only 21.4% of normal
esophageal mucosa samples (P<0.001), and correlated
significantly with the down-regulation of MGMT
transcripts (P=0.048) and protein expression (P=0.02).
The decrease of protein expression was significantly
Esophagus: Barrett's esophagus, dysplasia and adenocarcinoma Peng D, El-Rifai W
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 703
correlated with progressed stage of disease, lymph node
invasion and tumor size.
DNA / RNA
Genomic Size: 299903.
Exon Count: 5.
Coding Exon Count: 4.
Protein
O6-methylguanine-DNA methyltransferase is involved
in the cellular defense against the biological effects of
O6-methylguanine (O6-MeG) in DNA. It repairs
alkylated guanine in DNA by stoichiometrically
transferring the alkyl group at the O6 position to a
cysteine residue in the enzyme.
APC
Location
5q21
Note
LOH of 5q has been reported as a higher occurrence in
high-grade dysplasia and adenocarcinomas of the
esophagus. Hypermethylation of the APC gene has
been found in 68-100% of Barrett's adenocarcinomas
and approximately 50% of Barrett's esophagus. More
importantly, hypermethylation of APC with other genes
such as p16, strongly predicts progression to high-grade
dysplasia or cancer in patients with BE. Absence of p16
and APC hypermethylation is associated with a benign
course.
DNA / RNA
Genomic Size: 138719.
Exon Count: 16.
Coding Exon Count: 15.
Protein
Adenomatous polyposis coli protein which possesses
tumor suppressor functions, works as an antagonist of
the Wnt signaling pathway. APC binding to beta
catenin leads to ubiquitin-mediated beta catenin
destruction; loss of APC function increases
transcription of beta catenin targets, such as C-MYC
and Cyclin D. It is also involved in other processes
including cell migration and adhesion, transcriptional
activation, and apoptosis. Germline defects in this gene
cause familial adenomatous polyposis (FAP), an
autosomal dominant pre-malignant disease that usually
progresses to malignancy. Disease-associated
mutations tend to be clustered in a small region
designated the mutation cluster region (MCR) and
result in a truncated protein product.
References BARRETT NR. The lower esophagus lined by columnar epithelium. Surgery. 1957 Jun;41(6):881-94
El-Rifai W, Frierson HF Jr, Moskaluk CA, Harper JC, Petroni GR, Bissonette EA, Jones DR, Knuutila S, Powell SM. Genetic differences between adenocarcinomas arising in Barrett's esophagus and gastric mucosa. Gastroenterology. 2001 Sep;121(3):592-8
Bian YS, Osterheld MC, Fontolliet C, Bosman FT, Benhattar J. p16 inactivation by methylation of the CDKN2A promoter occurs early during neoplastic progression in Barrett's esophagus. Gastroenterology. 2002 Apr;122(4):1113-21
Koppert LB, Wijnhoven BP, van Dekken H, Tilanus HW, Dinjens WN. The molecular biology of esophageal adenocarcinoma. J Surg Oncol. 2005 Dec 1;92(3):169-90
Lee OJ, Schneider-Stock R, McChesney PA, Kuester D, Roessner A, Vieth M, Moskaluk CA, El-Rifai W. Hypermethylation and loss of expression of glutathione peroxidase-3 in Barrett's tumorigenesis. Neoplasia. 2005 Sep;7(9):854-61
Oberg S, Wenner J, Johansson J, Walther B, Willén R. Barrett esophagus: risk factors for progression to dysplasia and adenocarcinoma. Ann Surg. 2005 Jul;242(1):49-54
Wong A, Fitzgerald RC. Epidemiologic risk factors for Barrett's esophagus and associated adenocarcinoma. Clin Gastroenterol Hepatol. 2005 Jan;3(1):1-10
Fitzgerald RC. Molecular basis of Barrett's oesophagus and oesophageal adenocarcinoma. Gut. 2006 Dec;55(12):1810-20
Maley CC. Multistage carcinogenesis in Barrett's esophagus. Cancer Lett. 2007 Jan 8;245(1-2):22-32
Razvi MH, Peng D, Dar AA, Powell SM, Frierson HF Jr, Moskaluk CA, Washington K, El-Rifai W. Transcriptional oncogenomic hot spots in Barrett's adenocarcinomas: serial analysis of gene expression. Genes Chromosomes Cancer. 2007 Oct;46(10):914-28
Kuester D, El-Rifai W, Peng D, Ruemmele P, Kroeckel I, Peters B, Moskaluk CA, Stolte M, Mönkemüller K, Meyer F, Schulz HU, Hartmann A, Roessner A, Schneider-Stock R. Silencing of MGMT expression by promoter hypermethylation in the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus. Cancer Lett. 2009 Mar 8;275(1):117-26
Peng DF, Razvi M, Chen H, Washington K, Roessner A, Schneider-Stock R, El-Rifai W. DNA hypermethylation regulates the expression of members of the Mu-class glutathione S-transferases and glutathione peroxidases in Barrett's adenocarcinoma. Gut. 2009 Jan;58(1):5-15
This article should be referenced as such:
Peng D, El-Rifai W. Esophagus: Barrett's esophagus, dysplasia and adenocarcinoma. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):698-703.
