Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Atlas Journal

Atlas Journal versus Atlas Database: the accumulation of the issues of the Journal constitutes the body of the Database/Text-Book. TABLE OF CONTENTS

Volume 11, Number 2, Apr-Jun 2007 Previous Issue / Next Issue Genes

BOK (BCL2-related ovarian killer) (2q37.3).

Alexander G Yakovlev.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 119-123. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/BOKID824ch2q37.html

BIRC6 (Baculoviral IAP repeat-containing 6) (2p22).

Christian Pohl, Stefan Jentsch.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 124-129. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/BIRC6ID798ch2p22.html

AKAP12 (A kinase (PRKA) anchor 1) (6q25).

Irwin H Gelman.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 130-136. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/AKAP12ID607ch6q25.html

TRIM 24 (tripartite motif-containing 24) (7q34).

Jean Loup Huret.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 137-141. [Full Text] [PDF]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 - I - URL : http://AtlasGeneticsOncology.org/Genes/TRIM24ID504ch7q34.html

RUNX 2 (Runt-related transcription factor 2) (6p21).

Athanasios G Papavassiliou, Panos Ziros.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 142-147. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/RUNX2ID42183ch6p21.html

PTPRG (protein tyrosine phosphatase, receptor type, G) (3p14.2).

Cornelis P Tensen, Remco van Doorn.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 148-152. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/PTPRGID41930ch3p21.html

PPP1R13L (protein phosphatase 1, regulatory (inhibitor) subunit 13 like) (19q13.32).

Ulla Vogel.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 153-157. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/PPP1R13LID42997ch19q13.html

MDM2 (transformed mouse 3T3 cell double minute 2, p53 binding protein) (12q15).

Wenrui Duan, Miguel A Villalona-Calero.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 158-164. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/MDM2ID115ch12q15.html

LYL1 (lymphoblastic leukemia derived sequence 1) (19p13.2).

Yuesheng Meng, Mark D Minden.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 165-170. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/LYL1ID51ch19p13.html

FHIT (Fragile Histidine Triad) (3p14.2).

Teresa Druck, Kay Huebner.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 171-178. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/FHITID192ch3p14.html

ERCC1 (excision repair complementing defective repair in Chinese hamster.) (19q13.32).

Ulla Vogel.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 - II - Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 179-186. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/ERCC1ID40481ch19q13.html

CASP-9 (caspase 9, apoptosis-related cysteine peptidase) (1p36.2).

Sabrina Di Bartolomeo, Francesco Cecconi.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 187-193. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/CASP9ID423ch1p36.html

AATF (Apoptosis Antagonizing Transcription Factor) (17q12).

Deepak Kaul, Amit Khanna.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 194-198. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/AATFID534ch17q11.html

STK11 (serine/threonine kinase 11) (19p13.3).

Bharati Bapat, Sheron Perera.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 199-205. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/STK11ID292.html

RTN4 (reticulon 4) (2p16.3).

Masuo Yutsudo.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 206-213. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/RTN4ID42182ch2p16.html

RHOA (ras homolog family, member A) (3p21.31).

Teresa Gomez del Pulgar, Juan Carlos Lacal.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 214-222. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/RHOAID42107ch3p21.html

RARRES1 (retinoic acid receptor responder (tazarotene induced) 1) (3q25.32).

Kwok-Wai Lo, Grace TY Chung.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 223-229. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/RARRES1ID42050ch3q25.html

DDX43 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 43) (6q13).

Atlas Genet Cytogenet Oncol Haematol 2007; 2 - III - Etienne De Plaen.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 230-233. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/DDX43ID40288ch6q13.html

CDK4 (cyclin-dependent kinase 4) (12q14).

Anders Molven.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 234-238. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/CDK4ID238ch12q14.html

AXIN2 (axin 2) (17q24.1).

Thomas A Hughes.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 239-247. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Genes/AXIN2ID456ch17q24.html Leukaemias

t(2;12)(q31;p13).

Jean-Loup Huret.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 248. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t0212q31p13ID1459.html

t(12;17)(p11;q11) in acute myeloid leukemia.

David Betts.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 249-250. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/t1217p11q11ID1437.html Solid Tumours Cancer Prone Diseases

Stiff-person syndrome.

Franco Folli, Claudia Sommer.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 251-256. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Kprones/StiffpersonID10103.html

Perlman syndrome (renal hamartomas, nephroblastomatosis and fetal gigantism).

Atlas Genet Cytogenet Oncol Haematol 2007; 2 - IV - Maria Piccione, Giovanni Corsello.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 257-263. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Kprones/PerlmanID10117.html

Pallister Hall Syndrome (PHS).

Jennifer J Johnston, Leslie G Biesecker.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 264-267. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Kprones/PallisterHallID10126.html Deep Insights

Genetic Instability in Cancer.

Sheron Perera, Bharati Bapat.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 268-278. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Deep/GenetInstabilityCancerID20056.html Case Reports

Reciprocal translocation t(2;12)(q31;p13) in a case of CMML.

Despina Iakovaki, Markos Fisfis, Katy Stefanoudaki, Georgia Bardi.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 279-280. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/0212IakovakiID100017.html

t(8;13)(p12;q12) in an atypical chronic myeloid leukaemia case.

Valeria AS De Melo, Alistair G Reid.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 281-282. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/0813ReidID100018.html

A case of myeloproliferative disorder with t(5;10)(q33;q21.2).

Valeria AS De Melo, Alistair G Reid.

Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 283-284. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/0510ReidID100019.html A novel chromosomal translocation (6;14)(p22;q32) in a case of precursor B-cell Acute Lymphoblastic Leukemia. Siddharth G Adhvaryu, Alka Dwivedi, Peggy Stoll.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 - V - Atlas Genet Cytogenet Oncol Haematol 2007; 11 (2): 285-288. [Full Text] [PDF]

URL : http://AtlasGeneticsOncology.org/Anomalies/0614AdhvaryuID100020.html Educational Items

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BOK (BCL2-related ovarian killer)

Identity Other names Mtd (Matador) BOKL BCL2-like 9 BCL2L9 MGC4631 Hugo BOK Location 2q37.3 Local_order LOC728248 STK25 BOK THAP4 ATG4B DNA/RNA Description The gene encompasses 15,361 bp of DNA with 5 exons. Transcription Alternative splicing results in expression of two mRNA variants. The full-length (Bok-L) mRNA comprises 2.6 kb with the 639 bp open reading frame. The truncated form (Bok-S) results from skipping of exon three and a deletion of 43 bp in the Bok-L coding region. It has been shown that transcription activity of the Bok gene depends on expression of p53 and can be directly regulated at the gene promoter level by E2F transcription factors during cell cycle progression. Protein

Description A Bok transcript was initially isolated from a rat ovarian fusion cDNA library. Sequencing of this transcript has revealed that full-length BOK protein consists of 213 amino acids and contains three conserved BCL2 homology regions BH1, BH2, and BH3 in addition to a C-terminal transmembrane domain. BOK-S that results from the alternative splicing has its N-terminal BH3 domain part fused to the C-terminal part of the BH1 region. Using the yeast two-hybrid system, it has been demonstrated that, although the BH domains composition of BOK-L protein was similar to that of BAX and BAK, it interacted only with MCL-1, BHRF1, and BCL2A1/BFL-1 but not other anti- apoptotic multidomain BCL-2 family members. Expression Bok mRNA was isolated from the ovarian cDNA library. Results of Northern blot analysis revealed high expression levels of Bok mRNA in the reproductive tissues, such as ovary, testis, and uterus. Using in situ hybridization the authors localized Bok mRNA in granulosa cells. However, Bok expression is also evident in other mammalian tissues, such as brain, liver, thymus, lung, heart, kidney intestinal epithelium and lymphoid tissues. Localisation Intracellular localization of BOK protein remains to be clarified. Results of different studies suggest either its mitochondrial or cytosolic and nuclear localization. Function BOK promotes both caspase-dependent and caspase-independent apoptosis at the level of mitochondria in various cell types by promoting the release of pro-apoptotic mitochondrial factors to the cell cytosol. Inhibition of BOK induction using siRNA markedly decreases p53-dependent cell death. However, a specific mechanism, by which BOK increases mitochondrial membrane permeability, remains unknown. Apoptosis induced by BOK overexpression cannot be inhibited by Bcl-2 or Bcl-XL suggesting a unique role for BOK in apoptosis. A recent report indicates that BOK may

Atlas Genet Cytogenet Oncol Haematol 2007; 2 119 cooperate with a BH3-only member, NOXA in p53-dependent apoptosis induced by DNA damage in human neuroblastoma cells, where it substitutes for a function of pro- apoptotic BAX. Homology Evolutionary conserved from fly to human. Mutations Note Unknown. External links Nomenclature Hugo BOK GDB BOK Entrez_Gene BOK 666 BCL2-related ovarian killer Cards Atlas BOKID824ch2q37 GeneCards BOK Ensembl BOK Genatlas BOK GeneLynx BOK eGenome BOK euGene 666 Genomic and cartography GoldenPath BOK - 2q37.3 chr2:242146865-242162224 + 2q37.3 (hg18-Mar_2006) Ensembl BOK - 2q37.3 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene BOK Gene and transcription Genbank AF089746 [ ] Genbank AF174487 [ ENTREZ ] Genbank BC006203 [ ENTREZ ] Genbank BC017214 [ ENTREZ ] Genbank BG118500 [ ENTREZ ] RefSeq NM_032515 [ SRS ] NM_032515 [ ENTREZ ] RefSeq AC_000045 [ SRS ] AC_000045 [ ENTREZ ] RefSeq NC_000002 [ SRS ] NC_000002 [ ENTREZ ] RefSeq NT_005416 [ SRS ] NT_005416 [ ENTREZ ] RefSeq NW_921618 [ SRS ] NW_921618 [ ENTREZ ] AceView BOK AceView - NCBI Unigene Hs.293753 [ SRS ] Hs.293753 [ NCBI ] HS293753 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q5SZF6 [ SRS] Q5SZF6 [ EXPASY ] Q5SZF6 [ INTERPRO ] CluSTr Q5SZF6 Blocks Q5SZF6 HPRD Q5SZF6

Atlas Genet Cytogenet Oncol Haematol 2007; 2 120 Protein Interaction databases DIP Q5SZF6 IntAct Q5SZF6 Polymorphism : SNP, mutations, diseases OMIM 605404 [ map ] GENECLINICS 605404 SNP BOK [dbSNP-NCBI] SNP NM_032515 [SNP-NCI] SNP BOK [GeneSNPs - Utah] BOK] [HGBASE - SRS] HAPMAP BOK [HAPMAP] General knowledge Family BOK [UCSC Family Browser] Browser SOURCE NM_032515 SMD Hs.293753 SAGE Hs.293753 GO cellular_component [Amigo] cellular_component GO induction of apoptosis [Amigo] induction of apoptosis GO induction of apoptosis [Amigo] induction of apoptosis GO regulation of apoptosis [Amigo] regulation of apoptosis GO protein dimerization activity [Amigo] protein dimerization activity PubGene BOK Other databases Probes Probe BOK Related clones (RZPD - Berlin) PubMed PubMed 10 Pubmed reference(s) in LocusLink Bibliography Bok is a pro-apoptotic Bcl-2 protein with restricted expression in reproductive tissues and heterodimerizes with selective anti-apoptotic Bcl-2 family members. Hsu SY, Kaipia A, McGee E, Lomeli M, Hsueh AJ Proc Natl Acad Sci USA 1997; 94: 12401-12406. Medline 9356461

A splicing variant of the Bcl-2 member Bok with a truncated BH3 domain induces apoptosis but does not dimerize with antiapoptotic Bcl-2 in vitro. Hsu SY, Hsueh AJ J Biol Chem 1998; 273: 30139-30146. Medline 9804769

Mtd, a novel Bcl-2 family member activates apoptosis in the absence of heterodimerization with Bcl-2 and Bcl-XL. Inohara N, Ekhterae D, Garcia I, Carrio R, Merino J, Merry A, Chen S, Nunez G J Biol Chem 1998; 273: 8705-8710. Medline 9535847

Evolutionarily conserved Bok proteins in the Bcl-2 family.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 121 Zhang H, Holzgreve W, De Geyter C FEBS Lett 2000; 480: 311-313. Medline 11034351

The expression of Bok is regulated by serum in HC11 mammary epithelial cells. Ha SH, Lee SR, Lee TH, Kim YM, Bauk MG, Choi YJ Mol Cells 2001; 12: 368-371. Medline 11804337

The expression and regulation of Bcl-2-related ovarian killer (Bok) mRNA in the developing and adult rat testis. Suominen JS, Yan W, Toppari J, Kaipia A J Neurochem 2003; 85: 1500-1512. Medline 11720903

Bcl-2-related protein family during oligodendroglial differentiation. Itoh T, Itoh A, Pleasure D J Neurochem 2003; 85: 1500-1512. Medline 12787069

Role of Mtd/Bok in normal and neoplastic B-cell development in the bursa of Fabricius. Brown CY, Bowers SJ, Loring G, Heberden C, Lee RM, Neiman PE Dev Comp Immunol. 2004; 28: 619-634 Medline 15177115

BOK and NOXA are essential mediators of p53-dependent apoptosis. Yakovlev AG, Di Giovanni S, Wang G, Liu W, Stoica B, Faden AI J Biol Chem 2004; 279: 28367-28374. Medline 15102863

Membrane translocation and oligomerization of hBok are triggered in response to apoptotic stimuli and Bnip3. Gao S, Fu W, Durrenberger M, De Geyter C, Zhang H Cell Mol Life Sci 2005; 62: 1015-1024. Medline 15868100

Nuclear translocation of the pro-apoptotic Bcl-2 family member Bok induces apoptosis. Bartholomeusz G, Wu Y, Ali Seyed M, Xia W, Kwong KY, Hortobagyi G, Hung MC Mol Carcinog 2006; 45: 73-83. Medline 16302269

Loss of proapoptotic Bcl-2-related multidomain proteins in primary melanomas is associated with poor prognosis. Fecker LF, Geilen CC, Tchernev G, Trefzer U, Assaf C, Kurbanov BM, Schwarz C, Daniel PT, Eberle J J Invest Dermatol 2006; 126: 1366-1371. Medline 16528364

Bok, Bcl-2-related Ovarian Killer, Is Cell Cycle-regulated and Sensitizes to Stress-induced Apoptosis. Rodriguez JM, Glozak MA, Ma Y, Cress WD J Biol Chem 2006; 281: 22729-22735. Medline 16772296

Atlas Genet Cytogenet Oncol Haematol 2007; 2 122 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

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Contributor(s) Written 11-2006 Alexander G Yakovlev Citation This paper should be referenced as such : YakovlevAG . BOK (BCL2-related ovarian killer). Atlas Genet Cytogenet Oncol Haematol. November 2006 . URL : http://AtlasGeneticsOncology.org/Genes/BOKID824ch2q37.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 2 123 Atlas of Genetics and Cytogenetics in Oncology and Haematology

BIRC6 (Baculoviral IAP repeat-containing 6)

Identity Other names Baculoviral IAP repeat-containing ubiquitin-conjugating enzyme (BRUCE) Baculoviral IAP repeat-containing 6 (Apollon) FLJ13726 FLJ13786 KIAA1289 Hugo BIRC6 Location 2p22 CARD12 (caspase recruitment domain family member 12) {encoded on minus strand, 32.303.029-32.344.427} YPF4 (YIP1 domain family member 4) {32.356.483-32.385.159} Local_order BIRC6 {32.435.234-32.697.467} TTC27 (tetratricopeptide repeat domain 27) {32.706.633-32.899.620} LTBP1 (latent transforming growth factor beta binding protein 1) {33.025.896- 33.478.077} DNA/RNA Description The BIRC6 gene comprises 75 exons resulting in a transcript of 16066 bps. The ATG is in the first exon. Transcription Only one variant of BIRC6 has been found so far which comprises 14490 bps. There are several synonymous and nonsynonymous SNPs reported for BIRC6 (E589K, L1742F, R2187T, T2646S, T3708N, E3864K, Q4323H, N4324Y, S4325C, N4326T, P4329R). Pseudogene Not known. There is evidence for a processed pseudogene in M. musculus. Protein

Atlas Genet Cytogenet Oncol Haematol 2007; 2 124

BRUCE is component of the apoptosis regulatory network. Multiple protein-protein interactions allow a switch from apoptosis inhibition to inactivation in later steps in apoptosis. BRUCE¹s action on activated caspases and other pro-apoptotic molecules might be restricted to the trans-Golgi network and the vesicular system.

Description BIRC6 contains two functionally validated domains: A N-terminal BIR repeat (SMART SM00238, aa: 256-332) and a C-terminal UBC domain (SMART SM00212, aa: 4548 4712). The BIR repeat is needed for interactions with caspases and IAP-binding motiv (IBM) containing proteins (HtrA2, Smac). The UBC domain can form a thiolester linkage with ubiquitin transferred by E1. Between aa 1589-1633 a coiled-coil region can be found. Expression BRUCE is highly expressed in brain, testis, lymphatic cells and secretory organs and also found in any other tissue. It is highly expressed in the mouse embryos up to E11 and then transcript levels drop. Localisation Localized to membranes of the trans Golgi network (TGN) and the endosomal system. Function BRUCE is a peripheral membrane protein of the trans-Golgi network that protects cells from apoptosis by functioning as an inhibitor of apoptosis protein (IAP). BRUCE can bind and inhibit activated caspases CASP-3, CASP-6, CASP-7, CASP-8 and CASP-9. Furthermore it ubiquitylates caspase-9, HtrA2 (a pro-apoptotic serine protease) and DIABLO/Smac (a competitor for caspase-IAP interactions) thereby most likely targeting them for proteasomal degradation. The ubiquityltion reactions do not require an ubiquitin E3 ligase making BRUCE a chimeric E2/E3 ubiquitin ligase. Homology ubc-17 (C. elegans) IAP6 (A. gambiae) Bruce (D. melanogaster) BIRC6 (X. tropicalis) Birc6 (M. musculus). Mutations Note There are several synonymous and nonsynonymous SNPs reported for BIRC6

Atlas Genet Cytogenet Oncol Haematol 2007; 2 125 (E589K, L1742F, R2187T, T2646S, T3708N, E3864K, Q4323H, N4324Y, S4325C, N4326T, P4329R). Implicated in Entity Overexpression of BRUCE is found in several cancer cell lines (brain SF-268, SNB-78 ovarian cancer OVCAR-8). High level expression of BRUCE in these cell lines seems to correlate with their resistance to apoptotic reagents. Furthermore, bone marrow cells of myelodysplastic syndromes exhibit significant expression of BIRC6.

External links Nomenclature Hugo BIRC6 GDB BIRC6 Entrez_Gene BIRC6 57448 baculoviral IAP repeat-containing 6 (apollon) Cards Atlas BIRC6ID798ch2p22 GeneCards BIRC6 Ensembl BIRC6 Genatlas BIRC6 GeneLynx BIRC6 eGenome BIRC6 euGene 57448 Genomic and cartography GoldenPath BIRC6 - 2p22 chr2:32435234-32697467 + 2p22-p21 (hg18-Mar_2006) Ensembl BIRC6 - 2p22-p21 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene BIRC6 Gene and transcription Genbank AA315620 [ ENTREZ ] Genbank AB033115 [ ENTREZ ] Genbank AF265555 [ ENTREZ ] Genbank AK023788 [ ENTREZ ] Genbank AK023848 [ ENTREZ ] RefSeq NM_016252 [ SRS ] NM_016252 [ ENTREZ ] RefSeq AC_000045 [ SRS ] AC_000045 [ ENTREZ ] RefSeq NC_000002 [ SRS ] NC_000002 [ ENTREZ ] RefSeq NT_022184 [ SRS ] NT_022184 [ ENTREZ ] RefSeq NW_927719 [ SRS ] NW_927719 [ ENTREZ ] AceView BIRC6 AceView - NCBI Unigene Hs.150107 [ SRS ] Hs.150107 [ NCBI ] HS150107 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt O15392 [ SRS] O15392 [ EXPASY ] O15392 [ INTERPRO ] Prosite PS01282 BIR_REPEAT_1 [ SRS ] PS01282 BIR_REPEAT_1 [ Expasy ] Prosite PS50143 BIR_REPEAT_2 [ SRS ] PS50143 BIR_REPEAT_2 [ Expasy ]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 126 Interpro IPR001370 Prot_inh_I32_IAP [ SRS ] IPR001370 Prot_inh_I32_IAP [ EBI ] CluSTr O15392 Pfam PF00653 BIR [ SRS ] PF00653 BIR [ Sanger ] pfam00653 [ NCBI-CDD ] Smart SM00238 BIR [EMBL] Blocks O15392 PDB 1E31 [ SRS ] 1E31 [ PdbSum ], 1E31 [ IMB ] 1E31 [ RSDB ] PDB 1F3H [ SRS ] 1F3H [ PdbSum ], 1F3H [ IMB ] 1F3H [ RSDB ] PDB 1XOX [ SRS ] 1XOX [ PdbSum ], 1XOX [ IMB ] 1XOX [ RSDB ] HPRD O15392 Protein Interaction databases DIP O15392 IntAct O15392 Polymorphism : SNP, mutations, diseases OMIM 605638 [ map ] GENECLINICS 605638 SNP BIRC6 [dbSNP-NCBI] SNP NM_016252 [SNP-NCI] SNP BIRC6 [GeneSNPs - Utah] BIRC6] [HGBASE - SRS] HAPMAP BIRC6 [HAPMAP] General knowledge Family BIRC6 [UCSC Family Browser] Browser SOURCE NM_016252 SMD Hs.150107 SAGE Hs.150107 GO cysteine protease inhibitor activity [Amigo] cysteine protease inhibitor activity GO cellular_component [Amigo] cellular_component GO intracellular [Amigo] intracellular GO protein modification [Amigo] protein modification GO ubiquitin cycle [Amigo] ubiquitin cycle GO apoptosis [Amigo] apoptosis GO anti-apoptosis [Amigo] anti-apoptosis GO ligase activity [Amigo] ligase activity small conjugating protein ligase activity [Amigo] small conjugating protein ligase GO activity PubGene BIRC6 Other databases Probes Probe BIRC6 Related clones (RZPD - Berlin) PubMed PubMed 9 Pubmed reference(s) in LocusLink Bibliography A giant ubiquitin-conjugating enzyme related to IAP apoptosis inhibitors. Hauser HP, Bardroff M, Pyrowolakis G, Jentsch S.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 127 J Cell Biol. 1998; 141(6):1415-1422. Medline 9628897