Solid Tumour Section Review
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 704
Atlas of Genetics and Cytogenetics in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Head and neck: Retinoblastoma Hayyam Kiratli, Berçin Tarlan
Ocular Oncology Service, Department of Ophthalmology, Hacettepe University School of Medicine, Ankara,
Turkey (HK, BT)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Tumors/RetinoblastomID5008.html DOI: 10.4267/2042/44811
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Alias
Retinal glioma; Fungus hematodes
Note
Retinoblastoma is a malignant primary intraocular
tumor predominantly encountered in infancy and early
childhood. Another striking definition of
retinoblastoma is that it is a childhood cancer that can
be completely cured with radiotherapy alone. This
tumor develops from the retina and by the age of 5
years, 90% of cases are diagnosed.
Classification
Note
Retinoblastoma is evaluated on genetic basis, laterality
and focality. Approximately 85% of
retinoblastomas are sporadic and 15% of cases are
familial. Unilateral tumors account for 60% of cases
and bilateral involvement is seen in 40% of patients.
Eighty-five percent of unilateral tumors have somatic
mutations and 15% have germinal mutations.
Conversely, 90% of bilateral tumors have germinal
mutations and 10 have postzygotic somatic mutations.
When both eyes are involved multifocality is the rule.
There is an average of five tumors per eye in bilateral
cases. Trilateral retinoblastoma is a rare and often
lethal condition in which there is an undifferentiated
neuroectodermal tumor in the pineal gland or in
para/supra sellar region of the midbrain. Ninety percent
of pinealoblastomas develop in patients with bilateral
disease. Unilateral cases have a 0.5% risk of
developing trilateral retinoblastoma.
Group I a. Solitary tumor, less than 4 disc diameters in size, at or behind the equator.
b. Multiple tumors, none over 4 disc diameters in size, all at or behind the equator.
Group II a. Solitary tumor, 4 to 10 disc diameters in size, at or behind the equator.
b. Multiple tumors, 4 to 10 disc diameters in size, behind the equator.
Group III a. Any lesion anterior to the equator.
b. Solitary tumors larger than 10 disc diameters behind the equator.
Group IV a. Multiple tumors some larger than 10 disc diameters.
b. Any lesion extending anteriorly to the ora serrata.
Group V a. Massive tumors involving half of the retina.
b. Vitreous seeding.
Table 1. Reese-Ellsworth classification for intraocular retinoblastoma.
Group A All tumors ≤ 3mm, confined to the retina, at least 3 mm from the foveola, 1.5 mm from the disc. No
Head and neck: Retinoblastoma Kiratli H, Tarlan B
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 705
vitreous or subretinal seeding. (Very low risk).
Group B Discrete retinal tumor of any size and location without vitreous or subretinal seeding. Subretinal fluid
extending ≤ 5mm from the tumor base is allowed. (Low risk).
Group C Discrete retinal tumors of any size and location with focal vitreous or subretinal seeding treatable with
brachytherapy. One quadrant of subretinal fluid is allowed. (Moderate risk).
Group D Diffuse vitreous or subretinal seeding associated with massive, nondiscrete endophytic or exophytic
tumor. > 1 quadrant of retinal detachment. (High risk).
Group E
Eyes destroyed anatomically and functionally by: neovascular glaucoma, intraocular hemorrhage, tumor
in the anterior vitreous, tumor touching the lens, aseptic orbital cellulitis, diffuse type retinoblastoma,
phthisis bulbi. (Very high risk).
Table 2. International Classification of Retinoblastoma (Murphree).