A human IAP-family gene, apollon, expressed in human brain cancer cells. Chen Z, Naito M, Hori S, Mashima T, Yamori T, Tsuruo T Biochem Biophys Res Commun. 1999; 264(3):847-854. Medline 10544019

Inhibitor of apoptosis proteins and their relatives: IAPs and other BIRPs. Verhagen AM, Coulson EJ, Vaux DL. Genome Biol. 2001; 2(7):REVIEWS3009. Epub 2001. Review. Medline 11516343

Drosophila Bruce can potently suppress Rpr- and Grim-dependent but not Hid-dependent cell death. Vernooy SY, Chow V, Su J, Verbrugghe K, Yang J, Cole S, Olson MR, Hay BA. Curr Biol. 2002; 12(13):1164-1168. Medline 12121627

Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase. Bartke T, Pohl C, Pyrowolakis G, Jentsch S. Mol Cell. 2004; 14(6):801-811. Medline 15200957

Apollon ubiquitinates SMAC and caspase-9, and has an essential cytoprotection function. Hao Y, Sekine K, Kawabata A, Nakamura H, Ishioka T, Ohata H, Katayama R, Hashimoto C, Zhang X, Noda T, Tsuruo T, Naito M. Nat Cell Biol. 2004; 6(9):849-860. Medline 15300255

BRUCE, a giant E2/E3 ubiquitin ligase and inhibitor of apoptosis protein of the trans-Golgi network, is required for normal placenta development and mouse survival. Lotz K, Pyrowolakis G, Jentsch S. Mol Cell Biol. 2004; 24(21):9339-9350. Medline 15485903

An Apollon vista of death and destruction. Martin SJ. Nat Cell Biol. 2004; 6(9):804-806. Medline 15340445

Nrdp1-mediated degradation of the gigantic IAP, BRUCE, is a novel pathway for triggering apoptosis. Qiu XB, Markant SL, Yuan J, Goldberg AL. EMBO J. 2004; 23(4):800-810. Medline 14765125

Bone marrow cells of myelodysplastic syndromes exhibit significant expression of apollon, livin and ILP-2 with reduction after transformation to overt leukemia. Abe S, Yamamoto K, Hasegawa M, Inoue M, Kurata M, Hirokawa K, Kitagawa M, Nakagawa Y, Suzuki K. Leuk Res. 2005; 29(9):1095-1096. Medline 16038738

Atlas Genet Cytogenet Oncol Haematol 2007; 2 128 Progressive loss of the spongiotrophoblast layer of Birc6/Bruce mutants results in embryonic lethality. Hitz C, Vogt-Weisenhorn D, Ruiz P, Wurst W, Floss T. Genesis. 2005; 42(2):91-103. Erratum in: Genesis. 2005; 43(4):216. Medline 15887267

The membrane-associated inhibitor of apoptosis protein, BRUCE/Apollon, antagonizes both the precursor and mature forms of Smac and caspase-9. Qiu XB, Goldberg AL. J Biol Chem. 2005; 280(1):174-182. Medline 15507451

The Birc6 (Bruce) gene regulates p53 and the mitochondrial pathway of apoptosis and is essential for mouse embryonic development. Ren J, Shi M, Liu R, Yang QH, Johnson T, Skarnes WC, Du C. Proc Natl Acad Sci U S A. 2005; 102(3):565-570. Medline 15640352

HtrA2 cleaves Apollon and induces cell death by IAP-binding motif in Apollon-deficient cells. Sekine K, Hao Y, Suzuki Y, Takahashi R, Tsuruo T, Naito M. Biochem Biophys Res Commun. 2005; 330(1):279-285. Medline 15781261

Bruce/apollon promotes hippocampal neuron survival and is downregulated by kainic acid. Sokka AL, Mudo G, Aaltonen J, Belluardo N, Lindholm D, Korhonen L. Biochem Biophys Res Commun. 2005; 338(2):729-735. Medline 16236253

Comparative study of gene expression by cDNA microarray in human tissues and normal mucosa. Bianchini M, Levy E, Zucchini C, Pinski V, Macagno C, De Sanctis P, Valvassori L, Carinci P, Mordoh J. Int J Oncol. 2006; 29(1):83-94. Medline 16773188

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Contributor(s) Written 11-2006 Christian Pohl, Stefan Jentsch Citation This paper should be referenced as such : Pohl C, Jentsch S . BIRC6 (Baculoviral IAP repeat-containing 6). Atlas Genet Cytogenet Oncol Haematol. November 2006 . URL : http://AtlasGeneticsOncology.org/Genes/BIRC6ID798ch2p22.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 2 129 Atlas of Genetics and Cytogenetics in Oncology and Haematology

AKAP12 (A kinase (PRKA) anchor protein 1)

Identity Other names Gravin SSeCKS AKAP250 DKFZp686M0430 DKFZp686O0331 Hugo AKAP12 Location 6q25

AKAP12 (6q24-25.2) in normal cells probed with a about 5Kb human AKAP12 probe. Courtesy of Irwin Gelman; adapted from Xia et al., Cancer Res.61:5644-5651, 2001.

DNA/RNA

Atlas Genet Cytogenet Oncol Haematol 2007; 2 130 Note The AKAP12 gene is strongly conserved from fish to humans, including syntenic regions conserved in the mouse (chrom. 10) and rat (chrom. 1).

Human and mouse cells have similar exon/intron usage and spacing. AKAP12 has three independent promoters, alpha, beta, and gamma. The gamma promoter is active only in the testes while the alpha and beta are co-active in most cells and tissues studied. Exons 1A1 and 1A2 combine to then splice to a common splice acceptor on Exon 2 used by Exon 1B. Exons 1A1 and 1A2 produce the N-terminal 103 amino acids of "AKAP12alpha" whereas Exon 1B encodes the N-terminal 8 amino acids of "AKAP12beta"; the remaining amino acids are encoded in Exon 2. "AKAP12gamma" is encoded by a read-through transcript starting in the intron upstream of Exon 2, utilizing an in-frame ATG in Exon 2. Therefore, the alpha, beta, and gamma transcripts encode proteins that only differ in their N-termini.

Pseudogene None. Protein

Atlas Genet Cytogenet Oncol Haematol 2007; 2 131

A: Except for testes, most cells express four major isoforms of AKAP12 protein. The 305 kDa isoforms is the myristylated AKAP12alpha whereas the 287 kDa isoforms is AKAP12beta. The 250 kDa and 43 kDa isoforms are proteolytic cleavage products common to the AKAP12alpha and beta isoforms. B: Human AKAP12alpha encodes a 1,780 amino acids full-length protein. The first about 1,000 amino acids of human and rodent AKAP12 share 83% identity followed by about 600 amino acids with less than 20% identity. The N-terminal homology domain (green) shows about 40% identity to the Xgl (Xenopus gravin-like) gene in Xenopus. Both human and rodent AKAP12 share a shorter C-terminal domain containing the PKA-RII binding (AKAP) domain (green box in human AKAP12).

Expression AKAP12 isoforms are expressed in most tissue and organ types, with high expression levels in the testes, ovary, brain, lung and heart. Most mesenchyme, smooth muscle and some epithelial cells (breast, prostate, lung, ovary) express significant AKAP12 levels. Lower levels of AKAP12 are found in endothelial cells, although express in these cells is usually associated with wounding and/or inflammation. Localisation Most cell types display a cortical cytoskeletal staining pattern for AKAP12, with enrichment at the plasma membrane (presumably, the myristylated isoforms) and in the perinucleus. However, some staining has been observed in cell nuclei, probably directed by 4 SV40 Tag-like nuclear localization signals (NLS) found in the N-terminal third of the protein. Function 1) Facilitates the sensitization/resensitization reaction of beta-adrenergic receptors. 2) Scaffolds protein kinase (PK) A and PKC. 3) Autoantigen in some cases of myasthenia gravis. 4) Anti-angiogenic factor. The rodent orthologue has been shown to inhibit brain angiogenesis and induce the blood-brain barrier, and to inhibit VEGF-mediated metastasis. 5) Potential tumor suppressor. The rodent orthologue has been shown to suppress Src- and Ras-induced oncogenic proliferation in vitro and metastatic

Atlas Genet Cytogenet Oncol Haematol 2007; 2 132 potential in vivo. Homology Southern blotting analysis as well as analysis of sequenced genomes indicates that vertebrates encode single AKAP12 orthologues, with no gene family members. Thus, the protein diversity of this gene stems from promoter choice, alternative splicing, proteolytic maturation and post-translational modification. AKAP12 has limited based on short domains. For example, the C-terminal AKAP domain is homologous to the analogous domain in AKP79. Also, AKAP12 shares some so-called MARCKS protein-like effector domains- positively charged stretches of amino acids involved in plasma membrane targeting. Mutations Note No known mutations are associated with AKAP12. However, there are at least 539 single nucleotide polymorphisms (SNP) as described. External links Nomenclature Hugo AKAP12 GDB AKAP12 Entrez_Gene AKAP12 9590 A kinase (PRKA) anchor protein (gravin) 12 Cards Atlas AKAP12ID607ch6q25 GeneCards AKAP12 Ensembl AKAP12 Genatlas AKAP12 GeneLynx AKAP12 eGenome AKAP12 euGene 9590 Genomic and cartography GoldenPath AKAP12 - 6q25 chr6:151603202-151719601 + 6q24-q25 (hg18-Mar_2006) Ensembl AKAP12 - 6q24-q25 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene AKAP12 Gene and transcription Genbank AB003476 [ ENTREZ ] Genbank AB210003 [ ENTREZ ] Genbank AF001504 [ ENTREZ ] Genbank AF086250 [ ENTREZ ] Genbank BC000188 [ ENTREZ ] RefSeq NM_005100 [ SRS ] NM_005100 [ ENTREZ ] RefSeq NM_144497 [ SRS ] NM_144497 [ ENTREZ ] RefSeq AC_000049 [ SRS ] AC_000049 [ ENTREZ ] RefSeq NC_000006 [ SRS ] NC_000006 [ ENTREZ ] RefSeq NT_025741 [ SRS ] NT_025741 [ ENTREZ ] RefSeq NW_923184 [ SRS ] NW_923184 [ ENTREZ ] AceView AKAP12 AceView - NCBI Unigene Hs.371240 [ SRS ] Hs.371240 [ NCBI ] HS371240 [ spliceNest ]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 133 Protein : pattern, domain, 3D structure SwissProt O43572 [ SRS] O43572 [ EXPASY ] O43572 [ INTERPRO ] Prosite PS50132 RGS [ SRS ] PS50132 RGS [ Expasy ] Interpro IPR000342 RGS [ SRS ] IPR000342 RGS [ EBI ] CluSTr O43572 Smart SM00315 RGS [EMBL] Blocks O43572 HPRD O43572 Protein Interaction databases DIP O43572 IntAct O43572 Polymorphism : SNP, mutations, diseases OMIM 604698 [ map ] GENECLINICS 604698 SNP AKAP12 [dbSNP-NCBI] SNP NM_005100 [SNP-NCI] SNP NM_144497 [SNP-NCI] SNP AKAP12 [GeneSNPs - Utah] AKAP12] [HGBASE - SRS] HAPMAP AKAP12 [HAPMAP] General knowledge Family AKAP12 [UCSC Family Browser] Browser SOURCE NM_005100 SOURCE NM_144497 SMD Hs.371240 SAGE Hs.371240 GO protein binding [Amigo] protein binding GO cytoplasm [Amigo] cytoplasm GO protein targeting [Amigo] protein targeting GO [Amigo] signal transduction G-protein coupled receptor protein signaling pathway [Amigo] G-protein coupled GO receptor protein signaling pathway GO binding [Amigo] protein kinase A binding PubGene AKAP12 Other databases Probes Probe AKAP12 Related clones (RZPD - Berlin) PubMed PubMed 20 Pubmed reference(s) in LocusLink Bibliography Molecular cloning and preliminary characterization of a novel cytoplasmic antigen recognized by myasthenia gravis sera. Gordon T, Grove B, Loftus JC, O'Toole T, McMillan R, Lindstrom J, Ginsberg MH. J Clin Invest 1992; 90(3): 992-999. Medline 1522245

Atlas Genet Cytogenet Oncol Haematol 2007; 2 134

Gravin, an autoantigen recognized by serum from myasthenia gravis patients, is a kinase scaffold protein. Nauert JB, Klauck TM, Langeberg LK, Scott JD. Curr Biol.1997; 7(1): 52-62. Medline 9000000

Dynamic complexes of beta2-adrenergic receptors with protein kinases and phosphatases and the role of gravin. Shih M, Lin F, Scott JD, Wang HY, Malbon CC. J Biol Chem 1999; 274(3): 1588-1595. Medline 9880537

The scaffold protein gravin (cAMP-dependent protein kinase-anchoring protein 250) binds the beta 2-adrenergic receptor via the receptor cytoplasmic Arg-329 to Leu-413 domain and provides a mobile scaffold during desensitization. Fan G, Shumay E, Wang H, Malbon CC. J Biol Chem 2001; 276(26): 24005-24014. Medline 11309381

The role of SSeCKS/gravin/AKAP12 scaffolding proteins in the spaciotemporal control of signaling pathways in oncogenesis and development . Gelman, IH Front Biosci 2002; 7: d1782-1797. Review. Medline 12133808

Low expression of the putative tumour suppressor gene gravin in chronic myeloid leukaemia, myelodysplastic syndromes and acute myeloid leukaemia. Boultwood J, Pellagatti A, Watkins F, Campbell LJ, Esoof N, Cross NC, Eagleton H, Littlewood TJ, Fidler C, Wainscoat JS. Br J Haematol 2004; 126(4): 508-511. Medline 15287943

AKAP12/Gravin is inactivated by epigenetic mechanism in human gastric carcinoma and shows growth suppressor activity. Choi MC, Jong HS, Kim TY, Song SH, Lee DS, Lee JW, Kim TY, Kim NK, Bang YJ. Oncogene 2004; 23(42): 7095-7103. Medline 15258566

Multiple promoters direct expression of three AKAP12 isoforms with distinct subcellular and tissue distribution profiles. Streb JW, Kitchen CM, Gelman IH, Miano JM. J Biol Chem 2004; 279(53): 56014-56023. Medline 15496411

SSeCKS metastasis-suppressing activity in MatLyLu prostate cancer cells correlates with vascular endothelial growth factor inhibition. Su B, Zheng Q, Vaughan MM, Bu Y, Gelman IH. Cancer Res 2006; 66(11): 5599-5607. Medline 16740695

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Contributor(s) Written 11-2006 Irwin H Gelman Citation This paper should be referenced as such : Gelman IH . AKAP12. Atlas Genet Cytogenet Oncol Haematol. November 2006 . URL : http://AtlasGeneticsOncology.org/Genes/AKAP12ID607ch6q25.html

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Atlas Genet Cytogenet Oncol Haematol 2007; 2 136 Atlas of Genetics and Cytogenetics in Oncology and Haematology

TRIM 24 (tripartite motif-containing 24)

Identity Other names PTC6 TF1A TIF1 RNF82 TIF1A hTIF1 TIF1ALPHA Hugo TRIM24 Location 7q34 DNA/RNA Description The TRIM24 gene is organized in 19 exons. There are 2 corresponding transcripts, which give rise to 2 different isoforms (alternative splicing), the first one being shorter. transcript = 3905 bp; protein = 1016 amino acids; transcript = 4007 bp; protein = 1050 amino acids. Protein

Description TRIM24 encodes a nuclear protein, transcription intermediary factor 1a displaying an RBCC motif (RING finger, B-BOX, and coiled-coil domains, also called tripartite motif, TRIM) in its N-terminus and PHD and bromo domains at the C-terminus. The following is a scheme (not drawn to scale) of the protein and its domains. Expression ubiquitously and early in development, but also in many adult tissues Localisation The protein localizes to the nucleus (nuclear bodies). Function Transcriptional regulator of nuclear receptors, including retinoic acid, thyroid, vitamin D3, and estrogen receptors; participates in multiprotein complexes; interacts with numerous proteins involved in chromatin structure; recruitment of TRIM24 to specific sites in the genome would ensure the localization of initiating RNA polII, and of chromatin remodeling complexes; may function through modulation of chromatin states (regulator of higher order chromatin structures, in order to promote silencing on euchromatic genes); TRIM24 has been demonstrated to possess an intrinsic transcriptional silencing activity which requires histone deacetylation; interacts directly with members of the heterochromatin protein 1 family. May be a key regulator of developmental and physiological processes.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 137 Homology TRIM28/TIF1B, TRIM33/TIF1G, TRIM66/TIF1D Implicated in Entity t(7;8)(q34;p11) in leukemia --> TRIM24 - FGFR1 Disease acute myeloid leukemia (AML), 8p11 myeloproliferative syndrome (EMS). Cytogenetics t(7;8)(q34;p11) Hybrid/Mutated TRIM24-FGFR1; FGFR1-TRIM24 Gene Abnormal The 2 predicted fusion proteins are organized as follows: TRIM24-FGFR1 contains Protein the RING, BBOX and BBC domains from TRIM24 and the TK domain from FGFR1; FGFR1-TRIM24 contains the signal peptide along with the 3 IG-LIKE and transmembrane domains from FGFR1 and the PHD with the BROMO domains from TRIM24.

Entity t(7;10)(q34;q11) in papillary thyroid carcinoma: --> TRIM24- RET Disease Found in one case of papillary thyroid carcinoma, in a child (a boy aged 4 yrs) exposed to radioactive fallout after the Chernobyl reactor accident (note: children exposed to Chernobyl radioactive fallout frequently developped papillary thyroid carcinoma (PTC), and a very high prevalence of RET rearrangements was found in these childhood PTC, compared to PTC of adults). Abnormal Fusion of the 5' end of TRIM24 including the RBCC (RING finger, B-BOX, and coiled- Protein coil domains) motif to the 3' end of RET including the tyrosine kinase domain (and loosing the ligand binding and transmembrane domains of RET). Oncogenesis The fusion protein could form dimers (via the coiled coil domain) and show constitutive tyrosine phosphorylation?

External links Nomenclature Hugo TRIM24 GDB TRIM24 Entrez_Gene TRIM24 8805 tripartite motif-containing 24 Cards Atlas TRIM24ID504ch7q34 GeneCards TRIM24 Ensembl TRIM24 Genatlas TRIM24 GeneLynx TRIM24 eGenome TRIM24 euGene 8805 Genomic and cartography GoldenPath TRIM24 - 7q34 chr7:137795619-137920870 + 7q32-q34 (hg18-Mar_2006) Ensembl TRIM24 - 7q32-q34 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene TRIM24 Gene and transcription Genbank AA844662 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 138 Genbank AF009353 [ ENTREZ ] Genbank AF119042 [ ENTREZ ] Genbank AK075306 [ ENTREZ ] Genbank AK127592 [ ENTREZ ] RefSeq NM_003852 [ SRS ] NM_003852 [ ENTREZ ] RefSeq NM_015905 [ SRS ] NM_015905 [ ENTREZ ] RefSeq AC_000050 [ SRS ] AC_000050 [ ENTREZ ] RefSeq AC_000068 [ SRS ] AC_000068 [ ENTREZ ] RefSeq NC_000007 [ SRS ] NC_000007 [ ENTREZ ] RefSeq NT_007933 [ SRS ] NT_007933 [ ENTREZ ] RefSeq NT_079596 [ SRS ] NT_079596 [ ENTREZ ] RefSeq NW_923640 [ SRS ] NW_923640 [ ENTREZ ] AceView TRIM24 AceView - NCBI Unigene Hs.490287 [ SRS ] Hs.490287 [ NCBI ] HS490287 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P19474 [ SRS] P19474 [ EXPASY ] P19474 [ INTERPRO ] Prosite PS50188 B302_SPRY [ SRS ] PS50188 B302_SPRY [ Expasy ] Prosite PS50119 ZF_BBOX [ SRS ] PS50119 ZF_BBOX [ Expasy ] Prosite PS00518 ZF_RING_1 [ SRS ] PS00518 ZF_RING_1 [ Expasy ] Prosite PS50089 ZF_RING_2 [ SRS ] PS50089 ZF_RING_2 [ Expasy ] Interpro IPR001870 B302 [ SRS ] IPR001870 B302 [ EBI ] Interpro IPR003879 Butyrophylin [ SRS ] IPR003879 Butyrophylin [ EBI ] Interpro IPR006574 PRY [ SRS ] IPR006574 PRY [ EBI ] Interpro IPR003877 SPRY_rcpt [ SRS ] IPR003877 SPRY_rcpt [ EBI ] Interpro IPR000315 Znf_Bbox [ SRS ] IPR000315 Znf_Bbox [ EBI ] Interpro IPR001841 Znf_RING [ SRS ] IPR001841 Znf_RING [ EBI ] CluSTr P19474 Pfam PF00622 SPRY [ SRS ] PF00622 SPRY [ Sanger ] pfam00622 [ NCBI-CDD ] Pfam PF00643 zf-B_box [ SRS ] PF00643 zf-B_box [ Sanger ] pfam00643 [ NCBI-CDD ] PF00097 zf-C3HC4 [ SRS ] PF00097 zf-C3HC4 [ Sanger ] pfam00097 [ NCBI- Pfam CDD ] Smart SM00336 BBOX [EMBL] Smart SM00589 PRY [EMBL] Smart SM00184 RING [EMBL] Smart SM00449 SPRY [EMBL] Blocks P19474 HPRD P19474 Protein Interaction databases DIP P19474 IntAct P19474 Polymorphism : SNP, mutations, diseases OMIM 188550;603406 [ map ] GENECLINICS 188550;603406 SNP TRIM24 [dbSNP-NCBI]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 139 SNP NM_003852 [SNP-NCI] SNP NM_015905 [SNP-NCI] SNP TRIM24 [GeneSNPs - Utah] TRIM24] [HGBASE - SRS] HAPMAP TRIM24 [HAPMAP] General knowledge Family TRIM24 [UCSC Family Browser] Browser SOURCE NM_003852 SOURCE NM_015905 SMD Hs.490287 SAGE Hs.490287 GO DNA binding [Amigo] DNA binding specific RNA polymerase II transcription factor activity [Amigo] specific RNA GO polymerase II transcription factor activity GO transcription coactivator activity [Amigo] transcription coactivator activity GO intracellular [Amigo] intracellular GO nucleus [Amigo] nucleus GO cytoplasm [Amigo] cytoplasm GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent transcription from RNA polymerase II promoter [Amigo] transcription from RNA GO polymerase II promoter GO zinc ion binding [Amigo] zinc ion binding ligand-dependent nuclear receptor binding [Amigo] ligand-dependent nuclear GO receptor binding GO metal ion binding [Amigo] metal ion binding PubGene TRIM24 Other databases Probes Probe TRIM24 Related clones (RZPD - Berlin) PubMed PubMed 22 Pubmed reference(s) in LocusLink Bibliography A possible involvement of TIF1 alpha and TIF1 beta in the epigenetic control of transcription by nuclear receptors. Le Douarin B, Nielsen AL, Garnier JM, Ichinose H, Jeanmougin F, Losson R, Chambon P. EMBO J 1996;15: 6701-6715. Medline 8978696

Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1. Thenot S, Henriquet C, Rochefort H, Cavailles V. J Biol Chem 1997; 272: 12062-12068. Medline 9115274

The transcription coactivator HTIF1 and a related protein are fused to the RET receptor

Atlas Genet Cytogenet Oncol Haematol 2007; 2 140 tyrosine kinase in childhood papillary thyroid carcinomas. Klugbauer S, Rabes HM. Oncogene 1999; 18: 4388-4393. Medline 10439047

TIF1delta, a novel HP1-interacting member of the transcriptional intermediary factor 1 (TIF1) family expressed by elongating spermatids. Khetchoumian K, Teletin M, Mark M, Lerouge T, Cervino M, Oulad-Abdelghani M, Chambon P, Losson R. J Biol Chem 2004; 279: 48329-48341. Medline 15322135

8p11 Myeloproliferative Syndrome with a Novel t(7;8) Translocation Leading to Fusion of the FGFR1 and TIF1 Genes. Elena Belloni, Maurizio Trubia, Patrizia Gasparini, Carla Micucci, Cinzia Tapinassi, Stefano Gonfalonieri, Paolo Nuciforo, Bruno Martino, Francesco Lo Coco, Pier Giuseppe Pelicci, and Pier Paolo Di Fiore. Genes Cancer 2005; 42: 320325. Medline 15609342

Role of TIF1 as a modulator of embryonic transcription in the mouse zygote Torres-Padilla ME, Zernicka-Goetz M J Cell Biol 2006; 174: 329-338. Medline 16880268

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Contributor(s) Written 02-2006 Elena Belloni, Pier Giuseppe Pelicci, Pier Paolo Di Fiore. Updated 12-2006 Jean Loup Huret Citation This paper should be referenced as such : Belloni E, Pelicci PG, Di Fiore PP. . TRIM 24 (tripartite motif-containing 24). Atlas Genet Cytogenet Oncol Haematol. February 2006 . URL : http://AtlasGeneticsOncology.org/Genes/TRIM24ID504ch7q34.html Huret JL . TRIM 24 (tripartite motif-containing 24). Atlas Genet Cytogenet Oncol Haematol. December 2006 . URL : http://AtlasGeneticsOncology.org/Genes/TRIM24ID504ch7q34.html

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Atlas Genet Cytogenet Oncol Haematol 2007; 2 141 Atlas of Genetics and Cytogenetics in Oncology and Haematology

RUNX 2 (Runt-related transcription factor 2)

Identity Other names PEBP2-ALPHA-A OSF2 AML3 CBFA1 Hugo RUNX2 Location 6p21 DNA/RNA Description 124,63 kb, 8 Exon at least. Transcription The transcription of the RUNX2 gene is regulated by two different promoters. The larger P1 transcript gives rise to a protein starting with the amino acid sequence MASNS (Runx2-type II or OSF2/CBFA1a, 521 amino acids), whereas the P2 gives rise to a protein starting with MRIPV (Runx2-type I or isoform c, 507 amino acids). Transcript variants of this protein have been reported as well due to alternative splicing. Protein

Description Runx2 is a transcription factor belonging to Runx family. This family is characterized by a highly conserved region of 128 amino acids, termed the Runt domain. The Runt domain is responsible for DNA binding and heterodimerization with CBFB (PEBP2b), which increases its DNA-binding affinity and also stabilizes RUNX proteins against proteolytic degradation. The C-terminal portion is rich in proline, serine and threonine (PST region) and contains functional domains acting to regulate transcription. Expression Runx2 expression is largely restricted to osteoblasts and mesenchymal condensations forming bones, cartilages and teeth. Localisation Nuclear Function Runx2 is an osteoblast-specific transcription factor that plays a central role in osteoblast differentiation, chondrocyte maturation, bone formation and remodeling. Moreover, it is a key target of mechanical signals that affect bone biology. Homology RUNX family. Mutations Note Heterozygous mutations (frameshift, nonsense, missense, splicing mutations) of the Runx2 gene have been identified in patients with Cleidocranial dysplasia (CCD). Implicated in Entity Cleidocranial Dysplasia (CCD) Disease CCD is a dominantly inherited autosomal skeletal disorder that is characterized by open sutures and delayed closure of sutures, hypoplastic or aplastic clavicles, short stature, large fontanelles, dental anomalies and delayed skeletal development. Prognosis CCD does not affect life expectancy and most diagnosed persons enjoy good overall

Atlas Genet Cytogenet Oncol Haematol 2007; 2 142 health. There is no specific treatment for CCD and the dental problems are the most significant complications.

Entity Lymphomas Disease Runx2 and MYC collaborate in lymphoma development by suppressing apoptotic and growth arrest pathways in vivo.

Entity Multiple myeloma. Disease Human myeloma cells express the bone regulating gene Runx2 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients.

Entity Metastatic properties of cancer cells. Disease Runx2 control multiple genes that contribute to the metastatic properties of cancer cells and their activity in the bone microenvironment.

Entity Breast cancer. Disease Involvement of Runx2 transcription factors in breast cancer cells.

Entity Malignant melanoma. Disease Coexpression of bone sialoprotein and Runx2, in malignant melanoma.

Entity Prostate cancer. Disease Prostate cancer expression of runt-domain transcription factor Runx2.

External links Nomenclature Hugo RUNX2 GDB RUNX2 Entrez_Gene RUNX2 860 runt-related transcription factor 2 Cards Atlas RUNX2ID42183ch6p21 GeneCards RUNX2 Ensembl RUNX2 Genatlas RUNX2 GeneLynx RUNX2 eGenome RUNX2 euGene 860 Genomic and cartography GoldenPath RUNX2 - 6p21 chr6:45404032-45626796 + 6p21 (hg18-Mar_2006) Ensembl RUNX2 - 6p21 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene RUNX2 Gene and transcription

Atlas Genet Cytogenet Oncol Haematol 2007; 2 143 Genbank AF053952 [ ENTREZ ] Genbank AF087960 [ ENTREZ ] Genbank AL353944 [ ENTREZ ] Genbank BC108919 [ ENTREZ ] Genbank BC108920 [ ENTREZ ] RefSeq NM_001015051 [ SRS ] NM_001015051 [ ENTREZ ] RefSeq NM_001024630 [ SRS ] NM_001024630 [ ENTREZ ] RefSeq NM_004348 [ SRS ] NM_004348 [ ENTREZ ] RefSeq AC_000049 [ SRS ] AC_000049 [ ENTREZ ] RefSeq NC_000006 [ SRS ] NC_000006 [ ENTREZ ] RefSeq NT_007592 [ SRS ] NT_007592 [ ENTREZ ] RefSeq NW_923073 [ SRS ] NW_923073 [ ENTREZ ] AceView RUNX2 AceView - NCBI Unigene Hs.535845 [ SRS ] Hs.535845 [ NCBI ] HS535845 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q06455 [ SRS] Q06455 [ EXPASY ] Q06455 [ INTERPRO ] Prosite PS51119 TAFH [ SRS ] PS51119 TAFH [ Expasy ] Prosite PS01360 ZF_MYND_1 [ SRS ] PS01360 ZF_MYND_1 [ Expasy ] Prosite PS50865 ZF_MYND_2 [ SRS ] PS50865 ZF_MYND_2 [ Expasy ] Interpro IPR013289 ETO [ SRS ] IPR013289 ETO [ EBI ] Interpro IPR013290 MTG8 [ SRS ] IPR013290 MTG8 [ EBI ] Interpro IPR003894 TAFH_NHR1 [ SRS ] IPR003894 TAFH_NHR1 [ EBI ] Interpro IPR002893 Znf_MYND [ SRS ] IPR002893 Znf_MYND [ EBI ] CluSTr Q06455 Pfam PF07531 TAFH [ SRS ] PF07531 TAFH [ Sanger ] pfam07531 [ NCBI-CDD ] Pfam PF01753 zf-MYND [ SRS ] PF01753 zf-MYND [ Sanger ] pfam01753 [ NCBI-CDD ] Smart SM00549 TAFH [EMBL] Blocks Q06455 PDB 1WQ6 [ SRS ] 1WQ6 [ PdbSum ], 1WQ6 [ IMB ] 1WQ6 [ RSDB ] HPRD Q06455 Protein Interaction databases DIP Q06455 IntAct Q06455 Polymorphism : SNP, mutations, diseases OMIM 119600;600211 [ map ] GENECLINICS 119600;600211 SNP RUNX2 [dbSNP-NCBI] SNP NM_001015051 [SNP-NCI] SNP NM_001024630 [SNP-NCI] SNP NM_004348 [SNP-NCI] SNP RUNX2 [GeneSNPs - Utah] RUNX2] [HGBASE - SRS] HAPMAP RUNX2 [HAPMAP] General knowledge

Atlas Genet Cytogenet Oncol Haematol 2007; 2 144 Family RUNX2 [UCSC Family Browser] Browser SOURCE NM_001015051 SOURCE NM_001024630 SOURCE NM_004348 SMD Hs.535845 SAGE Hs.535845 GO osteoblast differentiation [Amigo] osteoblast differentiation GO chondrocyte differentiation [Amigo] chondrocyte differentiation GO chromatin binding [Amigo] chromatin binding GO transcription factor activity [Amigo] transcription factor activity GO transcription factor activity [Amigo] transcription factor activity RNA polymerase II transcription factor activity [Amigo] RNA polymerase II transcription factor GO activity GO protein binding [Amigo] protein binding GO ATP binding [Amigo] ATP binding GO nucleus [Amigo] nucleus GO cytoplasm [Amigo] cytoplasm GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO positive regulation of cell proliferation [Amigo] positive regulation of cell proliferation GO negative regulation of transcription [Amigo] negative regulation of transcription GO transcriptional activator activity [Amigo] transcriptional activator activity regulation of fibroblast growth factor receptor signaling pathway [Amigo] regulation of GO fibroblast growth factor receptor signaling pathway regulation of odontogenesis (sensu Vertebrata) [Amigo] regulation of odontogenesis (sensu GO Vertebrata) negative regulation of smoothened signaling pathway [Amigo] negative regulation of GO smoothened signaling pathway positive regulation of transcription from RNA polymerase II promoter [Amigo] positive GO regulation of transcription from RNA polymerase II promoter GO cell maturation [Amigo] cell maturation PubGene RUNX2 Other databases Other http://www.nlm.nih.gov/medlineplus/ency/article/001589.htm database Other http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Cleidocranial+Dysplasia database Other http://www.gfmer.ch/genetic_diseases_v2/gendis_detail_list.php?cat3=66 database Probes Probe RUNX2 Related clones (RZPD - Berlin) PubMed PubMed 98 Pubmed reference(s) in LocusLink Bibliography

Atlas Genet Cytogenet Oncol Haematol 2007; 2 145 Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G. Cell. 1997; 89: 747-754. Medline 9182762

Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao YH, Inada M, Sato M, Okamoto R, Kitamura Y, Yoshiki S, Kishimoto T. Cell. 1997; 89: 755-764. Medline 9182763

Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia. Lee B, Thirunavukkarasu K, Zhou L, Pastore L, Baldini A, Hecht J, Geoffroy V, Ducy P, Karsenty G. Nature Genet. 1997; 16: 307-310. Medline 9207800

Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Mundlos S, Otto F, Mundlos C, Mulliken JB, Aylsworth AS, Albright S, Lindhout D, Cole WG, Henn W, Knoll JHM, Owen MJ, Mertelsmann R, Zabel BU, Olsen BR. Cell. 1997; 89: 773-779. Medline 9182765

Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, Stamp GWH, Beddington RSP, Mundlos S, Olsen BR, Selby PB, Owen MJ. Cell. 1997; 89: 765-771. Medline 9182764

Genomic organization, expression of the human CBFA1 gene, and evidence for an alternative splicing event affecting protein function. Geoffroy V, Corral DA, Zhou L, Lee B, Karsenty G. Mammalian Genome. 1998; 9: 54-57. Medline 9434946

A natural history of cleidocranial dysplasia. Cooper SC, Flaitz CM, Johnston DA, Lee B, Hecht JT. Am. J. Med. Genet. 2001; 104: 1-6. Medline 11746020

RUNX: a trilogy of cancer genes. Lund AH, van Lohuizen M. Cancer Cell. 2002; 1:213-215. Review. Medline 12086855

The bone-specific transcriptional regulator Cbfa1 is a target of mechanical signals in osteoblastic cells. Ziros PG, Gil APR, Georgakopoulos T, Habeos I, Kletsas D, Basdra EK, Papavassiliou AG. J. Biol. Chem. 2002; 277: 23934-23941. Medline 11960980

Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression

Atlas Genet Cytogenet Oncol Haematol 2007; 2 146 of bone sialoprotein in human metastatic breast cancer cells. Barnes GL, Javed A, Waller SM, Kamal MH, Hebert KE, Hassan MQ, Bellahcene A,Van Wijnen AJ, Young MF, Lian JB, Stein GS, Gerstenfeld LC. Cancer Res. 2003; 63:2631-2637. Medline 12750290

Oncogenic potential of the RUNX gene family: overview. Ito Y. Oncogene. 2004; 23:4198-4208 Review. Medline 15156173

Impaired intranuclear trafficking of Runx2 (AML3/CBFA1) transcription factors in breast cancer cells inhibits osteolysis in vivo. Javed A, Barnes GL, Pratap J, Antkowiak T, Gerstenfeld LC, van Wijnen AJ, Stein JL, Lian JB, Stein GS. Proc Natl Acad Sci U S A. 2005; 102:1454-1459. Medline 15665096

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Contributor(s) Written 12-2006 Athanasios G Papavassiliou, Panos Ziros Citation This paper should be referenced as such : Papavassiliou AG, Ziros P . RUNX 2 (Runt-related transcription factor 2). Atlas Genet Cytogenet Oncol Haematol. December 2006 . URL : http://AtlasGeneticsOncology.org/Genes/RUNX2ID42183ch6p21.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 2 147 Atlas of Genetics and Cytogenetics in Oncology and Haematology

PTPRG (protein tyrosine phosphatase, receptor type, G)

Identity Other names HPTPG PTPG R-PTP-GAMMA RPTPG Hugo PTPRG Location 3p14.2 DNA/RNA Description The PTPRG gene is composed of 30 exons and is approximately 780 kb in size. Transcription The transcript length is 4338 bp. An alternatively spliced variant has been reported with a transcript length of 5655 bp. Pseudogene no pseudogenes have been reported. Protein

Description Amino acids: 1445. Molecular weight: 162058 Daltons. The PTPRG gene belongs to the receptor class 5 subfamily of the protein-tyrosine phosphatase family. Expression PTPRG is expressed in several tissues. Localisation Membrane. Single-pass type I membrane protein. Function Involved in regulating signaling through ligand-controlled protein tyrosine dephosphorylation. The protein contains an extracellular carbonic anhydrase-like and fibronectin type III-like domain, a single transmembrane domain, and a cytoplasmic region with 2 tandem catalytic tyrosine phosphatase domains. Y2H, animal models. Homology PTPRG shares a PTP domain, involved in dephosphorylating phosphorylated tyrosine residues, with the other receptor-like protein tyrosine phosphatases. The PTPRG gene is conserved in vertebrates. The human and mouse (1442-amino acid) sequences share 95% identity at the amino acid level. Mutations Germinal No germline mutations have been reported. Somatic 8 different missense mutations in the PTPRG gene have been identified in colon carcinomas: C1082T (T361M), C1385T (A462V), C1541T (T514M), C1777T (R593W), A2864G (E955G), A2918G (Y973C), C3934T (R1312W) A3976G (I1326V). Loss of heterozygosity (LOH) of a region which includes the PTPRG has been shown in clear renal cell carcinoma, lung carcinoma and colon carcinoma. Implicated in Note PTPRG has been considered a potential based on its function, antagonizing activity of protein tyrosine kinases that often function as oncoproteins. Secondly, because it maps to a region of human 3, 3p21, that is

Atlas Genet Cytogenet Oncol Haematol 2007; 2 148 frequently deleted in renal cell carcinoma and Lung carcinoma. Thirdly, because PTPRG has been shown to harbor point mutations in a subset of colon carcinomas. Fourthly, because the PTPRG gene shows promoter hypermethylation in cutaneous T- cell lymphoma and melanoma. Finally, lower expression levels of PTPRG have been reported for a number of cancerous tissues including gastric cancer. External links Nomenclature Hugo PTPRG GDB PTPRG Entrez_Gene PTPRG 5793 protein tyrosine phosphatase, receptor type, G Cards Atlas PTPRGID41930ch3p21 GeneCards PTPRG Ensembl PTPRG Genatlas PTPRG GeneLynx PTPRG eGenome PTPRG euGene 5793 Genomic and cartography GoldenPath PTPRG - 3p14.2 chr3:61522285-62254737 + 3p21-p14 (hg18-Mar_2006) Ensembl PTPRG - 3p21-p14 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene PTPRG Gene and transcription Genbank AB209871 [ ENTREZ ] Genbank AI872451 [ ENTREZ ] Genbank BC036018 [ ENTREZ ] Genbank BC047734 [ ENTREZ ] Genbank BC048961 [ ENTREZ ] RefSeq NM_002841 [ SRS ] NM_002841 [ ENTREZ ] RefSeq AC_000046 [ SRS ] AC_000046 [ ENTREZ ] RefSeq NC_000003 [ SRS ] NC_000003 [ ENTREZ ] RefSeq NT_022517 [ SRS ] NT_022517 [ ENTREZ ] RefSeq NW_921651 [ SRS ] NW_921651 [ ENTREZ ] AceView PTPRG AceView - NCBI Unigene Hs.654488 [ SRS ] Hs.654488 [ NCBI ] HS654488 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P10586 [ SRS] P10586 [ EXPASY ] P10586 [ INTERPRO ] Prosite PS50853 FN3 [ SRS ] PS50853 FN3 [ Expasy ] Prosite PS50835 IG_LIKE [ SRS ] PS50835 IG_LIKE [ Expasy ] PS00383 TYR_PHOSPHATASE_1 [ SRS ] PS00383 TYR_PHOSPHATASE_1 [ Expasy Prosite ] PS50056 TYR_PHOSPHATASE_2 [ SRS ] PS50056 TYR_PHOSPHATASE_2 [ Expasy Prosite ]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 149 PS50055 TYR_PHOSPHATASE_PTP [ SRS ] PS50055 TYR_PHOSPHATASE_PTP [ Prosite Expasy ] Interpro IPR003961 FN_III [ SRS ] IPR003961 FN_III [ EBI ] Interpro IPR008957 FN_III-like [ SRS ] IPR008957 FN_III-like [ EBI ] Interpro IPR003962 FnIII_subd [ SRS ] IPR003962 FnIII_subd [ EBI ] Interpro IPR007110 Ig-like [ SRS ] IPR007110 Ig-like [ EBI ] Interpro IPR013098 Ig_I-set [ SRS ] IPR013098 Ig_I-set [ EBI ] Interpro IPR003599 Ig_sub [ SRS ] IPR003599 Ig_sub [ EBI ] Interpro IPR003598 Ig_sub2 [ SRS ] IPR003598 Ig_sub2 [ EBI ] Interpro IPR003595 PTPc_motif [ SRS ] IPR003595 PTPc_motif [ EBI ] Interpro IPR000387 TYR_phosphatase [ SRS ] IPR000387 TYR_phosphatase [ EBI ] Interpro IPR000242 Tyr_PP [ SRS ] IPR000242 Tyr_PP [ EBI ] CluSTr P10586 Pfam PF00041 fn3 [ SRS ] PF00041 fn3 [ Sanger ] pfam00041 [ NCBI-CDD ] Pfam PF07679 I-set [ SRS ] PF07679 I-set [ Sanger ] pfam07679 [ NCBI-CDD ] PF00102 Y_phosphatase [ SRS ] PF00102 Y_phosphatase [ Sanger ] pfam00102 [ Pfam NCBI-CDD ] Smart SM00060 FN3 [EMBL] Smart SM00409 IG [EMBL] Smart SM00408 IGc2 [EMBL] Smart SM00194 PTPc [EMBL] Smart SM00404 PTPc_motif [EMBL] Blocks P10586 PDB 1LAR [ SRS ] 1LAR [ PdbSum ], 1LAR [ IMB ] 1LAR [ RSDB ] HPRD P10586 Protein Interaction databases DIP P10586 IntAct P10586 Polymorphism : SNP, mutations, diseases OMIM 176886 [ map ] GENECLINICS 176886 SNP PTPRG [dbSNP-NCBI] SNP NM_002841 [SNP-NCI] SNP PTPRG [GeneSNPs - Utah] PTPRG] [HGBASE - SRS] HAPMAP PTPRG [HAPMAP] General knowledge Family PTPRG [UCSC Family Browser] Browser SOURCE NM_002841 SMD Hs.654488 SAGE Hs.654488 Enzyme 3.1.3.48 [ Enzyme-SRS ] 3.1.3.48 [ Brenda-SRS ] 3.1.3.48 [ KEGG ] 3.1.3.48 [ WIT ] GO carbonate dehydratase activity [Amigo] carbonate dehydratase activity GO protein tyrosine phosphatase activity [Amigo] protein tyrosine phosphatase activity