Clinics and pathology
Note
Leukocoria (white reflex from the pupillary aperture)
(60%) and strabismus (20%) are the two major
presenting signs of retinoblastoma (see Figure 1A).
Rarely patients may present with buphthalmus, pseudo-
hypopyon, hyphema, vitreous hemorrhage, and pseudo-
orbital cellulitis. A typical retinoblastoma is a round or
oval shaped, variably vascularized pink mass. It may
sometimes appear chalky white because of
calcification. Endophytic retinoblastoma grows into the
vitreous cavity and accounts for 60% of typical
retinoblastomas (see Figure 1B).
Exophytic tumors (39%) grow under the subretinal
space and cause retinal detachment. Rarely the tumor
may show diffuse growth pattern (1%) in which there is
no detectable mass but a sheet-like dissemination of the
malignant cells within the retina. This latter type of
presentation usually occurs in older children. Currently,
the Reese-Ellsworth (RE) and International
Classification of Retinoblastoma (ICRB) systems are
used in staging the disease, which is very important in
treatment planning (see tables above).
Phenotype / cell stem origin
The cell of origin of retinoblastoma is a topic of hot
debate. In simple terms, the cell of origin is the cell in
which the tumor suppression activity of pRB is first
required. This may not necessarily be the cell in which
loss of RB1 gene occurs.
Several models and hypotheses exist on the cell of
origin. It was long believed that a retinal multipotent
cell committed to cone differentiation was the cell of
origin. Recent studies found strong expressions of
minimicrosome maintenance protein 2 (MCM2)
and ABCG2 (a casette-binding transmembrane protein
that confers drug resistance) on retinoblastoma cells
that favors a neural cancer stem cell origin. Also tumor
cells were found to express CD44 (hyaluronate
receptor), PROX1 and syntaxin 1A (retinal progenitor
markers), CD90 (retinal ganglion cell marker) and
CD133 (photoreceptor cell marker) all supporting the
cancer stem cell theory. Against the stem cell theory,
some studies showed expression of mature neural cell
markers including MAP2, NSE, synaptophysin and
opsin suggesting mature neural and amacrine cells as
the source of retinoblastoma. Others observed that a
fully differentiated retinal horizontal cell could reenter
the cell cycle and could form tumor foci.
Etiology
Inactivation of both wild type alleles of the
retinoblastoma susceptibility gene (RB1) is postulated
to cause the development of retinoblastoma.
Epidemiology
Retinoblastoma accounts for 4% of all pediatric cancers
and the cumulative incidence is 1/18000-30000 live
births per year regardless of sex, race or geographic
predilection. Each year, 5000 to 8000 new cases of
retinoblastoma are diagnosed on the global scale.
Retinoblastoma is responsible for 1% of all deaths
below 15 years of age. The incidence of hereditary
retinoblastoma is relatively constant in various parts of
the world. However, there seems to be increased
incidence of non-hereditary sporadic retinoblastoma in
underdeveloped parts of the world. This was partly
related to the widely common human papilloma virus
infections in those areas. Advanced paternal age is also
associated with more sporadic gene mutations.
Head and neck: Retinoblastoma Kiratli H, Tarlan B
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 706
Figure 1 A. Left leukocoria in a 2 year-old child. B. A typical macular endophytic retinoblastoma with another small tumor nasal to the optic disc. C. A Flexner-Wintersteiner rosette with a clear lumen at the centre of the figure. D. Fleurettes within a well-differentiated retinoblastoma.
Pathology
Retinoblastoma is composed of small, round densely
packed cells with large hyperchromic nuclei and
basophilic cytoplasms. There may be vast areas of
necrosis and calcification because of rapid tumor
growth and insufficient blood supply. Various degrees
of photoreceptor differentiation are evidenced by
typical cellular arrangements. Flexner-Wintersteiner
rosettes are aggregates of cuboidal or columnar cells
around a central lumen, considered as an aborted
attempt to form photoreceptors (see Figure 1C).
A more advanced step towards photoreceptor formation
is the fleurette type rosettes. These are formed by tumor
cells with eosinophilic cellular extensions arranged in a
semicircular fashion with bulb-like endings. It is
believed that red and green cones participate in the
formation of these rosettes whereas blue cones tend to
form structures called bacillettes.
Histopathological demonstration of tumor cells 1 mm
beyond the lamina cribrosa, scleral invasion, clumps of
cells within more than 50% of choroidal thickness are
established risk factors for extraocular dissemination of
retinoblastoma. Increased intraocular pressure, iris
neovascularisation and buphthalmus are risk factors for
optic nerve invasion (see Figure 1D).