Atlas Genet Cytogenet Oncol Haematol 2007; 2 150 transmembrane receptor protein tyrosine phosphatase activity [Amigo] transmembrane GO receptor protein tyrosine phosphatase activity GO integral to plasma membrane [Amigo] integral to plasma membrane GO protein amino acid dephosphorylation [Amigo] protein amino acid dephosphorylation one-carbon compound metabolic process [Amigo] one-carbon compound metabolic GO process transmembrane receptor protein tyrosine kinase signaling pathway GO [Amigo] transmembrane receptor protein tyrosine kinase signaling pathway GO zinc ion binding [Amigo] zinc ion binding GO membrane [Amigo] membrane GO hydrolase activity [Amigo] hydrolase activity GO phosphoric monoester hydrolase activity [Amigo] phosphoric monoester hydrolase activity KEGG Phosphatidylinositol Signaling System PubGene PTPRG Other databases Probes Probe PTPRG Related clones (RZPD - Berlin) PubMed PubMed 13 Pubmed reference(s) in LocusLink Bibliography Receptor protein-tyrosine phosphatase gamma is a candidate tumor suppressor gene at human chromosome region 3p21. LaForgia S, Morse B, Levy J, Barnea G, Cannizzaro LA, Li F, Nowell PC, Boghosian-Sell L, Glick J, Weston A, et al. Proc Natl Acad Sci U S A. 1991; 88(11): 5036-5040. Medline 1711217

Mutational analysis of the tyrosine phosphatome in colorectal cancers. Wang Z, Shen D, Parsons DW, Bardelli A, Sager J, Szabo S, Ptak J, Silliman N, Peters BA, van der Heijden MS, Parmigiani G, Yan H, Wang TL, Riggins G, Powell SM, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE. Science. 2004; 304(5674): 1164-1166. Medline 15155950

Epigenetic profiling of cutaneous T-cell lymphoma: promoter hypermethylation of multiple tumor suppressor genes including BCL7a, PTPRG, and p73. van Doorn R, Zoutman WH, Dijkman R, de Menezes RX, Commandeur S, Mulder AA, van der Velden PA, Vermeer MH, Willemze R, Yan PS, Huang TH, Tensen CP. J Clin Oncol. 2005; 23(17): 3886-3896. Medline 15897551

Silencing of Peroxiredoxin 2 and aberrant of 33 CpG islands in putative promoter regions in human malignant melanomas. Furuta J, Nobeyama Y, Umebayashi Y, Otsuka F, Kikuchi K, Ushijima T. Cancer Res. 2006; 66(12): 6080-6. Medline 16778180

Protein tyrosine-phosphatase expression profiling in gastric cancer tissues. Wu CW, Kao HL, Li AF, Chi CW, Lin WC. Cancer Lett. 2006; 242(1): 95-103.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 151 Medline 16338072

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Contributor(s) Written 12-2006 Cornelis P Tensen, Remco van Doorn Citation This paper should be referenced as such : Tensen CP, van Doorn R . PTPRG (protein tyrosine phosphatase, receptor type, G). Atlas Genet Cytogenet Oncol Haematol. December 2006 . URL : http://AtlasGeneticsOncology.org/Genes/PTPRGID41930ch3p21.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 2 152 Atlas of Genetics and Cytogenetics in Oncology and Haematology

PPP1R13L (protein phosphatase 1, regulatory (inhibitor) subunit 13 like)

Identity Other names RAI (relA associated inhibitor) IASPP (Inhibitor of ASPP protein) Hugo PPP1R13L Location 19q13.32 DNA/RNA Description 26,674 bp 13 exons. Transcription 3,076 bps. Protein

Description 828 amino acids. Function PPP1R13L was originally named RAI, an acronym for RelA associated inhibitor. It was originally identified by yeast two-hybrid screening using RelA as bait. PPP1R13L was shown to associate specifically with relA and inhibit relA mediated NF-kappaB activated transcription when NF-kappaB specific transcription was activated by TNF. Yang et al. found no interaction with p53. The mRNA expression was examined in several tissues and was found to be high in heart, placenta, prostate tissues and detectable in lung, kidney, pancreas, spleen thymus, ovary, small intestine and colon. Bergamaschi et al found that PPP1R13L interacts with p53. Antisense RNA or RNAi mediated down regulation of PPP1R13L expression and induced apoptosis. Increased expression of PPP1R13L lead to increased resistance towards cisplatin and UV- induced apoptosis. This indicates that RAI inhibits apoptosis. Several studies provide evidence that PPP1R13L expression is increased in tumor tissue. In a study of colorectal adenomas and colorectal cancers, PPP1R13L expression was found to be substantially higher in lesions than in the normal tissue from the same patient. PPP1R13L expression has also been found to be increased in breast carcinomas and in blood cells in patients with acute leukemia. In a prospective study of lung cancer among 265 lung cancer cases and 272 controls nested within the population based 'Diet, Cancer and Health study', PPP1R13L expression in mononuclear blood cells (isolated by buffy coat) was not associated with risk of lung cancer. mRNA levels were found to be 41% higher in women than in men. Mutations Note Genetic Epidemiology: The most frequently studied polymorphism in PPP1R13L is PPP1R13L IVS1 A4364G (rs1970764). Carriers of the variant allele have been shown to be at decreased risk of basal cell carcinoma among younger persons (< 50 years), breast cancer (<55 years) and lung cancer (<56 years). The polymorphism is part of a haplotype, which has a stronger association with risk of cancer than the polymorphism itself. Homozygous carriers of the haplotype ERCC1 Asn118AsnA, ASE-1 G-21AG, PPP1R13L IVS1 A4364GA have been shown to be at increased risk of breast cancer and lung cancer. Thus, women who were homozygous

Atlas Genet Cytogenet Oncol Haematol 2007; 2 153 carriers of the haplotype ERCC1 Asn118AsnA, ASE-1 G-21AG, RAI IVS1 A4364GA, had a 9.5-fold higher risk of breast cancer before 55 years of age than women who were not homozygous carriers of the haplotype. Older women and heterozygous carriers were not at an increased risk of breast cancer. Homozygous carriers of the haplotype were found to be at 4.9-fold increased risk of lung cancer in the age interval 50-55 years. The association was stronger among women than among men, although the difference was not statistically significant. In subsequent study including more cases and a larger comparison group, a statistically significant difference between genders was found. Furthermore, it was found that the haplotype interacts with smoking intensity. Thus, among women, who were carriers of the haplotype, additional smoking at high smoking intensity (>20 cigarettes/day) was associated with increased lung cancer risk. This was not seen among women who were not homozygous carriers of the haplotype or among men. The haplotype was not associated with risk of testis cancer or with risk of colorectal adenomas or colorectal cancer. Furthermore, the haplotype was not associated with risk of basal cell carcinoma among older persons (>60 years). These results indicate that the haplotype may be associated with risk of cancer primarily among young and middle aged persons and that it may be specific for women. Implicated in Entity General increased cancer risk Note No human disease has been linked to inactivation of PPP1R13L. However, polymorphisms in PPP1R13L may be associated with increased cancer risk (see above).

External links Nomenclature Hugo PPP1R13L GDB PPP1R13L Entrez_Gene PPP1R13L 10848 protein phosphatase 1, regulatory (inhibitor) subunit 13 like Cards Atlas PPP1R13LID42997ch19q13 GeneCards PPP1R13L Ensembl PPP1R13L Genatlas PPP1R13L GeneLynx PPP1R13L eGenome PPP1R13L euGene 10848 Genomic and cartography GoldenPath PPP1R13L - 19q13.32 chr19:50574739-50600129 - 19q13.32 (hg18-Mar_2006) Ensembl PPP1R13L - 19q13.32 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene PPP1R13L Gene and transcription Genbank AF078036 [ ENTREZ ] Genbank AF078037 [ ENTREZ ] Genbank AJ888472 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 154 Genbank AK130326 [ ENTREZ ] Genbank AY869712 [ ENTREZ ] RefSeq NM_006663 [ SRS ] NM_006663 [ ENTREZ ] RefSeq AC_000062 [ SRS ] AC_000062 [ ENTREZ ] RefSeq NC_000019 [ SRS ] NC_000019 [ ENTREZ ] RefSeq NT_011109 [ SRS ] NT_011109 [ ENTREZ ] RefSeq NW_927217 [ SRS ] NW_927217 [ ENTREZ ] AceView PPP1R13L AceView - NCBI Unigene Hs.466937 [ SRS ] Hs.466937 [ NCBI ] HS466937 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q6ZU84 [ SRS] Q6ZU84 [ EXPASY ] Q6ZU84 [ INTERPRO ] CluSTr Q6ZU84 Blocks Q6ZU84 HPRD Q6ZU84 Protein Interaction databases DIP Q6ZU84 IntAct Q6ZU84 Polymorphism : SNP, mutations, diseases OMIM 607463 [ map ] GENECLINICS 607463 SNP PPP1R13L [dbSNP-NCBI] SNP NM_006663 [SNP-NCI] SNP PPP1R13L [GeneSNPs - Utah] PPP1R13L] [HGBASE - SRS] HAPMAP PPP1R13L [HAPMAP] General knowledge Family PPP1R13L [UCSC Family Browser] Browser SOURCE NM_006663 SMD Hs.466937 SAGE Hs.466937 GO transcription corepressor activity [Amigo] transcription corepressor activity GO nucleus [Amigo] nucleus GO transcription [Amigo] transcription regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO apoptosis [Amigo] apoptosis GO transcription factor binding [Amigo] transcription factor binding PubGene PPP1R13L Other databases Probes Probe PPP1R13L Related clones (RZPD - Berlin) PubMed PubMed 12 Pubmed reference(s) in LocusLink Bibliography

Atlas Genet Cytogenet Oncol Haematol 2007; 2 155 Identification of a novel inhibitor of nuclear factor-kappaB, RelA-associated inhibitor. Yang JP, Hori M, Sanda T, Okamoto T. J Biol Chem. 1999; 274(22):15662-15670. Medline 10336463

Multiple single nucleotide polymorphisms on human chromosome 19q13.2-3 associate with risk of Basal cell carcinoma. Yin J, Rockenbauer E, Hedayati M, Jacobsen NR, Vogel U, Grossman L, Bolund L, Nexo BA. Cancer Epidemiol Biomarkers Prev. 2002; 11(11):1449-1453. Medline 12433725 iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Bergamaschi D, Samuels Y, O'Neil NJ, Trigiante G, Crook T, Hsieh JK, O'Connor DJ, Zhong S, Campargue I, Tomlinson ML, Kuwabara PE, Lu X. Nat Genet. 2003; 33(2):162-167. Medline 12524540

A specific haplotype of single nucleotide polymorphisms on chromosome 19q13.2-3 encompassing the gene RAI is indicative of postmenopausal breast cancer at an early age. Nexo BA, Vogel U, Olsen A, Ketelsen T, Bukowy Z, Thomsen BL, Wallin H, Overvad K, Tjonneland A. Carcinogenesis. 2003; 24(5):899-904. Medline 12771034

Two regions in q13.2-3 are associated with risk of lung cancer. Vogel U, Laros I, Jacobsen NR, Thomsen BL, Bak H, Olsen A, Bukowy Z, Wallin H, Overvad K, Tjonneland A, Nexo BA, Raaschou-Nielsen O. Mutation Research. 2004; 546:65-74. Medline 14757194

Polymorphisms in RAI and in genes of nucleotide and base excision repair are not associated with risk of testicular cancer. Laska MJ, Nexo BA, Vistisen K, Poulsen HE, Loft S, Vogel U. Cancer Lett. 2005; 225(2):245-251. Medline 15885892

Effect of polymorphisms in XPD, RAI, ASE-1 and ERCC1 on the risk of basal cell carcinoma among Caucasians after age 50. Vogel U, Olsen A, Wallin H, Overvad K, Tjonneland A, Nexo BA. Cancer Detect Prev. 2005; 29(3):209-214. Medline 15936590

The expression of iASPP in acute leukemias. Zhang X, Wang M, Zhou C, Chen S, Wang J. Leuk Res. 2005; 29(2):179-183. Medline 15607367

Increased mRNA expression levels of ERCC1, OGG1 and RAI in colorectal adenomas and carcinomas. Saebo M, Skjelbred CF, Nexo BA, Wallin H, Hansteen IL, Vogel U, Kure EH. BMC Cancer. 2006; 6:208.:208. Medline 16914027

Effects of polymorphisms in ERCC1, ASE-1 and RAI on the risk of colorectal carcinomas and adenomas: a case control study.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 156 Skjelbred CF, Saebo M, Nexo BA, Wallin H, Hansteen IL, Vogel U, Kure EH. BMC Cancer. 2006; 6:175.:175. Medline 16817948

ERCC1, XPD and RAI mRNA levels in lymphocytes are not associated with lung cancer risk in a prospective study of Danes. Vogel U, Nexo BA, Tjonneland A, Wallin H, Hertel O, Raaschou-Nielsen O. Mutat Res. 2006; 593(1-2):88-96. Medline 16054657

Gene-environment interactions between smoking and a haplotype of RAI, ASE-1 and ERCC1 polymorphisms among women in relation to risk of lung cancer in a population-based study. Vogel U, Sorensen M, Hansen RD, Tjonneland A, Overvad K, Wallin H, Nexo BA, Raaschou-Nielsen O. Cancer Lett. 2007; 247(1):159-65. Medline 16690207

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Contributor(s) Written 12-2006 Ulla Vogel Citation This paper should be referenced as such : Vogel U. . PPP1R13L (protein phosphatase 1, regulatory (inhibitor) subunit 13 like). Atlas Genet Cytogenet Oncol Haematol. December 2006 . URL : http://AtlasGeneticsOncology.org/Genes/PPP1R13LID42997ch19q13.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 2 157 Atlas of Genetics and Cytogenetics in Oncology and Haematology

MDM2 (transformed mouse 3T3 cell double minute 2, p53 binding protein)

Identity Other names HDMX hdm2 Hugo MDM2 Location 12q15 DNA/RNA Description The gene encompasses 33 kb of DNA; 12 exons. Transcription 2.3 kb nucleotides mRNA. 1476 b open reading frame. Protein

Description 491 amino acids; 90 kDa protein. Expression Expression of MDM2 during embryogenesis was studied in mice. During 14.5 to 18.5 days of prenatal development, the nasal respiratory epithelium expresses high levels of MDM2 RNA and protein in both wild type and p53 null embryos. MDM2 expression during development is tissue-specific and is independent of p53. The mdm2 basal mRNA expression appears relatively moderate in most organs in adult mice. MDM2 gene was overexpressed in some types of leukemias and lymphomas. Overexpression was significantly more frequent in the low-grade type of B-cell non- Hodgkin's lymphoma (B-NHL) than in the intermediate/high grade types of lymphoma and the overexpression was also significantly more frequent in the advanced rather than the earlier stages of B-cell chronic lymphocytic leukemia (B-CLL). Localisation MDM2 protein was found in nucleus and cytoplasm. Function MDM2 was originally cloned from transformed Balb/c3T3 cell line called 3T3DM and was identified as an amplified oncogene in murine cell lines. MDM2 was shown to be amplified in approximately 30% of osteosarcomas and soft tissue tumors and was subsequently found to act as an ubiquitin ligase promoting proteasome dependent degradation of p53. MDM2 is also a transcriptional target of p53 such that p53 activity controls the expression and protein level of its own negative regulator, providing for an elegant feedback loop. MDM2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein. The MDM2-p53 complex also inhibits p53 mediated transactivation. MDM2 knockout mouse embryos died during development and deletion of the p53 gene rescues MDM2 null embryos. These studies suggested that p53 is lethal in the absence of MDM2 during mouse development and MDM2 is a critical regulator to control p53 activity. In addition, MDM2 involves nuclear export of p53 protein. Interaction between the p53 and MDM2 is not sufficient to mediate p53 degradation. The p53MDM2 complex must be shuttled from the nucleus to the cytoplasm in order for p53 degradation. Besides, the MDM2 protein also promotes RB (retinoblastoma) protein degradation in a proteasome-dependent manner in human tumor cell lines. MDM2 overexpression contributes to cancer development in part by destabilizing RB.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 158 Interaction between MDM2 and the tumor suppressor genes p53 and Rb lead to deregulate cell proliferation and apoptosis. MDM2 is a key factor in human tumorigenesis. Both MDM2 and Pirh2 (RCHY1) proteins are p53 ubiquitin-protein E3 ligases promoting for degradation of p53 protein. However, MDM2 operates in a distinct manner from Pirh2 in response to DNA damage in cancer cells. MDM2 protein is reduced or absent in the p53 null cells compared to the p53 positive cells, Whereas, Pirh2 expression is not affected by the status of p53. A single nucleotide polymorphism (SNP309) found in the MDM2 promoter is shown to increase the affinity of the transcriptional activator Sp1, resulting in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 pathway. In humans, SNP309 is shown to associate with accelerated tumor formation in both hereditary and sporadic cancers. Homology The MDM2 gene has been identified in various organisms including mammals, amphibians and fishes. It belongs to the ring finger ubiquitin protein E3 ligase family, containing Conserved RING-finger Domain. Mutations Note MDM2 mutations are uncommon. Point mutations were reported in human cancers. Implicated in Entity Soft tissue tumors and osteosarcomas. Disease A set of data of MDM2 amplification based on 3889 samples from tumors or xenografts from 28 tumor types from previously published sources was collected. The overall frequency of MDM2 amplification in these human tumors was 7%. Gene amplification was observed in 19 tumor types, with the highest frequency observed in soft tissue tumors (20%), osteosarcomas (16%) and esophageal carcinomas (13%). Oncogenesis MDM2 is amplified in many cancers. Because the MDM2 is an ubiquitin-protein ligase that promotes p53 protein degradation, the increased MDM2 protein could play an important role in tumorigenesis, especially in the development of soft tissue tumors, osteosarcomas and esophageal carcinomas.

External links Nomenclature Hugo MDM2 GDB MDM2 MDM2 4193 Mdm2, transformed 3T3 cell double minute 2, p53 binding protein Entrez_Gene (mouse) Cards Atlas MDM2ID115ch12q15 GeneCards MDM2 Ensembl MDM2 Genatlas MDM2 GeneLynx MDM2 eGenome MDM2 euGene 4193 Genomic and cartography GoldenPath MDM2 - 12q15 chr12:67488247-67520481 + 12q14.3-q15 (hg18-Mar_2006) Ensembl MDM2 - 12q14.3-q15 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 159 HomoloGene MDM2 Gene and transcription Genbank AF092843 [ ENTREZ ] Genbank AF092844 [ ENTREZ ] Genbank AF092845 [ ENTREZ ] Genbank AF201370 [ ENTREZ ] Genbank AF201371 [ ENTREZ ] RefSeq NM_002392 [ SRS ] NM_002392 [ ENTREZ ] RefSeq NM_006878 [ SRS ] NM_006878 [ ENTREZ ] RefSeq NM_006879 [ SRS ] NM_006879 [ ENTREZ ] RefSeq NM_006881 [ SRS ] NM_006881 [ ENTREZ ] RefSeq NM_006882 [ SRS ] NM_006882 [ ENTREZ ] RefSeq AC_000055 [ SRS ] AC_000055 [ ENTREZ ] RefSeq NC_000012 [ SRS ] NC_000012 [ ENTREZ ] RefSeq NT_029419 [ SRS ] NT_029419 [ ENTREZ ] RefSeq NW_925395 [ SRS ] NW_925395 [ ENTREZ ] AceView MDM2 AceView - NCBI Unigene Hs.567303 [ SRS ] Hs.567303 [ NCBI ] HS567303 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P21741 [ SRS] P21741 [ EXPASY ] P21741 [ INTERPRO ] Prosite PS00619 PTN_MK_1 [ SRS ] PS00619 PTN_MK_1 [ Expasy ] Prosite PS00620 PTN_MK_2 [ SRS ] PS00620 PTN_MK_2 [ Expasy ] Interpro IPR000762 PTN_MK_hepar_bd [ SRS ] IPR000762 PTN_MK_hepar_bd [ EBI ] CluSTr P21741 PF01091 PTN_MK_C [ SRS ] PF01091 PTN_MK_C [ Sanger ] pfam01091 [ Pfam NCBI-CDD ] PF05196 PTN_MK_N [ SRS ] PF05196 PTN_MK_N [ Sanger ] pfam05196 [ Pfam NCBI-CDD ] Smart SM00193 PTN [EMBL] Prodom PD005592 PTN_MK[INRA-Toulouse] P21741 MK_HUMAN [ Domain structure ] P21741 MK_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks P21741 PDB 1MKC [ SRS ] 1MKC [ PdbSum ], 1MKC [ IMB ] 1MKC [ RSDB ] PDB 1MKN [ SRS ] 1MKN [ PdbSum ], 1MKN [ IMB ] 1MKN [ RSDB ] HPRD P21741 Protein Interaction databases DIP P21741 IntAct P21741 Polymorphism : SNP, mutations, diseases OMIM 164785 [ map ] GENECLINICS 164785 SNP MDM2 [dbSNP-NCBI] SNP NM_002392 [SNP-NCI]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 160 SNP NM_006878 [SNP-NCI] SNP NM_006879 [SNP-NCI] SNP NM_006881 [SNP-NCI] SNP NM_006882 [SNP-NCI] SNP MDM2 [GeneSNPs - Utah] MDM2] [HGBASE - SRS] HAPMAP MDM2 [HAPMAP]

General knowledge Family MDM2 [UCSC Family Browser] Browser SOURCE NM_002392 SOURCE NM_006878 SOURCE NM_006879 SOURCE NM_006881 SOURCE NM_006882 SMD Hs.567303 SAGE Hs.567303 regulation of progression through cell cycle [Amigo] regulation of progression through GO cell cycle negative regulation of transcription from RNA polymerase II promoter GO [Amigo] negative regulation of transcription from RNA polymerase II promoter GO ubiquitin-protein ligase activity [Amigo] ubiquitin-protein ligase activity GO protein binding [Amigo] protein binding GO intracellular [Amigo] intracellular GO nucleus [Amigo] nucleus GO nucleoplasm [Amigo] nucleoplasm GO nucleolus [Amigo] nucleolus GO cytoplasm [Amigo] cytoplasm GO protein complex assembly [Amigo] protein complex assembly traversing start control point of mitotic cell cycle [Amigo] traversing start control point GO of mitotic cell cycle GO zinc ion binding [Amigo] zinc ion binding GO zinc ion binding [Amigo] zinc ion binding GO negative regulation of cell proliferation [Amigo] negative regulation of cell proliferation GO protein ubiquitination [Amigo] protein ubiquitination GO ligase activity [Amigo] ligase activity negative regulator of basal transcription activity [Amigo] negative regulator of basal GO transcription activity GO enzyme binding [Amigo] enzyme binding GO regulation of protein catabolic process [Amigo] regulation of protein catabolic process GO metal ion binding [Amigo] metal ion binding BIOCARTA HIV-I Nef: negative effector of Fas and TNF [Genes] BIOCARTA Tumor Suppressor Arf Inhibits Ribosomal Biogenesis [Genes] BIOCARTA ATM Signaling Pathway [Genes] BIOCARTA CTCF: First Multivalent Nuclear Factor [Genes]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 161 BIOCARTA Cell Cycle: G2/M Checkpoint [Genes] BIOCARTA p53 Signaling Pathway [Genes] BIOCARTA Hypoxia and p53 in the Cardiovascular system [Genes] BIOCARTA Sumoylation by RanBP2 Regulates Transcriptional Repression [Genes] PubGene MDM2 Other databases Probes Probe MDM2 Related clones (RZPD - Berlin) PubMed PubMed 274 Pubmed reference(s) in LocusLink Bibliography Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line. Cahilly-Snyder L, Yang-Feng T, Francke U, George DL. Somat Cell Mol Genet. 1987; 13(3):235-244. Medline 3474784

Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line. Fakharzadeh SS, Trusko SP, George DL EMBO J. 1991; 10(6):1565-1569. Medline 2026149

The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Momand J, Zambetti GP, Olson DC, George D, Levine AJ. Cell 1992; 69(7):1237-1245. Medline 1535557

Amplification of a gene encoding a p53-associated protein in human sarcomas. Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B. Nature 1992; 358(6381):80-83. Medline 1614537 mdm2 expression is induced by wild type p53 activity. Barak Y, Juven T, Haffner R, Oren M. EMBO J.1993; 12(2):461-468. Medline 8440237

Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B. Nature 1993; 362(6423):857-860. Medline 8479525

The mdm-2 gene is induced in response to UV light in a p53-dependent manner. Perry ME, Piette J, Zawadzki JA, Harvey D, Levine AJ. Proc Natl Acad Sci U S A. 1993; 90(24):11623-11627. Medline 8265599

Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway. Chen CY, Oliner JD, Zhan Q, Fornace AJ Jr, Vogelstein B, Kastan MB.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 162 Proc Natl Acad Sci U S A. 1994; 91(7):2684-2688. Medline 8146175

Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Jones SN, Roe AE, Donehower LA, Bradley A. Nature 1995; 378(6553):206-208. Medline 7477327

Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Montes de Oca Luna R, Wagner DS, Lozano G. Nature 1995; 378(6553):203-206. Medline 7477326 mdm-2 inhibits the G1 arrest and apoptosis functions of the p53 tumor suppressor protein. Chen J, Wu X, Lin J, Levine AJ. Mol Cell Biol.1996; 16(5):2445-2452. Medline 8628312

Overexpression of the MDM2 oncogene in leukemia and lymphoma. Watanabe T, Ichikawa A, Saito H, Hotta T. Leuk Lymphoma 1996; 21(5-6):391-397. Medline 9172803

Mdm2 promotes the rapid degradation of p53. Haupt Y, Maya R, Kazaz A, Oren M. Nature 1997; 387(6630):296-299. Medline 9153395

Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. Honda R, Tanaka H, Yasuda H. FEBS Lett. 1997; 420(1):25-27. Medline 9450543

Regulation of p53 stability by Mdm2. Kubbutat MH, Jones SN, Vousden KH. Nature 1997; 387(6630):299-303. Medline 9153396

Point mutations and nucleotide insertions in the MDM2 zinc finger structure of human tumours. Schlott T, Reimer S, Jahns A, Ohlenbusch A, Ruschenburg I, Nagel H, Droese M. J Pathol.1997; 182(1):54-61. Medline 9227342

Nuclear export is required for degradation of endogenous p53 by MDM2 and human papillomavirus E6. Freedman DA, Levine AJ. Mol Cell Biol. 1998; 18(12):7288-7293. Medline 9819415

MDM2 expression during mouse embryogenesis and the requirement of p53. Leveillard T, Gorry P, Niederreither K, Wasylyk B. Mech Dev. 1998; 74(1-2):189-193. Medline 9651526

Atlas Genet Cytogenet Oncol Haematol 2007; 2 163

The MDM2 gene amplification database. Momand J, Jung D, Wilczynski S, Niland J. Nucleic Acids Res. 1998; 26(15):3453-3459. Medline 9671804

P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2. Tao W, Levine AJ. Proc Natl Acad Sci U S A. 1999; 96(12):6937-6941. Medline 10359817

A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, Bargonetti J, Bartel F, Taubert H, Wuerl P, Onel K, Yip L, Hwang SJ, Strong LC, Lozano G, Levine AJ. Cell 2004; 119(5):591-602. Medline 15550242

MDM2 promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma protein. Sdek P, Ying H, Chang DL, Qiu W, Zheng H, Touitou R, Allday MJ, Xiao ZX. Mol Cell 2005; 20(5):699-708. Medline 16337594

Differential response between the p53 ubiquitin-protein ligases Pirh2 and MdM2 following DNA damage in human cancer cells. Duan W, Gao L, Wu X, Zhang Y, Otterson GA, Villalona-Calero MA. Exp Cell Res. 2006; 312(17):3370-3378. Medline 16934800

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Contributor(s) Written 12-2006 Wenrui Duan, Miguel A Villalona-Calero Citation This paper should be referenced as such : Duan W, Villalona-Calero MA . MDM2 (transformed mouse 3T3 cell double minute 2, p53 binding protein). Atlas Genet Cytogenet Oncol Haematol. December 2006 . URL : http://AtlasGeneticsOncology.org/Genes/MDM2ID115ch12q15.html

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Atlas Genet Cytogenet Oncol Haematol 2007; 2 164 Atlas of Genetics and Cytogenetics in Oncology and Haematology

LYL1 (lymphoblastic leukemia derived sequence 1)

Identity Hugo LYL1 Location 19p13.2 DNA/RNA Note DNA size: 3.83 kb; mRNA size: 1492 bp; Exons: 4.

Description Location of the LYL1 gene, identified by Non-random chromosomal translocation t(7;19)(q35;p13) associated with T-cell acute lymphoblastic leukemia (T-ALL), was mapped to the short arm of chromosome 19 (19p13) by in situ hybridization. Transcription Expression levels of LYL1 are comparatively higher in normal bone marrow, spleen, lung, thymus and spinal cord tissues. Ectopic transcription is observed in T- lymphoblastic and myeloblastic leukemic cells. Protein

Description LYL1 encodes a basic helix-loop-helix (bHLH) protein, with 267 amino acids and molecular weight of 28628 Da. Localisation Subcellular location is potentially intracellular (nucleus). However, ectopic protein staining was observed in cytoplasm of myeloid leukemia cells with immunohistochemistry. Function Recent studies show that LYL1 is required for fetal and adult hematopoietic stem cell function and B-cell differentiation. Overexpression of LYL1 is implicated in the pathogenesis of T-ALL as well as myeloid malignancies (see below, disease implications). The LYL1 protein is a transcription factor (TF), structurally and functionally similar to another bHLH protein TAL1/SCL which is also implicated in T- ALL. Expression of both LYL1 and TAL1/SCL are regulated by the Ets and GATA factors; However, ectopic expression of SCL but not Lyl1 can rescue haematopoietic differentiation in SCL(-/-) ES-cells, providing a molecular explanation for the vastly different phenotypes of SCL(-/-) and Lyl1(-/-) mouse embryos. Efficient DNA binding of LYL1 requires dimerization with proteins. Specific in vivo association was observed between the bHLH and LIM proteins (LMO1 and LMO2). LYL1 readily forms heterodimeric complexes with E2A and may function as a dominant-negative preventing the activation of E2A responsive genes. LYL1 interacts also with p105 the precursor of NF-KappaB1 p50. Homology The bHLH region of LYL1 and TAL1/SCL proteins show 82% amino acid identity, suggesting that these two proteins share at least some target genes and biologic functions. However, LYL-1 and TAL1diverge largely outside the bHLH region and display a distinct expression pattern in hematopoietic cells. Mouse Lyl-1 protein is 78% identical to human LYL1. Implicated in Entity t(7;19)(q35;p13) --> TCRB/LYL1inT-cell acute lymphoblastic leukemia, other T-ALL,

Atlas Genet Cytogenet Oncol Haematol 2007; 2 165 acute myeloblastic leukemia (AML) or myelodysplastic syndrome (MDS) Disease The LYL1 gene was originally identified at the chromosomal translocation t(7;19)(q35;p13) associated with T-ALL. However, over-expression of LYL1 has been reported in T-ALL cases without apparent chromosome aberration. Recent studies on leukemia cell lines and patient samples suggested its involvement in myeloid malignancies. Using real-time quantitative RT-PCR assay, the authors found that the expression of LYL1 was at a significantly higher level than normal bone marrow cells in the majority of cases of acute myeloblastic leukemia (AML) or myelodysplastic syndrome when compared to normal bone marrow. This study also showed that LYL1 was highly expressed in most AML cell lines and in CD34(+) AML cells. Prognosis Expression of LYL1 is associated with unfavorable prognosis in T-ALL cases. LYL1(+) cases have a gene expression signature corresponding to that of the most immature normal T-cell precursors (CD4/CD8 double-negative cells), which express CD34 but not CD4, CD8, or CD3. Less favorable outcomes were observed in subgroups defined by gene expression profiles characteristic of TAL1(+) or LYL1(+) samples, which resemble late cortical and early pro-T thymocytes, respectively. Cytogenetics The LYL1 gene was originally identified at the breakpoint of the translocation t(7;19)(q35;p13) in cases of T-ALL. It is the LYL1 gene but not protein that is structurally altered following t(7;19), resulting in its head-to-head juxtaposition with the T-cell antigen receptor beta gene (TCR-beta). The translocation resulted in truncation of the LYL1 gene and production of abnormal-sized RNAs, bringing LYL1 gene under the regulatory control of TCR-beta, and thus resulting in its ectopic expression. In addition to the t(7;19)(q35;p13), other translocations are t(1;19)(p34;p13), t(1;19)(p32;p13), t(9;19)(q34;p13), t(9;19)(q32;p13), t(10;19)(q24;p13), t(11;19)(p13;p13), t(15;19)(q22;p13) etc; it is not known if all of the translocations lead to enhanced expression of LYL1. Hybrid/Mutated The TCR-beta locus at 7q35 spans 685 kb (64-67 variable genes TRBV, 2 clusters of Gene diversity, joining and constant segments). Oncogenesis As discussed above, the LYL1 gene was first identified at t(7;19)(q35;p13) associated T-ALL. However, over-expression of LYL1 has been reported in T-ALL cases without apparent chromosome aberration. LYL1, TAL1 and TAL2 constitute a discrete subgroup of helix-loop-helix proteins, each of which can potentially contribute to the development of T-ALL. Specific in vivo association between the bHLH and LIM proteins is implicated in human T cell leukemia. LYL1 can readily form heterodimers with E2A and NF-KappaB1 p105 protein. It is possible that LYL1 may function as a dominant-negative preventing the activation of the tumor suppressors like E2A. Ectopic expression of LYL1 may also be involved in myeloid leukemia.

External links Nomenclature Hugo LYL1 GDB LYL1 Entrez_Gene LYL1 4066 lymphoblastic leukemia derived sequence 1 Cards Atlas LYL1ID51ch19p13 GeneCards LYL1 Ensembl LYL1 Genatlas LYL1 GeneLynx LYL1 eGenome LYL1 euGene 4066 Genomic and cartography

Atlas Genet Cytogenet Oncol Haematol 2007; 2 166 GoldenPath LYL1 - 19p13.2 chr19:13070848-13074681 - 19p13.2 (hg18-Mar_2006) Ensembl LYL1 - 19p13.2 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM]

HomoloGene LYL1 Gene and transcription Genbank BC002796 [ ENTREZ ] Genbank CR626486 [ ENTREZ ] Genbank M22637 [ ENTREZ ] Genbank M22637 [ ENTREZ ] RefSeq NM_005583 [ SRS ] NM_005583 [ ENTREZ ] RefSeq AC_000062 [ SRS ] AC_000062 [ ENTREZ ] RefSeq NC_000019 [ SRS ] NC_000019 [ ENTREZ ] RefSeq NT_011295 [ SRS ] NT_011295 [ ENTREZ ] RefSeq NW_927195 [ SRS ] NW_927195 [ ENTREZ ] AceView LYL1 AceView - NCBI Unigene Hs.46446 [ SRS ] Hs.46446 [ NCBI ] HS46446 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q5JPI2 [ SRS] Q5JPI2 [ EXPASY ] Q5JPI2 [ INTERPRO ] PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 PROTEIN_KINASE_DOM [ Prosite Expasy ] Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ] Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ] CluSTr Q5JPI2 Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI-CDD ] Prodom PD000001 Prot_kinase[INRA-Toulouse] Q5JPI2 Q5JPI2_HUMAN [ Domain structure ] Q5JPI2 Q5JPI2_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks Q5JPI2 HPRD Q5JPI2 Protein Interaction databases DIP Q5JPI2 IntAct Q5JPI2 Polymorphism : SNP, mutations, diseases OMIM 151440 [ map ] GENECLINICS 151440 SNP LYL1 [dbSNP-NCBI] SNP NM_005583 [SNP-NCI] SNP LYL1 [GeneSNPs - Utah] LYL1] [HGBASE - SRS] HAPMAP LYL1 [HAPMAP] General knowledge Family LYL1 [UCSC Family Browser] Browser

Atlas Genet Cytogenet Oncol Haematol 2007; 2 167 SOURCE NM_005583 SMD Hs.46446 SAGE Hs.46446 GO DNA binding [Amigo] DNA binding GO nucleus [Amigo] nucleus regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA- GO dependent GO transcription regulator activity [Amigo] transcription regulator activity PubGene LYL1 Other databases Other http://www.cleanex.isb-sib.ch/cgi- database bin/cleanex_query_result.pl?out_format=NICE&Entry_0=HGNC:6734 Probes Probe LYL1 Related clones (RZPD - Berlin) PubMed PubMed 11 Pubmed reference(s) in LocusLink Bibliography Lyl-1, a novel gene altered by chromosomal translocation in T cell leukemia, codes for a protein with a helix-loop-helix DNA binding motif. Mellentin JD, Smith SD, Cleary ML. Cell. 1989; 58 (1), 77-83. Medline 2752424

Structure, chromosome mapping, and expression of the mouse Lyl-1 gene. Kuo SS, Mellentin JD, Copeland NG, Gilbert DJ, Jenkins NA, Cleary ML. Oncogene. 1991; 6(6):961-968. Medline 2067848

Specific in vivo association between the bHLH and LIM proteins implicated in human T cell leukemia. Wadman I, Li J, Bash RO, Forster A, Osada H, Rabbitts TH, Baer R. EMBO J 1994; 13 (20), 4831-4839. Medline 7957052

Helix-loop-helix proteins LYL1 and E2a form heterodimeric complexes with distinctive DNA- binding properties in hematolymphoid cells. Miyamoto A, Cui X, Naumovski L, Cleary ML. Mol. Cell. Biol. 1996; 16 (5), 2394-2401 Medline 8628307

Physical interaction of the bHLH LYL1 protein and NF-kappaB1 p105. Ferrier R, Nougarede R, Doucet S, Kahn-Perles B, Imbert J, Mathieu-Mahul D. Oncogene. 1999; 18 (4), 995-1005 Medline 10023675

Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Ferrando AA, Neuberg DS, Staunton J, Loh ML, Huard C, Raimondi SC, Behm FG, Pui CH, Downing JR, Gilliland DG, Lander ES, Golub TR, Look AT. Cancer Cell. 2002; 1(1):75-87. Medline 12086890

Atlas Genet Cytogenet Oncol Haematol 2007; 2 168

Gene expression profiling in T-cell acute lymphoblastic leukemia. Ferrando AA, Look AT. Semin Hematol. 2003; 40(4):274-280. Medline 14582078

Age-related phenotypic and oncogenic differences in T-cell acute lymphoblastic leukemias may reflect thymic atrophy. Asnafi V, Beldjord K, Libura M, Villarese P, Millien C, Ballerini P, Kuhlein E, Lafage-Pochitaloff M, Delabesse E, Bernard O, Macintyre E. Blood 2004; 104(13):4173-4180. Medline 15054041

Biallelic transcriptional activation of oncogenic transcription factors in T-cell acute lymphoblastic leukemia. Ferrando AA, Herblot S, Palomero T, Hansen M, Hoang T, Fox EA, Look AT. Blood. 2004; 103(5):1909-1911. Medline 14604958

Prognostic importance of TLX1 (HOX11) oncogene expression in adults with T-cell acute lymphoblastic leukaemia. Ferrando AA, Neuberg DS, Dodge RK, Paietta E, Larson RA, Wiernik PH, Rowe JM, Caligiuri MA, Bloomfield CD, Look AT. Lancet. 2004; 363(9408):535-536. Medline 14975618

Oncogenic potential of the transcription factor LYL1 in acute myeloblastic leukemia. Meng YS, Khoury H, Dick JE, Minden MD. Leukemia. 2005; 19 (11):1941-1947. Medline 16094422

The SCL relative LYL-1 is required for fetal and adult hematopoietic stem cell function and B- cell differentiation. Capron C, Lecluse Y, Kaushik AL, Foudi A, Lacout C, Sekkai D, Godin I, Albagli O, Poullion I, Svinartchouk F, Schanze E, Vainchenker W, Sablitzky F, Bennaceur-Griscelli A, Dumenil D. Blood. 2006; 107(12):4678-4686. Medline 16514064

The paralogous haemopoietic regulators Lyl1 and SCL are co-regulated by Ets and GATA factors yet Lyl1 cannot rescue the early SCL-/- phenotype. Chan WY, Follows GA, Lacaud G, Pimanda JE, Landry JR, Kinston S, Knezevic K, Piltz S, Donaldson IJ, Gambardella L, Sablitzky F, Green AR, Kouskoff V, Gottgens B. Blood. 2006 Oct 19; Epub ahead of print Medline 17053063

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Contributor(s) Written 12-2006 Yuesheng Meng, Mark D. Minden

Atlas Genet Cytogenet Oncol Haematol 2007; 2 169 Citation This paper should be referenced as such : Meng Y, Minden MD . LYL1 (lymphoblastic leukemia derived sequence 1). Atlas Genet Cytogenet Oncol Haematol. December 2006 . URL : http://AtlasGeneticsOncology.org/Genes/LYL1ID51ch19p13.html

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Atlas Genet Cytogenet Oncol Haematol 2007; 2 170 Atlas of Genetics and Cytogenetics in Oncology and Haematology

FHIT (Fragile Histidine Triad)

Identity Hugo FHIT Location 3p14.2 DNA/RNA

Depiction of the more than 1.67 Mb FHIT gene genomic locus with coding exons 5 through 9 (dark purple) and untranslated exons 1-4 and 10 (light purple). The position of the familial kidney cancer associated chromosome translocation is also shown.

Description The FHIT gene spans more than 1.6 Mb of genomic DNA and is composed of 10 exons. Transcription The FHIT gene encodes a 1.1 kb mRNA which is expressed at low levels in most tissue types. FHIT encompasses the common fragile site FRA3B, where carcinogen- induced damage can lead to deletions, translocations and subsequent aberrant transcripts. Aberrant transcripts from this gene have been found in about half of all esophageal carcinomas, stomach carcinomas, and other carcinomas. Pseudogene A pseudogene, with sequences nearly identical to the 5¹UTR of FHIT, is located on chromosome 1. Protein

Description FHIT encodes a 147 amino acid (16.8 kDa) protein that can be phosphorylated at tyrosine 114 by Src family proteins. Expression Fhit is expressed at low to moderate levels in most tissue types, with kidney and liver expressing the highest steady state levels Localisation Fhit is primarily located in the cytosol, but is also found in the mitochondria. Function Fhit protein is a tumor suppressor with reduced or no expression in many types of cancer. Fhit expression is more frequently lost in cancers of individuals with familial mutations causing deficiency in DNA repair genes such as BRCA1 and BRCA2 and MSH2. In vitro Fhit acts as a hydrolase that cleaves diadenosine triphosphate (Ap3A) to ADP and AMP. The Fhit-Ap3A enzyme-substrate complex appears to be the tumor suppressor signal. Restoration of Fhit expression in Fhit-deficient cancer cells causes death by apoptosis, involving the intrinsic caspase pathway, in cancer-derived cells and in tumor xenografts. Homology Fhit is similar to a yeast enzyme, diadenosine tetraphosphate (Ap4A) hydrolase and is a member of the large HIT family of proteins characterized by the histidine triad motif, HxHxHxx (where x is a hydrophobic residue). Mutations

Atlas Genet Cytogenet Oncol Haematol 2007; 2 171 Note The following FHIT polymorphisms have been described: 524 A/G (exon 6) silent 545 G/A (exon 6) silent 626 C/T (exon 7) silent 651 G/T (exon 8) valine to phenylalanine 656 T/C (exon 8) silent several intronic splice regions Somatic No bona fide somatic point mutations thus far confirmed. Implicated in Entity Various types of cancer Disease Loss of expression occurs in more than 60% of human cancers; loss is very early in some cancers such as lung cancer. In a large, 4 generation family, a balanced translocation between FHIT (in intron 3) at 3p14.2 and TRC8, a patched related gene, at chromosome 8q24 is associated with bilateral, multifocal clear cell kidney carcinoma. Also, microsatellite loci within the FHIT gene, were shown to be closely linked to a gene that contributes to susceptibility to familial prostate cancer. Prognosis There are numerous reports of association of Fhit loss with specific prognostic or other clinical features of specific types of cancer. Cytogenetics The FHIT locus is involved in translocations and deletions in some fraction of many types of cancer, likely due to the recombinogenicity of the fragile region within FHIT and subsequent selective growth or survival advantage of cells with reduced Fhit protein expression.