Treatment
Several options exist depending on the stage and
laterality of the tumor.
1. Chemotherapy: Systemic chemotherapy has
become the most commonly used method worldwide
within the past 10 years for almost all intraocular
retinoblastomas. The rationale is to shrink the tumor
(chemoreduction) so that subsequent local
consolidation treatments are used to further destroy the
tumor and thus avoid enucleation or external beam
radiotherapy.
In general, eyes having a potential of a useful vision
but containing large tumors untreatable with local
methods, children under the age of one year, and
advanced bilateral cases are eligible for
chemoreduction. Current protocols include vincristine,
carboplatin and etoposide or teniposide. A successful
outcome can be obtained in 100% of
Head and neck: Retinoblastoma Kiratli H, Tarlan B
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 707
Figure 2 A. RE IIIb or ICRB group C retinoblastoma before chemotherapy. B. The same eye shown above following 9 cycles of VEC chemoreduction protocol. C. Multiple small tumors easily treatable with TTT. D. Atrophic scars following TTT. E. Osteogenic sarcoma of the maxillary sinus 11 years after external beam radiotherapy.
group A, 93% in group B, 90% in group C, and 47% in
group D eyes. Most tumors regress more than 50%
within 3-4 weeks. The most important complication of
chemoreduction therapy is recurrence of the tumor,
which is more common in macular tumors. Also, new
ocular tumors may develop while under systemic
chemotherapy. Transient myelosuppression, cytopenia
and neutropenia occur in 100% of patients. The
Head and neck: Retinoblastoma Kiratli H, Tarlan B
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 708
development of secondary non-ocular cancers
following chemotherapy is an unresolved issue.
Preliminary studies suggest an increased incidence of
AML particularly in patients who had received
teniposide, which acts on chromosome 11q35. (see
Figure 2A and 2B).
2. Local chemotherapy: Local administration of
chemotherapeutic agents is in use to deliver higher
concentrations of the drug into the eye and avoid
systemic toxicity and side effects. Large molecules can
easily pass the sclera regardless of lipophilicity.
Injection of carboplatin into the subtenon space is
effective against localized mild amounts of vitreous
seedings but this effect is transient and rarely curative.
Additionally, carboplatin is rapidly cleared from the
vitreous limiting its effects. To overcome this
inconvenience, a sustained delivery system of
carboplatin from fibrin sealants is developed. Recently,
supraselective intra-arterial infusion of melphelan into
the ophthalmic artery resulted in satisfactory tumor
regression in eyes that would otherwise have to be
enucleated.
3. Enucleation: This time-honored surgical treatment
is indicated for most of group E or RE V eyes where
there is no prospect of vision. Eyes with elevated
intraocular pressure, rubeosis iridis, tumor in the
anterior chamber, buphthalmus and evidence for optic
nerve involvement need to be enucleated. Failure of
prior chemotherapy and radiotherapy are other
indications for enucleation. In general, enucleation
becomes necessary in 75% of unilateral cases because
of the advanced stage at the time of diagnosis.
Likewise, enucleation of at least one eye (the worst
eye) becomes unavoidable in 60% of bilateral cases.
Bilateral enucleation may be performed in 1% of cases.
4. Cryotherapy: Rapid freezing of the tumor to -90°C
damages the vascular endothelia causing platelet plugs
to form thrombosis and induces tumor ischemia. In
addition, intracellular ice crystal formation causes
rupture of the cellular membranes. All tumors with less
than 5 mm basal diameter and few vitreous seedings
close to the tumor can successfully be treated with
cryotherapy.
5. Brachytherapy: Iodine-125 and Ruthenium-106
radioactive plaques are widely used to treat solitary
tumors having 6-15 mm basal diameters and less than 9
mm thickness. The trend is to prescribe 4000-4500 cGy
radiation to the tumor apex. To overall success rate is
90% but there is a tumor recurrence rate of 12% at one
year. Radiation induced retinopathy and optic
neuropathy are the most common complications.
6. Transpupillary thermotherapy (TTT): 810 nm
infrared diode laser is used for this treatment. Tumors
smaller than 3 mm of basal diameter without vitreous
seedings can be reliably treated with TTT either
primarily or following chemoreduction. Because of
technical difficulties, peripheral tumors are avoided.