External links Nomenclature Hugo FHIT GDB FHIT Entrez_Gene FHIT 2272 fragile histidine triad gene Cards Atlas FHITID192ch3p14 GeneCards FHIT Ensembl FHIT Genatlas FHIT GeneLynx FHIT eGenome FHIT euGene 2272 Genomic and cartography GoldenPath FHIT - 3p14.2 chr3:59710078-61212164 - 3p14.2 (hg18-Mar_2006) Ensembl FHIT - 3p14.2 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene FHIT Gene and transcription Genbank BC032336 [ ENTREZ ] Genbank DQ120721 [ ENTREZ ] Genbank U46922 [ ENTREZ ] RefSeq NM_002012 [ SRS ] NM_002012 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 172 RefSeq AC_000046 [ SRS ] AC_000046 [ ENTREZ ] RefSeq NC_000003 [ SRS ] NC_000003 [ ENTREZ ] RefSeq NT_022517 [ SRS ] NT_022517 [ ENTREZ ] RefSeq NW_921651 [ SRS ] NW_921651 [ ENTREZ ] AceView FHIT AceView - NCBI Unigene Hs.655995 [ SRS ] Hs.655995 [ NCBI ] HS655995 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P07954 [ SRS] P07954 [ EXPASY ] P07954 [ INTERPRO ] Prosite PS00163 FUMARATE_LYASES [ SRS ] PS00163 FUMARATE_LYASES [ Expasy ] Interpro IPR003031 D_crystallin [ SRS ] IPR003031 D_crystallin [ EBI ] Interpro IPR005677 Fum_hydII [ SRS ] IPR005677 Fum_hydII [ EBI ] Interpro IPR000362 Fumarate_lyase [ SRS ] IPR000362 Fumarate_lyase [ EBI ] Interpro IPR008948 L-Aspartase-like [ SRS ] IPR008948 L-Aspartase-like [ EBI ] CluSTr P07954 Pfam PF00206 Lyase_1 [ SRS ] PF00206 Lyase_1 [ Sanger ] pfam00206 [ NCBI-CDD ] Blocks P07954 HPRD P07954 Protein Interaction databases DIP P07954 IntAct P07954 Polymorphism : SNP, mutations, diseases OMIM 601153 [ map ] GENECLINICS 601153 SNP FHIT [dbSNP-NCBI] SNP NM_002012 [SNP-NCI] SNP FHIT [GeneSNPs - Utah] FHIT] [HGBASE - SRS]

HAPMAP FHIT [HAPMAP] General knowledge Family FHIT [UCSC Family Browser] Browser SOURCE NM_002012 SMD Hs.655995 SAGE Hs.655995 Enzyme 4.2.1.2 [ Enzyme-SRS ] 4.2.1.2 [ Brenda-SRS ] 4.2.1.2 [ KEGG ] 4.2.1.2 [ WIT ] GO magnesium ion binding [Amigo] magnesium ion binding GO cytoplasm [Amigo] cytoplasm GO DNA replication [Amigo] DNA replication GO cell cycle [Amigo] cell cycle GO nucleotide metabolic process [Amigo] nucleotide metabolic process GO hydrolase activity [Amigo] hydrolase activity GO manganese ion binding [Amigo] manganese ion binding negative regulation of progression through cell cycle [Amigo] negative regulation of GO progression through cell cycle

Atlas Genet Cytogenet Oncol Haematol 2007; 2 173 bis(5'-adenosyl)-triphosphatase activity [Amigo] bis(5'-adenosyl)-triphosphatase GO activity KEGG Purine Metabolism PubGene FHIT Other databases Probes Probe FHIT Related clones (RZPD - Berlin) PubMed PubMed 98 Pubmed reference(s) in LocusLink Bibliography Fhit, a putative tumor suppressor in humans, is a dinucleoside 5',5"'-P1,P3-triphosphate hydrolase. Barnes LD, Garrison PN, Siprashvili Z, Guranowski A, Robinson AK, Ingram SW, Croce CM, Ohta M, Huebner K. Biochemistry. 1996; 35: 11529-11535. Medline 8794732

The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Ohta M, Inoue H, Cotticelli MG, Kastury K, Baffa R, Palazzo J, Siprashvili Z, Mori M, McCue P, Druck T, Croce CM, Huebner K. Cell. 1996; 84: 587-597. Medline 8598045

Analysis of the FHIT gene and FRA3B region in sporadic breast cancer, preneoplastic lesions, and familial breast cancer probands. Ahmadian M, Wistuba II, Fong KM, Behrens C, Kodagoda DR, Saboorian MH,Shay J, Tomlinson GE, Blum J, Minna JD, Gazdar AF. Cancer Res. 1997; 57: 3664-3668. Medline 9288768

Purification and crystallization of complexes modeling the active state of the fragile histidine triad protein. Brenner C, Pace HC, Garrison PN, Robinson AK, Rosler A, Liu XH, Blackburn GM, Croce CM, Huebner K, Barnes LD. Protein Eng. 1997; 10: 1461-1463. Medline 9543008

Structure and expression of the human FHIT gene in normal and tumor cells. Druck T, Hadaczek P, Fu TB, Ohta M, Siprashvili Z, Baffa R, Negrini M, Kastury K, Veronese ML, Rosen D, Rothstein J, McCue P, Cotticelli MG, Inoue H, Croce CM, Huebner K. Cancer Res. 1997; 57: 504-512. Medline 9012482

Replacement of Fhit in cancer cells suppresses tumorigenicity. Siprashvili Z, Sozzi G, Barnes LD, McCue P, Robinson AK, Eryomin V, Sard L, Tagliabue E, Greco A, Fusetti L, Schwartz G, Pierotti MA, Croce CM, Huebner K. Proc Natl Acad Sci U S A. 1997; 94: 13771-13776. Medline 9391102

FHITness and cancer. Druck T, Berk L, Huebner K.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 174 Oncol Res. 1998; 10: 341-345. (REVIEW) Medline 10063967

The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8. Gemmill RM, West JD, Boldog F, Tanaka N, Robinson LJ, Smith DI, Li F, Drabkin HA. Proc Natl Acad Sci U S A. 1998; 95: 9572-9577. Medline 9689122

Instability at chromosomal fragile sites. Glover TW. Recent Results Cancer Res. 1998; 154: 185-199. (REVIEW) Medline 10027000

The role of the FHIT/FRA3B locus in cancer. Huebner K, Garrison PN, Barnes LD, Croce CM. Annu Rev Genet. 1998; 32: 7-31. (REVIEW) Medline 9928473

Genetic, biochemical, and crystallographic characterization of Fhit-substrate complexes as the active signaling form of Fhit. Pace HC, Garrison PN, Robinson AK, Barnes LD, Draganescu A, Rosler A, Blackburn GM, Siprashvili Z, Croce CM, Huebner K, Brenner C. Proc Natl Acad Sci U S A. 1998; 95: 5484-5489. Medline 9576908

The histidine triad superfamily of nucleotide-binding proteins. Brenner C, Bieganowski P, Pace HC, Huebner K. J Cell Physiol. 1999; 181: 179-187. Medline 10497298

Induction of apoptosis and inhibition of tumorigenicity and tumor growth by adenovirus vector-mediated fragile histidine triad (FHIT) gene overexpression. Ji L, Fang B, Yen N, Fong K, Minna JD, Roth JA. Cancer Res. 1999; 59: 3333-3339. Medline 10416589

Muir-Torre-like syndrome in Fhit-deficient mice. Fong LY, Fidanza V, Zanesi N, Lock LF, Siracusa LD, Mancini R, Siprashvili Z, Ottey M, Martin SE, Druck T, McCue PA, Croce CM, Huebner K. Proc Natl Acad Sci U S A. 2000; 97: 4742-4747. Medline 10758156

FHIT gene therapy prevents tumor development in Fhit-deficient mice. Dumon KR, Ishii H, Fong LY, Zanesi N, Fidanza V, Mancini R, Vecchione A, Baffa R, Trapasso F, During MJ, Huebner K, Croce CM. Proc Natl Acad Sci U S A. 2001; 98: 3346-3351. Medline 11248081

Fragile histidine triad expression delays tumor development and induces apoptosis in human pancreatic cancer. Dumon KR, Ishii H, Vecchione A, Trapasso F, Baldassarre G, Chakrani F, Druck T, Rosato EF, Williams NN, Baffa R, During MJ, Huebner K, Croce CM. Cancer Res. 2001; 61: 4827-4836.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 175 Medline 11406559

Translocation breakpoints in FHIT and FRA3B in both homologs of in an esophageal adenocarcinoma. Fang JM, Arlt MF, Burgess AC, Dagenais SL, Beer DG, Glover TW. Genes Chromosomes Cancer. 2001; 30: 292-298. Medline 11170287

FRA3B and other common fragile sites: the weakest links. Huebner K, Croce CM. Nat Rev Cancer. 2001; 1: 214-221. (REVIEW) Medline 11902576

Potential cancer therapy with the fragile histidine triad gene: review of the preclinical studies. Ishii H, Dumon KR, Vecchione A, Fong LY, Baffa R, Huebner K, Croce CM. JAMA. 2001; 286: 2441-2449. (REVIEW) Medline 11712940

Effect of adenoviral transduction of the fragile histidine triad gene into esophageal cancer cells. Ishii H, Dumon KR, Vecchione A, Trapasso F, Mimori K, Alder H, Mori M, Sozzi G, Baffa R, Huebner K, Croce CM. Cancer Res. 2001; 61: 1578-1584. Medline 11245468

The tumor spectrum in FHIT-deficient mice. Zanesi N, Fidanza V, Fong LY, Mancini R, Druck T, Valtieri M, Rudiger T, McCue PA, Croce CM, Huebner K. Proc Natl Acad Sci U S A. 2001; 98: 10250-10255. Medline 11517343

5' CpG island methylation of the FHIT gene is correlated with loss of gene expression in lung and breast cancer. Zochbauer-Muller S, Fong KM, Maitra A, Lam S, Geradts J, Ashfaq R, Virmani AK, Milchgrub S, Gazdar AF, Minna JD. Cancer Res. 2001; 61: 3581-3585. Medline 11325823

Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases. Brenner C. Biochemistry. 2002; 41: 9003-9014. Medline 12119013

Loss of fragile histidine triad (FHIT) expression and microsatellite instability in periocular sebaceous gland carcinoma in patients with Muir-Torre syndrome. Holbach LM, von Moller A, Decker C, Junemann AG, Rummelt-Hofmann C, Ballhausen WG. Am J Ophthalmol. 2002; 134: 147-148. Medline 12095833

FHIT: from gene discovery to cancer treatment and prevention. Pekarsky Y, Zanesi N, Palamarchuk A, Huebner K, Croce CM. Lancet Oncol. 2002; 3: 748-754. (REVIEW) Medline 12473516

Atlas Genet Cytogenet Oncol Haematol 2007; 2 176

Loss of heterozygosity at the FHIT gene in different solid human tumours and its association with survival in colorectal cancer patients. Petursdottir TE, Hafsteinsdottir SH, Jonasson JG, Moller PH, Thorsteinsdottir U, Huiping C, Egilsson V, Ingvarsson S. Anticancer Res. 2002; 22: 3205-3212. Medline 12530066

The fragile histidine triad/common chromosome fragile site 3B locus and repair-deficient cancers. Turner BC, Ottey M, Zimonjic DB, Potoczek M, Hauck WW, Pequignot E, Keck-Waggoner CL, Sevignani C, Aldaz CM, McCue PA, Palazzo J, Huebner K, Popescu NC. Cancer Res. 2002; 62: 4054-4060. Medline 12124341

Two-hit inactivation of FHIT by loss of heterozygosity and hypermethylation in breast cancer. Yang Q, Nakamura M, Nakamura Y, Yoshimura G, Suzuma T, Umemura T, Shimizu Y, Mori I, Sakurai T, Kakudo K. Clin Cancer Res. 2002; 8: 2890-2893. Medline 12231533

Cancer and the FRA3B/FHIT fragile locus: it's a HIT. Huebner K, Croce CM. Br J Cancer. 2003; 88: 1501-1506. (REVIEW) Medline 12771912

Designed FHIT alleles establish that Fhit-induced apoptosis in cancer cells is limited by substrate binding. Trapasso F, Krakowiak A, Cesari R, Arkles J, Yendamuri S, Ishii H, Vecchione A, Kuroki T, Bieganowski P, Pace HC, Huebner K, Croce CM, Brenner C. Proc Natl Acad Sci U S A. 2003; 100: 1592-1597. Medline 12574506

The fragile genes FHIT and WWOX are inactivated coordinately in invasive breast carcinoma. Guler G, Uner A, Guler N, Han SY, Iliopoulos D, Hauck WW, McCue P, Huebner K. Cancer. 2004; 100: 1605-1614. Medline 15073846

Fhit is a physiological target of the protein kinase Src. Pekarsky Y, Garrison PN, Palamarchuk A, Zanesi N, Aqeilan RI, Huebner K, Barnes LD, Croce CM. Proc Natl Acad Sci U S A. 2004; 101: 3775-3779. Medline 15007172

Genetic linkage of prostate cancer risk to the chromosome 3 region bearing FHIT. Larson GP, Ding Y, Cheng LS, Lundberg C, Gagalang V, Rivas G, Geller L, Weitzel J, MacDonald D, Archambeau J, Slater J, Neuberg D, Daly MB, Angel I, Benson AB 3rd, Smith K, Kirkwood JM, O'Dwyer PJ, Raskay B, Sutphen R, Drew R, Stewart JA, Werndli J, Johnson D, Ruckdeschel JC, Elston RC, Krontiris TG. Cancer Res. 2005; 65: 805-814. Medline 15705877

Concordant loss of fragile gene expression early in breast cancer development. Guler G, Uner A, Guler N, Han SY, Iliopoulos D, McCue P, Huebner K. Pathol Int. 2005; 55: 471-478. Medline 15998374

Atlas Genet Cytogenet Oncol Haematol 2007; 2 177

Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer. Iliopoulos D, Guler G, Han SY, Johnston D, Druck T, McCorkell KA, Palazzo J, McCue PA, Baffa R, Huebner K. Oncogene. 2005; 24: 1625-1633. Medline 15674328

Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential. Semba S, Trapasso F, Fabbri M, McCorkell KA, Volinia S, Druck T, Iliopoulos D, Pekarsky Y, Ishii H, Garrison PN, Barnes LD, Croce CM, Huebner K. Oncogene. 2006; 20: 2860-2872. Medline 16407838

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Contributor(s) Written 12-2006 Teresa Druck, Kay Huebner Citation This paper should be referenced as such : Druck T, Huebner K. . FHIT (Fragile Histidine Triad). Atlas Genet Cytogenet Oncol Haematol. December 2006 . URL : http://AtlasGeneticsOncology.org/Genes/FHITID192ch3p14.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 2 178 Atlas of Genetics and Cytogenetics in Oncology and Haematology

ERCC1 (excision repair complementing defective repair in Chinese hamster.)

Identity Hugo ERCC1 Location 19q13.32 DNA/RNA Description 14 305 bp and 10 exons Transcription 1,101 bps Protein

Description 297 amino acids Expression ERCC1 is expressed at higher levels in tumor tissue compared to normal tissue and the expression shows more inter-individual variation among cancer patients than among healthy individuals. ERCC1 expression and ERCC1 protein levels in tumor tissue may predict response to chemotherapy. Thus, non-small cell lung cancer patients with undetectable ERCC1 protein levels in tumor tissue had a longer survival after cisplatin-based adjuvant chemotherapy than patients with detectable ERCC1 protein levels. However, high ERCC1 protein levels were associated with increased survival among patients who were not treated with chemotherapy). Function ERCC1 was originally identified as a gene that complemented a certain DNA repair defective Chinese Hamster Ovary cells (CHO) UV20. ERCC1 forms a heterodimer with XPF (also called ERCC4) to form the endonuclease which makes the 5¹ incision during nucleotide excision repair.

ERCC1 mRNA levels in lymphocytes correlate positively with DNA repair capacity measured by host cell reactivation. ERCC1 mRNA levels correlate closely with XPD, OGG1 and RAI mRNA levels in lymphocytes.

In case-control studies of lung cancer patients, lung cancer patients were shown to have lower mRNA levels and lower DNA repair capacity than healthy controls. This was also found in a case-control study of head and neck cancer. However, in a prospective study of lung cancer, persons, who were later diagnosed with lung cancer did not have a lower ERCC1 mRNA level than those who did not get lung cancer, indicating that the low ERCC1 expression level observed in cancer patients may be a result of the disease rather than a cause.

ERCC1 expression seems to be inducible at least at the mRNA level. Thus, the expression of ERCC1 in human lymphocytes correlated with increased solar influx indicating that UV irradiation may induce ERCC1 expression. In mice, X-ray irradiation lead to increased ERCC1 expression in lung tissue, and ingestion of diesel exhaust particles increased ERCC1 expression in liver. This indicates that ERCC1 expression is inducible, and thus that ERCC1 expression levels may rather be a biomarker of the internal dose of DNA damage than a biomarker of DNA repair capacity or a mix of the two.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 179 Mutations Note One of the most frequently studied polymorphisms in ERCC1 is ERCC1 Asn118Asn (rs11615). Homozygous carriers of the haplotype ERCC1 Asn118AsnA, ASE-1 G- 21AG, PPP1R13L IVS1 A4364GA have been shown to be at increased risk of breast cancer and lung cancer. The ERCC1 Asn118Asn polymorphism was found not to correlate with mRNA levels. ERCC1 C8092A (rs3212986) was found to interact with smoking in relation to risk of lung cancer in a large case-control study. ERCC1 C8092A was found not to correlate with mRNA levels in peripheral blood cells. Implicated in Entity Breast cancer Prognosis Thus, women who were homozygous carriers of the haplotype had a 9.5-fold higher risk of breast cancer before 55 years of age than women who were not homozygous carriers. Older women and heterozygous carriers were not at an increased risk of breast cancer.

Entity Lung cancer Disease Homozygous carriers of the haplotype were found to be at 4.9-fold increased risk of lung cancer in the age interval 50-55 years. The association was stronger among women than among men, although the difference was not statistically significant. In subsequent study including more cases and a larger comparison group, a statistically significant difference between genders was found. Furthermore, it was found that the haplotype interacts with smoking intensity. Thus, among women, who were carriers of the haplotype, additional smoking at high smoking intensity (>20 cigarettes/day) was associated with increased lung cancer risk. This was not seen among women who were not homozygous carriers of the haplotype or among men.

The haplotype was not associated with risk of testis cancer or with risk of colorectal adenomas or colorectal cancer. Furthermore, the haplotype was not associated with risk of basal cell carcinoma among older persons (>60 years).These results indicate that the haplotype may be associated with risk of cancer primarily among young and middle aged persons and that it may be specific for women.

Entity Leukemia and bladder cancer Disease The variant allele of ERCC1 Asn118Asn has also been combined with the polymorphisms XPD Asp312Asn and XPD Lys752Gln in haplotype analysis. Here, the haplotype GAT was associated with increased risk of leukemia and bladder cancer among non-smokers and the ACC haplotype was associated with lowered risk of bladder cancer.

Entity Colorectal cancer, small cell lung cancer, and non small cell lung cancer Disease Carriers of the variant allele of ERCC1 Asn118Asn were found to have a worse prognosis of colorectal cancer, small cell lung cancer and non-small cell lung cancer, whereas no association with risk of colorectal cancer has been found.