The power is usually set at 200-1000 mW and 1.2 to 3
mm spot sizes are used for 1 minute each, aiming
directly the tumor. The result is a flat and atrophic scar.
There is an overall 86% success rate with
complications including focal iris atrophy, lens
opacities, optic disc atrophy, retinal tractions, vascular
occlusions, and retinal hemorrhages. (see Figure 2C
and 2D).
7. External Beam Radiotherapy (EBRT): This
modality continues to be very effective in selected
patients despite fears for secondary cancers. Eyes with
multifocal tumors not treatable by other local
techniques, macular tumors where other methods may
ultimately destroy the central vision, and advanced
bilateral disease are good candidates for EBRT. Also,
EBRT can be performed after failure of other methods
as a salvage therapy, in patients with extraocular orbital
tumor invasion or tumor at the surgical margin of the
resected optic nerve. The target tumor receives 4200-
4600 cGy radiation in 180-200 cGy fractionated doses
daily. Local tumor control rates vary between 50% to
88% depending on the stage of the disease. If vitreous
seedings are present the success rate of EBRT is only
17%. The most significant concern with the use of
EBRT is the development of second non-ocular and
periocular cancers particularly in survivors of
hereditary retinoblastoma. There is a 400-600 fold
increase in the risk of developing second cancers in
hereditary retinoblastoma if treated with EBRT and this
risk is further multiplied by 8 if the treatment is given
below the age of 1 year. Second malignant tumors
develop in 4.4% of patients during the first 10 years, in
18.3% within 20 years and in 26.1% after 30 years. The
most common second cancers include osteogenic
sarcoma, leiomyosarcoma, pinealoblastoma, skin
melanoma, Hodgkin's lymphoma, lung and breast
carcinomas. (see Figure 2E).
8. Gene Therapy: The preliminary results of
intravitreal injection of adenovirus carrying the coding
sequence of thymidine kinase followed by ganciclovir
injection appear promising. In human subjects, this
treatment decreased vitreous seedings but main tumors
remained intact.
9. Experimental Therapies:
- COX-2, which is expressed in retinoblastoma, is a
prostaglandin synthetase promoting angiogenesis,
suppressing apoptosis and increasing tumor
invasiveness. The role of COX-2 inhibitors is
investigated in retinoblastoma.
- Oxidative stress, which is high in retinoblastoma,
upregulates aA-crystallins, member of heath shock
proteins, helping tumor cells to escape apoptosis. Anti-
aA-crystallin therapy is thought to have a potential to
limit tumor growth in retinoblastoma.
- Retinoblastoma cells can produce VEGF and basic
fibroblast growth factor both of which induce
angiogenesis. The initial enthusiasm on anti-angiogenic
drugs vanished because it was found that these drugs
were active against immature vasculature found in the
periphery of the tumor. Vessels that are more central
had pericyte components and thus became mature no
Head and neck: Retinoblastoma Kiratli H, Tarlan B
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 709
more dependant on angiogenic stimuli. This seriously
limits the effects of anti-angiogenic agents.
- Arsenic trioxide has been shown to have effect on
retinoblastoma cells by generating reactive oxygen
species which oxidize lipids in the mitochondria
membranes. This results in cytochrome C release and
activation of the caspase system leading to apoptosis.
- Retinoblastoma contains many hypoxic areas where
cellular proliferation is slower compared to areas close
to blood vessels. These slow proliferating cells usually
do not respond to available chemotherapeutic drugs. 2-
deoxy-D-glucose (2-DG), a glycolytic inhibitor, holds
promise against these non-responding cell populations.
Prognosis
With increased awareness and early diagnosis coupled
with the current diagnostic techniques and management
options, 99% of children with intraocular
retinoblastoma survive the disease and 90% of patients
retain useful vision in at least one eye. The prognosis is
still dismal if there is orbital extension of the tumor or
distant hematogenous metastasis.
Cytogenetics
Note
Retinoblastoma develops because of inactivation of
both alleles of the RB1 tumor suppressor gene after two
successive mutations (M1 and M2). In patients with
hereditary (germinal) retinoblastoma, the germline
contains an inactivated RB1 allele that is also present in
all cells of the individual. The tumor develops when the
other allele is lost (M2) in a retinal cell. The result is
bilateral and multifocal tumors. In non-hereditary
cases, both M1 and M2 occur in a single retinal cell
thus producing unilateral and unifocal disease.
Genes involved and proteins
Note
The RB1 is the first gene to be discovered to have
tumor suppression function. In most cases, the first
allele is lost because of a point mutation (M1). Most
mutations are non-sense which produces a premature
stop codon and a resultant non functional protein. Loss
of heterozygosity (M2) is responsible for the loss of the
second allele in 60% of tumors. It is now recognized
that M1 and M2 are not sufficient to drive the cell into
malignant transformation and that other genomic
changes (M3-MX) are necessary. Recent studies
identified gains and amplifications at 1q32 (MDM4 and
KIF14 genes) and 6p22 (E2F3 and DEK genes) as M3
and M4 respectively. Less frequent but important
genomic changes include 16q22 loss (CDH11 and
RBL2 genes) and 2p24 gains (MYCN and DDX1
genes).
RB1
Location
13q14
Note
The retinoblastoma gene RB1 is localized on
chromosome 13q14. In only 3% of tumors,
karyotypically visible large deletions can be
demonstrated in this location.
RB1 spans 180 kb and is composed of 27 exons. This
gene encodes a 4.8 kb mRNA and the protein is a 110
kD nuclear phosphoprotein (pRB) containing 928
aminoacids. This protein has anti-oncogenic function,
induces differentiation and blocks the anti-apoptotic
properties of MDM2. The tumor suppressor function is
through E2F at the cell cycle checkpoint between G1
and S-phase entry. The protein has many pockets which
bind several molecules the most important being E2F
transcription factors.
When pRB is in normal hypophosphorylated state,
E2F1 is bound and the cell cannot enter the S-phase.
When pRB is phosphorylated or other competing
molecules for the pockets including SV40 virus,
papillomavirus or adenovirus oncoproteins bind, E2F1
is released and the cascade for uncontrolled cellular
proliferation proceeds.
References Abramson DH, Schefler AC. Update on retinoblastoma. Retina. 2004 Dec;24(6):828-48
Abramson DH. Retinoblastoma in the 20th century: past success and future challenges the Weisenfeld lecture. Invest Ophthalmol Vis Sci. 2005 Aug;46(8):2683-91
Shields JA, Shields CL, Meadows AT. Chemoreduction in the management of retinoblastoma. Am J Ophthalmol. 2005 Sep;140(3):505-6
Shields CL, Mashayekhi A, Au AK, Czyz C, Leahey A, Meadows AT, Shields JA. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology. 2006 Dec;113(12):2276-80
Kim JW, Abramson DH, Dunkel IJ. Current management strategies for intraocular retinoblastoma. Drugs. 2007;67(15):2173-85
Schefler AC, Abramson DH. Retinoblastoma: what is new in 2007-2008. Curr Opin Ophthalmol. 2008 Nov;19(6):526-34
Shields CL, Ramasubramanian A, Thangappan A, Hartzell K, Leahey A, Meadows AT, Shields JA. Chemoreduction for group E retinoblastoma: comparison of chemoreduction alone versus chemoreduction plus low-dose external radiotherapy in 76 eyes. Ophthalmology. 2009 Mar;116(3):544-551.e1
This article should be referenced as such:
Kiratli H, Tarlan B. Head and neck: Retinoblastoma. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):704-709.
Case Report Section Paper co-edited with the European LeukemiaNet
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 710
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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t(1;21)(p32;q22) as a non-random abnormality in AML M4 Lena Reindl, Claudia Haferlach
MLL, Munich Leukemia Laboratory, Max-Lebsche-Platz 31, Germany (LR, CH)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Reports/0121ReindlID100041.html DOI: 10.4267/2042/44812
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
63 years old female patient.
Previous history
No preleukemia; no previous malignancy; no inborn
condition of note.
Organomegaly
No hepatomegaly , no splenomegaly , no enlarged
lymph nodes, no central nervous system involvement.
Blood WBC : 3.980X 10
9/l
HB : 7.9g/dl
Platelets : 64.000X 109/l
Blasts : 48,5%
Cyto-Pathology Classification
Cytology
(FAB) AML M4.
Immunophenotype
Hypercellular bone marrow showed a myelomonocytic
blast population. 49.5% blasts were detected in total
bone marrow. 30% of the cells were clearly EST
positive.
Futhermore POX was positive, no ringsiderobalsts
were found and erythropoiesis showed dysplasia.