External links Nomenclature Hugo ERCC1 GDB ERCC1 ERCC1 2067 excision repair cross-complementing rodent repair deficiency, Entrez_Gene complementation group 1 (includes overlapping antisense sequence)

Atlas Genet Cytogenet Oncol Haematol 2007; 2 180 Cards Atlas ERCC1ID40481ch19q13 GeneCards ERCC1 Ensembl ERCC1 Genatlas ERCC1 GeneLynx ERCC1 eGenome ERCC1 euGene 2067 Genomic and cartography ERCC1 - 19q13.32 chr19:50604712-50619017 - 19q13.2-q13.3 (hg18- GoldenPath Mar_2006) Ensembl ERCC1 - 19q13.2-q13.3 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene ERCC1 Gene and transcription Genbank AA761510 [ ENTREZ ] Genbank AB069681 [ ENTREZ ] Genbank AF001925 [ ENTREZ ] Genbank AF433652 [ ENTREZ ] Genbank BC008930 [ ENTREZ ] RefSeq NM_001983 [ SRS ] NM_001983 [ ENTREZ ] RefSeq NM_202001 [ SRS ] NM_202001 [ ENTREZ ] RefSeq AC_000062 [ SRS ] AC_000062 [ ENTREZ ] RefSeq NC_000019 [ SRS ] NC_000019 [ ENTREZ ] RefSeq NT_011109 [ SRS ] NT_011109 [ ENTREZ ] RefSeq NW_927217 [ SRS ] NW_927217 [ ENTREZ ] AceView ERCC1 AceView - NCBI Unigene Hs.435981 [ SRS ] Hs.435981 [ NCBI ] HS435981 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt O15083 [ SRS] O15083 [ EXPASY ] O15083 [ INTERPRO ] Interpro IPR002017 Spectrin [ SRS ] IPR002017 Spectrin [ EBI ] CluSTr O15083 Blocks O15083 HPRD O15083 Protein Interaction databases DIP O15083 IntAct O15083 Polymorphism : SNP, mutations, diseases OMIM 126380;610758 [ map ] GENECLINICS 126380;610758 SNP ERCC1 [dbSNP-NCBI] SNP NM_001983 [SNP-NCI] SNP NM_202001 [SNP-NCI]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 181 SNP ERCC1 [GeneSNPs - Utah] ERCC1] [HGBASE - SRS] HAPMAP ERCC1 [HAPMAP] General knowledge Family ERCC1 [UCSC Family Browser] Browser SOURCE NM_001983 SOURCE NM_202001 SMD Hs.435981 SAGE Hs.435981 GO nucleotide-excision repair complex [Amigo] nucleotide-excision repair complex GO damaged DNA binding [Amigo] damaged DNA binding GO endonuclease activity [Amigo] endonuclease activity GO intracellular [Amigo] intracellular GO nucleus [Amigo] nucleus GO DNA repair [Amigo] DNA repair GO nucleotide-excision repair [Amigo] nucleotide-excision repair GO hydrolase activity [Amigo] hydrolase activity GO sequence-specific DNA binding [Amigo] sequence-specific DNA binding PubGene ERCC1 Other databases Probes Probe ERCC1 Related clones (RZPD - Berlin) PubMed PubMed 36 Pubmed reference(s) in LocusLink Bibliography Correction of a nucleotide-excision-repair mutation by human chromosome 19 in hamster- human hybrid cells. Thompson LH, Mooney CL, Burkhart-Schultz K, Carrano AV, Siciliano MJ. Somat Cell Mol Genet 1985; 11(1): 87-92. Medline 3919454

ERCC1 and ERCC2 expression in malignant tissues from ovarian cancer patients. Dabholkar M, Bostick-Bruton F, Weber C, Bohr VA, Egwuagu C, Reed E. J Natl Cancer Inst 1992; 19: 1512-1517. Medline 1433335

Expression of excision repair genes in non-malignant bone marrow from cancer patients. Dabholkar M, Bostick-Bruton F, Weber C, Egwuagu C, Bohr VA, Reed E. Mutation Research 1993; 293: 151-160. Medline 7678143

Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. Dabholkar M, Vionnet J, Bostick-Bruton F, Yu JJ, Reed E. J Clin Invest 1994; 94: 703-708. Medline 8040325

Human DNA repair excision nuclease. Analysis of the roles of the subunits involved in dual

Atlas Genet Cytogenet Oncol Haematol 2007; 2 182 incisions by using anti-XPG and anti-ERCC1 antibodies. Matsunaga T, Mu D, Park CH, Reardon JT, Sancar A. J Biol Chem 1995; 270(35): 20862-20869. Medline 7657672

Purification and characterization of the XPF-ERCC1 complex of human DNA repair excision nuclease. Park CH, Bessho T, Matsunaga T, Sancar A. J Biol Chem 1995; 270(39): 22657-22660. Medline 7559382

Reduced DNA repair capacity in lung cancer patients. Wei Q, Cheng L, Hong WK, Spitz MR. Cancer Research 1996; 56: 4103-4107. Medline 8797573

Reduced expression levels of nucleotide excision repair genes in lung cancer: a case-control analysis. Cheng L, Spitz MR, Hong WK, Wei Q. Carcinogenesis 2000; 21(8):1527-1530. Medline 10910954

DNA repair capacity: inconsistency between effect of over-expression of five NER genes and the correlation to mRNA levels in primary lymphocytes. Vogel U, Dybdahl M, Frentz G, Nexo BA. Mutat Res 2000; 461(3): 197-210. Medline 11056291

Inter-individual variation, seasonal variation and close correlation of OGG1 and ERCC1 mRNA levels in full blood from healthy volunteers. Vogel U, Moller P, Dragsted L, Loft S, Pedersen A, Sandstrom B. Carcinogenesis 2002; 23(9): 1505-1509 Medline 12189194

DNA adduct formation and oxidative stress in colon and liver of Big Blue rats after dietary exposure to diesel particles. Dybdahl M, Risom L, Moller P, Autrup H, Wallin H, Vogel U, Bornholdt J, Daneshvar B, Dragsted LO, Weimann A, Poulsen HE, Loft S. Carcinogenesis 2003; 24(11): 1759-1766. Medline 12919963

A specific haplotype of single nucleotide polymorphisms on chromosome 19q13.2-3 encompassing the gene RAI is indicative of postmenopausal breast cancer before age 55. Nexo BA, Vogel U, Olsen A, Ketelsen T, Bukowy Z, Thomsen BL. Wallin H, Overvad K, Tjonneland A. Carcinogenesis 2003; 24(5): 899-904. Medline 12771034

ERCC1 gene polymorphism as a predictor for clinical outcome in advanced colorectal cancer patients treated with platinum-based chemotherapy. Park DJ, Zhang W, Stoehlmacher J, Tsao-Wei D, Groshen S, Gil J, Yun J, Sones E, Mallik N, Lenz HJ. Clin Adv Hematol Oncol 2003; 1(3): 162-166. Medline 16224397

Atlas Genet Cytogenet Oncol Haematol 2007; 2 183 Oxidative DNA damage and defence gene expression in the mouse lung after short-term exposure to diesel exhaust particles by inhalation. Risom L, Dybdahl M, Bornholdt J, Vogel U, Wallin H, Moller P, Loft S. Carcinogenesis 2003; 24(11): 1847-1852. Medline 12919962

Single nucleotide polymorphisms and outcome in docetaxel-cisplatin-treated advanced non- small-cell lung cancer. Isla D, Sarries C, Rosell R, Alonso G, Domine M, Taron M, Lopez-Vivanco G, Camps C, Botia M, Nunez L, Sanchez-Ronco M, Sanchez JJ, Lopez-Brea M, Barneto I, Paredes A, Medina B, Artal A, Lianes P. Ann Oncol 2004; 15(8): 1194-1203. Medline 15277258

Association between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy. Ryu JS, Hong YC, Han HS, Lee JE, Kim S, Park YM, Kim YC, Hwang TS. Lung Cancer 2004; 44(3): 311-316. Medline 15140544

Two regions in chromosome 19 q13.2-3 are associated with risk of lung cancer. Vogel U, Laros I, Jacobsen NR, Thomsen BL, Bak H, Olsen A, Bukowy Z, Wallin H, Overvad K, Tjonneland A, Nexo BA, Raaschou-Nielsen O. Mutation Research 2004; 546: 65-74. Medline 14757194

Polymorphisms in RAI and in genes of nucleotide and base excision repair are not associated with risk of testicular cancer. Laska MJ, Nexo BA, Vistisen K, Poulsen HE, Loft S, Vogel U. Cancer Lett 2005; 225(2): 245-251. Medline 15885892

Polymorphisms/haplotypes in DNA repair genes and smoking: a bladder cancer case-control study. Matullo G, Guarrera S, Sacerdote C, Polidoro S, Davico L, Gamberini S, Karagas M, Casetta G, Rolle L, Piazza A, Vineis P. Cancer Epidemiol Biomarkers Prev 2005; 14(11 Pt 1): 2569-2578. Medline 16284380

Effect of polymorphisms in XPD, RAI, ASE-1 and ERCC1 on the risk of basal cell carcinoma among Caucasians after age 50. Vogel U, Olsen A, Wallin H, Overvad K, Tjonneland A, Nexo BA. Cancer Detect Prev 2005; 29(3): 209-214. Medline 15936590

Gene-Smoking Interaction Associations for the ERCC1 Polymorphisms in the Risk of Lung Cancer. Zhou W, Liu G, Park S, Wang Z, Wain JC, Lynch TJ, Su L, Christiani DC. Cancer Epidemiol Biomarkers Prev 2005; 14(2): 491-496. Medline 15734977

DNA repair polymorphisms and cancer risk in non-smokers in a cohort study. Matullo G, Dunning AM, Guarrera S, Baynes C, Polidoro S, Garte S, Autrup H, Malaveille C, Peluso M, Airoldi L, Veglia F, Gormally E, Hoek G, Krzyzanowski M, Overvad K, Raaschou-Nielsen O, Clavel- Chapelon F, Linseisen J, Boeing H, Trichopoulou A, Palli D, Krogh V, Tumino R, Panico S, Bueno-de-

Atlas Genet Cytogenet Oncol Haematol 2007; 2 184 Mesquita HB, Peeters PH, Lund E, Pera G, Martinez C, Dorronsoro M, Barricarte A, Tormo MJ, Quiros JR, Day NE, Key TJ, Saracci R, Kaaks R, Riboli E, Vineis P. Carcinogenesis 2006; 27(5): 997-1007. Medline 16308313

Polymorphisms in genes of nucleotide and base excision repair: risk and prognosis of colorectal cancer. Moreno V, Gemignani F, Landi S, Gioia-Patricola L, Chabrier A, Blanco I, Gonzalez S, Guino E, Capella G, Canzian F. Clin Cancer Res 2006; 12(7 Pt 1): 2101-2108. Medline 16609022

DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. Olaussen KA, Dunant A, Fouret P, Brambilla E, Andre F, Haddad V, Taranchon E, Filipits M, Pirker R, Popper HH, Stahel R, Sabatier L, Pignon JP, Tursz T, Le Chevalier T, Soria JC. N Engl J Med 2006; 355(10): 983-991. Medline 16957145

Increased mRNA expression levels of ERCC1, OGG1 and RAI in colorectal adenomas and carcinomas. Saebo M, Skjelbred CF, Nexo BA, Wallin H, Hansteen IL, Vogel U, Kure EH. BMC Cancer 2006; 6: 208. Medline 16914027

Effects of polymorphisms in ERCC1, ASE-1 and RAI on the risk of colorectal carcinomas and adenomas: a case control study. Skjelbred CF, Saebo M, Nexo BA, Wallin H, Hansteen IL, Vogel U, Kure EH. BMC Cancer 2006; 6: 175. Medline 16817948

ERCC1, XPD and RAI mRNA levels in lymphocytes are not associated with lung cancer risk in a prospective study of Danes. Vogel U, Nexo BA, Tjonneland A, Wallin H, Hertel O, Raaschou-Nielsen O. Mutat Res 2006a; 593(1-2): 88-96. Medline 16054657

Gene-environment interactions between smoking and a haplotype of RAI, ASE-1 and ERCC1 polymorphisms among women in relation to risk of lung cancer in a population-based study. Vogel U, Sorensen M, Hansen RD, Tjonneland A, Overvad K, Wallin H, Nexo BA, Raaschou-Nielsen O. Cancer Lett 2006b; 247: 159-165. Medline 16690207

Effects of ERCC1 expression in peripheral blood on the risk of head and neck cancer. Yang M, Kim WH, Choi Y, Lee SH, Kim KR, Lee HS, Tae K. Eur J Cancer Prev 2006; 15(3): 269-273. Medline 16679872

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Atlas Genet Cytogenet Oncol Haematol 2007; 2 185 Contributor(s) Written 12-2006 Ulla Vogel Citation This paper should be referenced as such : Vogel U . ERCC1 (excision repair complementing defective repair in Chinese hamster.). Atlas Genet Cytogenet Oncol Haematol. December 2006 . URL : http://AtlasGeneticsOncology.org/Genes/ERCC1ID40481ch19q13.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 2 186 Atlas of Genetics and Cytogenetics in Oncology and Haematology

CASP-9 (caspase 9, apoptosis-related cysteine peptidase)

Identity Other names APAF-3 ICE-LAP6 MCH6 Hugo CASP9 Location 1p36.2 DNA/RNA Description The human caspase-9 gene contains 9 exons and 8 introns and was predicted to span over approximately 35 kb of the genomic DNA. Transcription Three mRNA isoforms have been identified in Homo sapiens. Caspase-9S, also classified as caspase-9b or caspase-9beta, is a small variant of caspase-9 lacking exons 3-6, which contain the catalytic domain. Caspase-9S functions as an endogenous dominant-negative isoform of full-length caspase-9 by binding to the Apaf-1 protein thus hampering its binding and processing of the full- length procaspase-9. Recently, it has been cloned and characterized a novel caspase-9 splice variant, named caspase9-gamma. Caspase9-gamma is generated from an alternative splicing of the fourth exon of caspase-9 gene, that results in a 58 nucleotide-long insertion, absent in caspase-9 full length. As the inserted fragment introduces a stop codon, the resulting RNA sequence is prematurely terminated and translated in a 154 aminoacids protein corresponding to only the CARD domain of the caspase-9 full length. Caspase9-gamma does not contain small and large catalytic subunits and cannot promote apoptosis, but like caspase-S, it can function as an apoptosis inhibitor by interferring with the CARD-CARD interaction between procaspase-9 and Apaf-1. Protein

Description Like for other caspase genes, caspase-9 mRNA is translated in a precursor protein, the procaspase, that is subsequently converted to the active enzyme. The procaspase-9 consists of 416 amino acids corresponding to a molecular weight of 46281 Da. Cleavages at Asp315 and Asp330 by granzyme B and CPP32 (caspase-3), respectively, generate two active peptides. The active caspase-9 is, in fact, constituted by an heterodimer of a 35kDa (p35) and a 10 kDa (p10) subunit. It belongs to the peptidase C14 family and contains three major domains: a prodomain (in which a CARD domain is located), a large subunit catalytic domain (LSCD) and a small subunit catalytic domain (SSCD). Expression Caspase-9 expression is ubiquitous, with highest expression in the heart and a moderate expression in liver, skeletal muscle, and pancreas. Localisation Mainly cytosolic, but both proenzyme and active caspase-9 have been also observed in the mitochondria and in the nucleus. Function Caspase-9 is a member of the cysteine aspartic acid protease, or caspase, family. The procaspase-9 is activated in apoptotic conditions and it is involved in the activation of

Atlas Genet Cytogenet Oncol Haematol 2007; 2 187 the caspase cascade responsible for apoptosis execution. The procaspase-9 and Apaf-1 interact each other through their CARD domains generating, in presence of cytochrome c and ATP, the protein complex named "apoptosome". The latter one, in turn, cleaves and activates the effector caspases such the caspase-3. Caspase-9 plays an essential role in apoptosis during normal development. The majority of homozygous CASP-9 null mice die perinatally with an enlarged and malformed cerebrum caused by a reduced apoptosis during brain development. Homology CASP9 (Canis familiaris, Pan troglodytes, Gallus gallus), Casp9 (Rattus norvegicus, Mus musculus), Casp9-A (Xenopous Laevis), Dr.16035 (Danio Rerio). Mutations Germinal Not known in Homo sapiens Somatic Three different somatic mutations have been detected in two colorectal carcinomas and in one gastric carcinoma among 353 cancer specimen analyzed, including 180 gastric, 104 colorectal and 69 lung adenocarcinomas. However, all these mutations were silent mutation, thus not contributing to the pathogenesis of these cancers. Implicated in Entity Lung cancer Cytogenetics CASP-9 promoter polymorphisms influence the promoter activity and are associated with the risk of developing lung cancer. Oncogenesis It has been examined the association of four CASP-9 promoter polymorphisms with the risk of lung cancer in a Korean population comprising 432 lung cancer patients and 432 healthy controls. The -1263 GG genotype was associated with a significantly decreased risk of lung cancer compared with -1263 AA or combined -1263 AA + AG. Moreover, individuals with at least one -712T allele had a significantly increased risk of lung cancer compared with those carrying the -712 CC genotype. In brief, the polymorphisms that result in an higher promoter activity seem to be associated with a decreased risk to develop lung cancer. Polymorphisms in CASP-9 promoter can then be useful markers for determining genetic susceptibility to this cancer. However, the association between CASP-9 polymorphisms and risk of lung cancer seem to be influenced by tobacco smoking, no association being present in never-smoker patients. Moreover, as polymorphisms can show ethnic variations, the observations should be extended to diverse ethnic groups.

Disease Colon cancer Oncogenesis Caspase-9 was shown to be downregulated in colon cancer samples in comparison with normal mucosa tissues. Immunohistochemical analysis reveals that the expression of caspase-9 is variable in the healthy enterocytes. However, in the enterocytic component of 12 among 26 cancer samples analyzed, a decrease in caspase-9 immunostaining intensity has been observed: a profile similar, but to a smaller extent, to that observed for caspase 7.

Entity Head and neck squamous cell carcinoma Oncogenesis In a certain type of head and neck squamous cell carcinoma cells (HNSCCs), the inhibition of caspase-9 activity and Apaf-1 expression may represent a mechanism of acquired cisplatin resistance. It has been reported that cisplatin induced caspase-9 activation and apoptosis in cisplatin-sensitive HNSCCs in vitro. On the contrary, the cisplatin-resistant HNSCCs analyzed were not able to activate caspase-9 following cisplatin treatment, thus not responding to the therapy.

Entity Testicular germ cell cancer Oncogenesis Similarly to head and neck squamous cell carcinama cells, failure of activation of caspase-9 induces cisplatin resistance in testicular cancer cells in vitro. Testicular germ cell cancer is a tumor highly responsive to cisplatin-based chemotherpy, but in a

Atlas Genet Cytogenet Oncol Haematol 2007; 2 188 few cases a phenomenon of chemoresistence can occour leading to an unfavourable prognosis. In in vitro experiments, it has been shown that a cisplatin-resistant human testicular germ cell cancer cell line (1411HP) failed to activate caspase-9 and apoptosis after cisplatin treatment in comparison with two cisplatin-sensitive human testicular germ cell cancer cell line (2102EP and H12.1). In the resistant cell line, however, it was possible induce a caspase-9 independent apoptosis using a 3.3-fold higher cisplatin dose.

Entity Nodal diffuse large B-cell lymphoma Oncogenesis By using biopsy specimens of primary diffuse large B-cell lymphoma (DLBCL) it has been demonstrated that a cellular profile consistent with inhibition of the caspase-9 pathway is associated with poor response to chemotherapy and fatal outcome. On the contrary, a cellular profile consistent with caspase-8 pathway inhibition is associated with an excellent response to chemotherapy. Identifying the functional status of caspase-9 and caspase-8 in patients may have implications for the outcome prediction and for development of alternative therapeutics strategies.

Entity Gastric cancer Oncogenesis Seven cell lines derived from human gastric cancers were used to investigate the involvement of caspases in chemoresistance mechanisms. Among those examined, the cell line most resistant to apoptotic stimuli expressed the highest levels of the caspase-9 isoform beta, thus confirming the role of caspase-9 in promoting apoptosis in treated cancer cells.

To be noted Caspase-9 molecular manipulation could be useful for T-cell therapy and for antiangiogenic gene therapy. It has been observed that the local delivery of an inducible caspase-9 resulted in endothelial cell apoptosis and local ablation of vicrovessels in a mouse model of human angiogenesis. Adenoviral vectors containing inducible forms of caspase-9 could be used as antiangiogenic drugs for treatment of angiogenesis-dependent diseases, as, in example, cancer. External links Nomenclature Hugo CASP9 GDB CASP9 Entrez_Gene CASP9 842 caspase 9, apoptosis-related cysteine peptidase Cards Atlas CASP9ID423ch1p36 GeneCards CASP9 Ensembl CASP9 Genatlas CASP9 GeneLynx CASP9 eGenome CASP9 euGene 842 Genomic and cartography GoldenPath CASP9 - 1p36.2 chr1:15691384-15723377 - 1p36.3-p36.1 (hg18-Mar_2006) Ensembl CASP9 - 1p36.3-p36.1 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 189 HomoloGene CASP9 Gene and transcription Genbank AB015653 [ ENTREZ ] Genbank AB020979 [ ENTREZ ] Genbank AB209147 [ ENTREZ ] Genbank AF093130 [ ENTREZ ] Genbank AF110376 [ ENTREZ ] RefSeq NM_001229 [ SRS ] NM_001229 [ ENTREZ ] RefSeq NM_032996 [ SRS ] NM_032996 [ ENTREZ ] RefSeq AC_000044 [ SRS ] AC_000044 [ ENTREZ ] RefSeq NC_000001 [ SRS ] NC_000001 [ ENTREZ ] RefSeq NT_004873 [ SRS ] NT_004873 [ ENTREZ ] RefSeq NW_925794 [ SRS ] NW_925794 [ ENTREZ ] AceView CASP9 AceView - NCBI Unigene Hs.329502 [ SRS ] Hs.329502 [ NCBI ] HS329502 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q5T791 [ SRS] Q5T791 [ EXPASY ] Q5T791 [ INTERPRO ] CluSTr Q5T791 Blocks Q5T791 HPRD Q5T791 Protein Interaction databases DIP Q5T791 IntAct Q5T791 Polymorphism : SNP, mutations, diseases OMIM 602234 [ map ] GENECLINICS 602234 SNP CASP9 [dbSNP-NCBI] SNP NM_001229 [SNP-NCI] SNP NM_032996 [SNP-NCI] SNP CASP9 [GeneSNPs - Utah] CASP9] [HGBASE - SRS] HAPMAP CASP9 [HAPMAP] General knowledge Family CASP9 [UCSC Family Browser] Browser SOURCE NM_001229 SOURCE NM_032996 SMD Hs.329502 SAGE Hs.329502 GO protein binding [Amigo] protein binding GO protein binding [Amigo] protein binding GO intracellular [Amigo] intracellular GO soluble fraction [Amigo] soluble fraction GO nucleus [Amigo] nucleus GO cytosol [Amigo] cytosol

Atlas Genet Cytogenet Oncol Haematol 2007; 2 190 GO proteolysis [Amigo] proteolysis GO enzyme activator activity [Amigo] enzyme activator activity GO cysteine-type peptidase activity [Amigo] cysteine-type peptidase activity GO apoptotic program [Amigo] apoptotic program GO caspase activation via cytochrome c [Amigo] caspase activation via cytochrome c GO caspase activity [Amigo] caspase activity GO caspase activity [Amigo] caspase activity GO regulation of apoptosis [Amigo] regulation of apoptosis BIOCARTA HIV-I Nef: negative effector of Fas and TNF [Genes] BIOCARTA West Nile Virus [Genes] BIOCARTA AKT Signaling Pathway [Genes] BIOCARTA Caspase Cascade in Apoptosis [Genes] BIOCARTA Apoptotic Signaling in Response to DNA Damage [Genes] BIOCARTA D4-GDI Signaling Pathway [Genes] BIOCARTA Induction of apoptosis through DR3 and DR4/5 Death Receptors [Genes] BIOCARTA Stress Induction of HSP Regulation [Genes] BIOCARTA Role of Mitochondria in Apoptotic Signaling [Genes] BIOCARTA Ras Signaling Pathway [Genes] BIOCARTA Trefoil Factors Initiate Mucosal Healing [Genes] PubGene CASP9 Other databases Probes Probe CASP9 Related clones (RZPD - Berlin) PubMed PubMed 120 Pubmed reference(s) in LocusLink Bibliography Genomic organization of the human caspase-9 gene on Chromosome 1p36.1-p36.3. Hadano S, Nasir J, Nichol K, Rasper DM, Vaillancourt JP, Sherer SW, Beatty BG, Ikeda JE, Nicholson DW, Hayden MR. Mammalian Genome 1999;10:757-760. Medline 10384055