Myelomonocytic cells with MPO+ (48%), CD13+
(17%), CD33+ (63%), CD14 (19%) and CD64 (37%).
Diagnosis
AML M4
Survival
Date of diagnosis: 06-2008
Treatment: None
Complete remission : no
Treatment related death : no
Relapse : no
Status : Lost
Karyotype
Sample: bone marrow
Culture time: 24 - 48h
Banding: GAG.
Results: 46,XX,t(1;21)(p32;q22)[15/15].
Other molecular cytogenetics technics:
FISH with commercial AML1 probe (Abbott) and
whole chromosome painting with WCP#1 and
WCP#21 (MetaSystems).
Other molecular cytogenetics results:
40% of cells with AML1-split.
Other Molecular Studies
Technics: PCR
Results: Tandem duplication of MLL gene (MLL-PTD
positive).
t(1;21)(p32;q22) as a non-random abnormality in AML M4 Reindl L, Haferlach C
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 711
Partial GTG-banding karyotype showing t(1;21)(p32;q22).
FISH and whole chromosome painting of the same metaphase with t(1;21)(p32;q22); Left picture: AML1 probe on metaphase; Right picture: whole chromosome painting, WCP#1 green, WCP#21 red.
Comments Only two cases with t(1;21)(p32;q22) were described
so far in literature. The first reported case is a 25-year-
old male with an acute myelomonoblastic leukemia
(M4 by FAB subtype) (Cherry et al., 2001). The second
patient, a 29-year-old Japanese male, showed a acute
myelogenous leukemia M4 with NUP98-HOXA9
fusion detected by PCR at the initial diagnosis. In
relapse he acquired additional to the NUP98-HOXA9
fusion a t(1;22)(p32;q22) (Aoki et al., 2008). The here
reported case is a 63-year-old female with an acute
myeloid leukemia (M4 by FAB subtype). So far the
cases have the same morphology in common.
Correlations to age or sex cannot be determined yet.
Call for Collaborations
Lena Reindl
MLL, Munich Leukemia Laboratory,
Max-Lebsche-Platz 31, Germany
lena.reindl@mll-online.com
References Cherry AM, Bangs CD, Jones P, Hall S, Natkunam Y. A unique AML1 (CBF2A) rearrangement, t(1;21)(p32;q22), observed in a patient with acute myelomonocytic leukemia. Cancer Genet Cytogenet. 2001 Sep;129(2):155-60
La Starza R, Trubia M, Crescenzi B, Matteucci C, Negrini M, Martelli MF, Pelicci PG, Mecucci C. Human homeobox gene HOXC13 is the partner of NUP98 in adult acute myeloid leukemia with t(11;12)(p15;q13). Genes Chromosomes Cancer. 2003 Apr;36(4):420-3
Dal Cin P, Yee AJ, Dey B.. A de novo AML with a t(1;21)(p36;q22) in an elderly patient. Atlas Genet Cytogenet Oncol Haematol. March 2007 URL : http://AtlasGeneticsOncology.org/Reports/0121DalCinID100021.html .
Aoki T, Miyamoto T, Yoshida S, Yamamoto A, Yamauchi T, Yoshimoto G, Mori Y, Kamezaki K, Iwasaki H, Takenaka K, Harada N, Nagafuji K, Teshima T, Akashi K. Additional acquisition of t(1;21)(p32;q22) in a patient relapsing with acute myelogenous leukemia with NUP98-HOXA9. Int J Hematol. 2008 Dec;88(5):571-4
This article should be referenced as such:
Reindl L, Haferlach C. t(1;21)(p32;q22) as a non-random abnormality in AML M4. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):710-711.
Case Report Section Paper co-edited with the European LeukemiaNet
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 712
Atlas of Genetics and Cytogenetics in Oncology and Haematology
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t(3;7)(q26;q21) as a secondary abnormality in MDS RAEB-2 Lena Reindl, Claudia Haferlach
MLL, Munich Leukemia Laboratory, Max-Lebsche-Platz 31, Germany (LR, CH)
Published in Atlas Database: August 2009
Online updated version : http://AtlasGeneticsOncology.org/Reports/0307ReindlID100042.html DOI: 10.4267/2042/44813
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
72 years old male patient.
Previous history
No preleukemia; no previous malignancy; no inborn
condition of note.
Organomegaly
No hepatomegaly , no splenomegaly , no enlarged
lymph nodes , no central nervous system involvement.
Blood WBC : 12.700X 10
9/l
HB : 11.9g/dl
Platelets : 70.000X 109/l
Blasts : 15%
Bone marrow : 15 (The hypercellular bone marrow
shows 15% blasts and multilineage dyplasias.
Granulopoesis shows significant dysplasia and
dyplasias were also found in the decreased
erythropoiesis and thrombopoiesis. No Auer rods were
detected.)
Cyto-Pathology Classification
Cytology
MDS RAEB-2
Immunophenotype
12% myeloid blasts CD33+, CD117+; 31%
hypogranulated granuloyctes; 11% monocytes CD56+.
Survival
Date of diagnosis: 07-2008
Status: Lost
Karyotype
Sample : bone marrow
Culture time : 24 - 72h
Banding : GAG.
Results : 46,XY,del(20)(q11) [2]/46,XY,idem,
t(3;7)(q26;q21)[14].
Other molecular cytogenetics technics:
FISH with commercial EVI/3q26 probe (Kreatech).
Other molecular cytogenetics results:
65% cells with EVI-rearrangement.
Partial GTG-karyotype showing t(3;7)(q26;q21).
t(3;7)(q26;q21) as a secondary abnormality in MDS RAEB-2 Reindl L, Haferlach C
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7) 713
EVI1 break-apart probe on metaphase chromosomes, one green signal left on derivatives chromosome 3 and one yellow signal is located on derivative chromosome 7.
Whole chromosome painting, WCP#3 yellow, WCP#7 red and WCP#20 green.
Comments 5 cases with t(3;7)(q26;q21) were described so far in
literature. 4 cases showed chronic myeloid leukemia
with t(3;7)(q26;q21) as a additional aberration to
t(9;22)(q34;q11) (Storlazzi et al., 2004; Henzan et al.,
2004; Bobadilla et al., 2007; Tien et al., 1989). One
case suffered from acute myeloid leukemia (NOS) and
had a trisomy 13 as additional aberration to
t(3;7)(q26;q21) (Madrigal et al., 2006). The here
described case - a 72-year-old male - had a MDS
RAEB-2 (FAB) and the t(3;7)(q26;q21) was found as
additional aberration to a 20q-deletion. So in this case
for the first time a t(3;7)(q26;q21) was found in MDS
and the translocation appears also as secondary
aberration as seen in 4 cases with CML before.
Call for Collaborations
Lena Reindl
MLL, Munich Leukemia Laboratory,
Max-Lebsche-Platz 31,
81377 Munich, Germany
Lena.reind@mll-online.com
References Tien HF, Chuang SM, Wang CH, Lee FY, Chien SH, Chen YC, Shen MC, Liu CH. Chromosomal characteristics of Ph-positive chronic myelogenous leukemia in transformation. A study of 23 Chinese patients in Taiwan. Cancer Genet Cytogenet. 1989 May;39(1):89-97
Henzan H, Yoshimoto G, Okeda A, Nagasaki Y, Hirano G, Takase K, Tanimoto T, Miyamoto T, Fukuda T, Nagafuji K, Harada M. Myeloid/natural killer cell blast crisis representing an additional translocation, t(3;7)(q26;q21) in Philadelphia-positive chronic myelogenous leukemia. Ann Hematol. 2004 Dec;83(12):784-8
Storlazzi CT, Anelli L, Albano F, Zagaria A, Ventura M, Rocchi M, Panagopoulos I, Pannunzio A, Ottaviani E, Liso V, Specchia G. A novel chromosomal translocation t(3;7)(q26;q21) in myeloid leukemia resulting in overexpression of EVI1. Ann Hematol. 2004 Feb;83(2):78-83
Madrigal I, Carrió A, Gómez C, Rozman M, Esteve J, Nomdedeu B, Campo E, Costa D. Fluorescence in situ hybridization studies using BAC clones of the EVI1 locus in hematological malignancies with 3q rearrangements. Cancer Genet Cytogenet. 2006 Oct 15;170(2):115-20
Bobadilla D, Enriquez EL, Alvarez G, Gaytan P, Smith D, Slovak ML. An interphase fluorescence in situ hybridisation assay for the detection of 3q26.2/EVI1 rearrangements in myeloid malignancies. Br J Haematol. 2007 Mar;136(6):806-13
This article should be referenced as such:
Reindl L, Haferlach C. t(3;7)(q26;q21) as a secondary abnormality in MDS RAEB-2. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(7):712-713.
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