Identification of an alternative form of caspase-9 in human gastric cancer cell lines: a role of a caspase-9 variant in apoptosis resistance. Izawa M, Mori T, Satoh K, Teramachi K, Sairenji T. Apoptosis 1999; 4: 321-325 Medline 14634335

A caspase-9 variant missing the catalytic site is and endogenous inhibitor of apoptosis. Seol DW, Billiar TR. J Biol Chem 1999; 274: 2072-2076 Medline 9890966

Identification of an endogenous dominant-negative short isoform of caspase-9 that can regulate apoptosis. Srinivasula SM, Ahmad M, Guo Y, Zhan Y, Lazebnik Y, Fernandes-Alnemri T, Alnemri ES. Cancer Res 1999; 59: 999-1002 Medline 10070954

Atlas Genet Cytogenet Oncol Haematol 2007; 2 191

Mitochondrial release of caspase-2 and -9 during the apoptotic process. Susin SA, Lorenzo HK, Zamzami N, Marzo I, Brenner C, Larochette N, Prevost MC, Alzari PM, Kroemer G. J Exp Med 1999; 189: 381-394 Medline 9892620

Caspase-9. Kuida K. Int J Biochem Cell Biol. 2000; 32: 121-124. Review Medline 10687948

Caspase-9 regulates cisplatin-induced apoptosis in human head and neck squamous cell carcinoma cells. Kuwahara D, Tsutsumi K, Kobayashi T, Hasunuma T, Nishioka K. Cancer Lett. 2000; 148: 65-71 Medline 10680594

Nuclear localization of procaspase-9 and processing by a caspase-3-like activity in mammary epithelial cells. Ritter PM, Marti A, Blanc C, Baltzer A, Krajewski S, Reed JC, Jaggi R. Eur J Cell Biol 2000; 79: 358-364 Medline 10887967

Caspase 7 downregulation as an immunohistochemical marker of colonic carcinoma. Palmerini F, Devilard E, Jarry A, Birg F, Xerry L. Human Pathology 2001; 32: 461-467 Medline 11381362

Inhibition of caspase-9 activity and Apaf-1 expression in cisplatin-resistant head and neck squamous cell carcinoma cells. Kuwahara D, Tsutsumi K, Oyake D, Ohta T, Nishikawa H, Koizuka I. Auris Nasus Larynx 2003; 30: Suppl S85-88 Medline 12543167

Failure of activation of caspase-9 induces a higher threshold for apoptosis and cisplatin resistance in testicular cancer. Mueller T, Voigt W, Simon H, Fruehauf A, Bulankin A, Grothey, Schmoll HJ. Cancer Research 2003; 63: 513-521 Medline 12543810

Caspase-9 regulation: An update. Johnson CR, Jarvis WD Apoptosis 2004; 9: 423-427. Review Medline 15192324

Caspases and cancer: mechanisms of inactivation and new treatment modalities. Philchenkov A, Zavelevich M, Kroczak TJ, Los M. Exp Oncol 2004; 26: 82-97. Review Medline 15273659

Immunohistochemical profiling of caspase signaling pathways predicts clinical response to chemotherapy in primary nodal diffuse large B-cell lymphomas. Muris JJ, Cillessen SA, Vos W, van Houdt IS, Kummer A, van Krieken JH, Jiwa NM, Jansen PM,

Atlas Genet Cytogenet Oncol Haematol 2007; 2 192 Kluin-Nelemans HC, Ossenkoppele GJ, Gundy C, Meijer CJ, Oudejans JJ. Blood 2005; 105:2916-2923 Medline 15576477

Inhibition of caspase 9 and not caspase 8 mediated apoptosis may determine clinical response to chemotherapy in primary nodal diffuse large B-cell lymphomas. Oudejans JJ, Muris JJ, Meijer CJ. Cell cycle 2005; 4: 526-528. Review Medline 15876872

Antiangiogenic gene therapy: disruption of neovascular networks mediated by inducible caspase-9 delivered with a trascriptionally targeted adenoviral vector. Song W, Sun Q, Dong Z, Spencer DM, Nunez G, Nor JE. Gene therapy 2005; 12: 320-329 Medline 15616606

Caspase 9 promoter polymorphisms and risk of primary lung cancer. Park JY, Park JM, Jang JS, Choi JE, Kim KM, Cha SI, Kim CH, Kang YM, Lee WK, Kam S, Park RW, Kim IS, Lee JT, Jung TH. Human Molecular Genetics 2006; 15: 1963-1971 Medline 16687442

Mutational analysis of proapoptotic caspase-9 gene in common human carcinomas. Soung YH, Lee JW, Kim SY, Park WS, Nam SW, Lee JY, Yoo NJ, Lee SH. APMIS 2006; 114: 292-297 Medline 16689829

Cloning of a novel human caspase-9 splice variant containing only the CARD domain. Wang P. Shi T., Ma D. Life Sciences 2006; 79: 934-940 Medline 16780893

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Contributor(s) Written 12-2006 Sabrina Di Bartolomeo, Francesco Cecconi Citation This paper should be referenced as such : Di Bartolomeo S, Cecconi F . CASP-9 (caspase 9, apoptosis-related cysteine peptidase). Atlas Genet Cytogenet Oncol Haematol. December 2006 . URL : http://AtlasGeneticsOncology.org/Genes/CASP9ID423ch1p36.html

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Atlas Genet Cytogenet Oncol Haematol 2007; 2 193 Atlas of Genetics and Cytogenetics in Oncology and Haematology

AATF (Apoptosis Antagonizing Transcription Factor)

Identity Other names DED CHE1 CHE-1 Hugo AATF Location 17q12 Note AATF affects cell growth by interfering with the recruitment of HDAC1 by retinoblastoma protein. Its over-expression activates DNA synthesis in quiescent NIH- 3T3 cells through HFDAC1 displacement. Also, it is considered as a general HDAC1 competitor and its down-regulation is involved in colon carcinoma cell proliferation. It is also found to bind to TSG101 in a process that enhances androgen receptor-mediated transcription by promoting its mono-ubiquitination. It has been observed lately that AATF 12th exon truncation by HIV-1 specific encoded miRNA leads to HIV-1 disease progression. On other side its over-expression has been observed in various leukemic cell lines and is considered to be important for maintaining leukemic state. DNA/RNA Note Protein AATF (Apoptosis-antagonizing transcription factor) (Rb-binding protein Che-1). Total gene size being 107.996 kb and having transcribed region of 2.141 kb it codes for 561 amino acids. Description Spans on 107.996 kb on genomic fragment and contains 12 exons. Transcription 2023 bp mRNA Pseudogene No pseudogenes for AATF are known. Protein

Note 561 amino acids long protein contains POLR2J binding site at 273-315 amino acids, RB1 binding site at 316-372 amino acids, RB1 and SP1 binding site at 373-472 amino acids and Glu-rich region at 96-195 amino acids. Description AATF was identified as an interacting partner with MAP3K12/DLK which happens to be a protein kinase known to be involved in the induction of cell apoptosis. Its protein contains a leucine zipper, which is a characteristic motif of transcription factors, and was shown to exhibit strong transactivation activity when fused to Gal4 DNA binding domain. Overexpression of this gene interfered with MAP3K12 induced apoptosis. Expression Ubiquitously expressed. Expressed at high levels in brain, heart, kidney, placenta, thymus and moderate levels in blood mononuclear cells. Localisation Nucleus; nucleolus. Function It functions as a general inhibitor of the histone deacetylase HDAC1. Binding to the pocket region of RB1 may displace HDAC1 from RB1/E2F complexes, leading to activation of E2F target genes and cell cycle progression. Conversely, displacement of HDAC1 from SP1 bound to the CDKN1A promoter leads to increased expression of this CDK inhibitor and blocks cell cycle progression. Also antagonizes PAWR mediated induction of aberrant amyloid peptide production in Alzheimer disease

Atlas Genet Cytogenet Oncol Haematol 2007; 2 194 (presenile and senile dementia), although the molecular basis for this phenomenon has not been described to date. Mutations Note Several polymorphisms have been identified and but none of them has shown any association with any disease. Implicated in Entity Leukemia Note AATF plays a major role in immortalization of leukemic cells through up-regulation of Bcl2 gene expression. Disease Haematopoitic malignancies

AATF dependent cross talk between cellular apoptosis and proliferation.

Entity AIDS Note HIV-1 encodes a specific miRNA that has the inherent capacity to cleave 12th exon of AATF gene resulting in truncated AATF gene product which is destined to undergo degradation. Down-regulation of AATF gene expression is always accompanied by significant reduction in cell viability and down-regulation of gene coding for dicer which plays a crucial role in providing immunity at the nucleic acid level. Disease Immunodeficiency, Lymphoadenopathy, Kaposi's sarcoma, AIDS dementia

HIV-1 encoded miRNA dependent AATF gene down-regulation and subsequent cell death.

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External links Nomenclature Hugo AATF GDB AATF Entrez_Gene AATF 26574 apoptosis antagonizing transcription factor Cards Atlas AATFID534ch17q11 GeneCards AATF Ensembl AATF Genatlas AATF GeneLynx AATF eGenome AATF euGene 26574 Genomic and cartography GoldenPath AATF - 17q12 chr17:32380288-32488283 + 17q11.2-q12 (hg18-Mar_2006) Ensembl AATF - 17q11.2-q12 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene AATF Gene and transcription Genbank AF083208 [ ENTREZ ] Genbank AF161395 [ ENTREZ ] Genbank AJ249940 [ ENTREZ ] Genbank AK026173 [ ENTREZ ] Genbank AK057229 [ ENTREZ ] RefSeq NM_012138 [ SRS ] NM_012138 [ ENTREZ ] RefSeq AC_000060 [ SRS ] AC_000060 [ ENTREZ ] RefSeq NC_000017 [ SRS ] NC_000017 [ ENTREZ ] RefSeq NT_078100 [ SRS ] NT_078100 [ ENTREZ ] RefSeq NW_926817 [ SRS ] NW_926817 [ ENTREZ ] AceView AATF AceView - NCBI Unigene Hs.195740 [ SRS ] Hs.195740 [ NCBI ] HS195740 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q4L235 [ SRS] Q4L235 [ EXPASY ] Q4L235 [ INTERPRO ] Prosite PS50075 ACP_DOMAIN [ SRS ] PS50075 ACP_DOMAIN [ Expasy ] Prosite PS00455 AMP_BINDING [ SRS ] PS00455 AMP_BINDING [ Expasy ] Interpro IPR009081 ACP_like [ SRS ] IPR009081 ACP_like [ EBI ] Interpro IPR000873 AMP-bind [ SRS ] IPR000873 AMP-bind [ EBI ] Interpro IPR006163 Phsphopanteth_bd [ SRS ] IPR006163 Phsphopanteth_bd [ EBI ] Interpro IPR011047 Quino_alc_DH [ SRS ] IPR011047 Quino_alc_DH [ EBI ] CluSTr Q4L235 Pfam PF00501 AMP-binding [ SRS ] PF00501 AMP-binding [ Sanger ] pfam00501 [

Atlas Genet Cytogenet Oncol Haematol 2007; 2 196 NCBI-CDD ] PF00550 PP-binding [ SRS ] PF00550 PP-binding [ Sanger ] pfam00550 [ NCBI- Pfam CDD ] Blocks Q4L235 HPRD Q4L235 Protein Interaction databases DIP Q4L235 IntAct Q4L235 Polymorphism : SNP, mutations, diseases OMIM 608463 [ map ] GENECLINICS 608463 SNP AATF [dbSNP-NCBI] SNP NM_012138 [SNP-NCI] SNP AATF [GeneSNPs - Utah] AATF] [HGBASE - SRS] HAPMAP AATF [HAPMAP] General knowledge Family AATF [UCSC Family Browser] Browser SOURCE NM_012138 SMD Hs.195740 SAGE Hs.195740 GO transcription factor activity [Amigo] transcription factor activity GO protein binding [Amigo] protein binding GO nucleus [Amigo] nucleus GO anti-apoptosis [Amigo] anti-apoptosis PubGene AATF Other databases Probes Probe AATF Related clones (RZPD - Berlin) PubMed PubMed 16 Pubmed reference(s) in LocusLink Bibliography Che-1 affects cell growth by interfering with the recruitment of HDAC1 by Rb. Bruno T, De Angelis R, De Nicola F, Barbato C, Di Padova M, Corbi N, Libri V, Benassi B, Mattei E, Chersi A, Soddu S, Floridi A, Passananti C, Fanciulli M. Cancer Cell. 2002; 2(5): 387-99. Medline 12450794

Che-1 arrests human colon carcinoma cell proliferation by displacing HDAC1 from the p21WAF1/CIP1 promoter. Di Padova M, Bruno T, De Nicola F, Iezzi S, D'Angelo C, Gallo R, Nicosia D, Corbi N, Biroccio A, Floridi A, Passananti C, Fanciulli M. J Biol Chem. 2003; 278(38): 36496-504. Medline 12847090

TSG101 interacts with apoptosis-antagonizing transcription factor and enhances androgen receptor-mediated transcription by promoting its monoubiquitination.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 197 Burgdorf S, Leister P, Scheidtmann KH. J Biol Chem. 2004; 279(17): 17524-34. Medline 14761944

Evidence and Nature of a novel miRNA Encoded by HIV-1. Kaul D, Khanna A, Suman Proc Indian Natn Sci Acad 72 No.2 pp91-95 2006

Functional characterization of AATF transcriptome in human leukemic cells. Kaul D, Mehrotra A. Mol Cell Biochem. 2006 Sep 28 Medline 17006618

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Contributor(s) Written 12-2006 Deepak Kaul, Amit Khanna Citation This paper should be referenced as such : Kaul D, Khanna A . AATF (Apoptosis Antagonizing Transcription Factor). Atlas Genet Cytogenet Oncol Haematol. December 2006 . URL : http://AtlasGeneticsOncology.org/Genes/AATFID534ch17q11.html

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STK11 (serine/threonine kinase 11)

Identity Other names LKB1 PJS (Peutz-Jeghers syndrome) EC 2.7.11.1 NY-REN-19 antigen Hugo STK11 Location 19p13.3 DNA/RNA Description 10 Exons spanning 23 kb, the 10th exon occurs within the 3' untranslated region of the gene. The gene is transcribed in telomere to centromere direction. Transcription The length of this transcript has not been reconciled. The curated human Vega transcript is the longest transcript reported to date (3,627 bp, Vega external transcript). The GeneBank sequence is the same but is shorter (3,286 bp) at the 3' end (NM_000455.4). The exon/intron structures in GeneBank are given for 2 alternative assemblies (aligned with NT_011255.14 and NW_927173.1), of which the NT_0112255.14 is consistent with the Vega annotation. Alternative transcripts although shown to occur, have not be been well characterized. Protein

Diagram of STK11 protein (not drawn to scale). The kinase domain is depicted by the green box. The second box outlined by the dashed lines illustrates the location of the nuclear localization signal (NLS) and the purple box indicates the prenylation motif. This protein is believed to contain a putative cytoplasmic retention signal (not shown).

Description 433 amino acids, 48.6 kDa; N-term with a nuclear localization domain and a putative cytoplasmic retention signal, a kinase domain, and a C-terminal CAAX box prenylation motif. Expression Ubiquitous, especially high expression in the testis and fetal liver. Localisation Found in both the nucleus and the cytoplasm. Localization is thought to be dependent on interaction with proteins such as BRG1, LIP1, STRAD, MO25. Function A serine/threonine protein kinase, recently classified as a part of the Ca2+/ calmodulin kinase group of kinases. STK11 was shown to associate and activate the pseudokinase, STRAD, resulting in the reorganization of non-polarized cells so they form asymmetrical apical and basal structures. Another mechanism by which this may occur is by the interaction of STK11 with the PAR1 family of serine/threonine kinases.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 199 AMPK is a protein kinase cascade that plays an important role in regulating energy homeostasis. The first report of an upstream regulator came when it was discovered that STK11, in complex with STRAD and the scaffolding protein MO25, can phosphorylate and activate AMPK. Subsequently, it was demonstrated that STK11 can phosphorylate the T-loop of 12 other AMPK related human kinases. In addition it has been implicated in a range of processes including, chromatin remodeling, cell cycle arrest, ras-induced cell transformation, p53-mediated apoptosis and Wnt signaling. Homology Orthologs found in several species and include: Xenopus laevis egg and embryonic kinase 1(XEEK1), Caenorhabditis elegans partitioning defective gene 4 (PAR4), mouse LKB1 and drosophila LKB1. Mutations Germinal Most mutations identified to date are in the catalytic domain of STK11, indicating that kinase activity is likely essential for its function as a tumor suppressor. Several types of mutations including insertions, deletions, nonsense, missense and splice site alterations have been identified to date. One family has been identified with complete germline deletion of this gene. Somatic Many of the polyps that develop in Peutz-Jeghers syndrome (see below) show loss of heterozygosity and sometimes somatic mutations. Somatic mutations rarely occur in sporadic tumours, with the exception of adenocarcinoma of the lung. The inactivation of the LKB1 can also occur through promoter hypermethylation. Implicated in Entity Peutz-Jeghers syndrome (PJS) Disease Autosomal dominant syndrome associated with mucocutaneous hyperpigmentation and benign intestinal polyps known as hamartomas. The relative incidence is estimated to vary from 1/29 000 to 1/120 000 births. Patients are at an increased risk of developing malignancies in epithelial tissues, for example it has been estimated that there is a about 84, about 213 and about 520 fold increased risk of developing colon, gastric and small intestinal cancers respectively. PJS patients are also at an increased risk of developing cancers in the breast, lung, ovaries, uterus, cervix and testes. Hybrid/Mutated A majority (60-70%) of Peutz-Jeghers patients show germline mutations in STK11. Gene Genetic locus heterogeneity may exist for this disease. A small percentage of families with no mutations in STK11/LKB1 have been identified, however no other candidate genes that predispose to Peutz-Jeghers syndrome have been identified to date. Oncogenesis Patients inherit mutations in one allele, and the remaining allele is later inactivated generally by LOH or sometimes somatic mutation. This biallelic inactivation of STK11 leads to a loss of tumour suppressor activity, thereby promoting tumourigenesis.

Entity Lung adenocarcinoma Disease Adenocarcinoma is the most common non-small-cell lung cancer accounting for about 30-40% of all cases diagnosed to date. These tumors are thought to derive from epithelial cells that line the peripheral small airways and the heterogeneity of lung tumours is well documented. The outcome of non-small cell lung cancer is more difficult to predict, and about 50% of patients die from metastatic disease even after surgery of the primary tumour. Hybrid/Mutated As many as 33% of sporadic lesions analyzed display somatic mutations in STK11. Gene Oncogenesis Loss of protein function is seen in sporadic lung adenocarcinoma tumours.

External links Nomenclature

Atlas Genet Cytogenet Oncol Haematol 2007; 2 200 Hugo STK11 GDB STK11 Entrez_Gene STK11 6794 serine/threonine kinase 11 Cards Atlas STK11ID292 GeneCards STK11 Ensembl STK11 Genatlas STK11 GeneLynx STK11 eGenome STK11 euGene 6794 Genomic and cartography GoldenPath STK11 - 19p13.3 chr19:1156798-1179434 + 19p13.3 (hg18-Mar_2006) Ensembl STK11 - 19p13.3 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene STK11 Gene and transcription Genbank AB209553 [ ENTREZ ] Genbank AF035625 [ ENTREZ ] Genbank AF217978 [ ENTREZ ] Genbank AJ844634 [ ENTREZ ] Genbank AK128518 [ ENTREZ ] RefSeq NM_000455 [ SRS ] NM_000455 [ ENTREZ ] RefSeq AC_000062 [ SRS ] AC_000062 [ ENTREZ ] RefSeq NC_000019 [ SRS ] NC_000019 [ ENTREZ ] RefSeq NT_011255 [ SRS ] NT_011255 [ ENTREZ ] RefSeq NW_927173 [ SRS ] NW_927173 [ ENTREZ ] AceView STK11 AceView - NCBI Unigene Hs.515005 [ SRS ] Hs.515005 [ NCBI ] HS515005 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt O94804 [ SRS] O94804 [ EXPASY ] O94804 [ INTERPRO ] PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 PROTEIN_KINASE_ATP [ Prosite Expasy ] PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 PROTEIN_KINASE_DOM [ Prosite Expasy ] PS00108 PROTEIN_KINASE_ST [ SRS ] PS00108 PROTEIN_KINASE_ST [ Prosite Expasy ] Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ] Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ] Interpro IPR008271 Ser_thr_pkin_AS [ SRS ] IPR008271 Ser_thr_pkin_AS [ EBI ] Interpro IPR002290 Ser_thr_pkinase [ SRS ] IPR002290 Ser_thr_pkinase [ EBI ] CluSTr O94804 Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI-CDD ]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 201 Smart SM00220 S_TKc [EMBL] Prodom PD000001 Prot_kinase[INRA-Toulouse] O94804 STK10_HUMAN [ Domain structure ] O94804 STK10_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks O94804 HPRD O94804 Protein Interaction databases DIP O94804 IntAct O94804 Polymorphism : SNP, mutations, diseases OMIM 175200;602216 [ map ] GENECLINICS 175200;602216 SNP STK11 [dbSNP-NCBI] SNP NM_000455 [SNP-NCI] SNP STK11 [GeneSNPs - Utah] STK11] [HGBASE - SRS] HAPMAP STK11 [HAPMAP] General knowledge Family STK11 [UCSC Family Browser] Browser SOURCE NM_000455 SMD Hs.515005 SAGE Hs.515005 2.7.11.1 [ Enzyme-SRS ] 2.7.11.1 [ Brenda-SRS ] 2.7.11.1 [ KEGG ] 2.7.11.1 [ Enzyme WIT ] GO nucleotide binding [Amigo] nucleotide binding GO magnesium ion binding [Amigo] magnesium ion binding protein serine/threonine kinase activity [Amigo] protein serine/threonine kinase GO activity GO protein binding [Amigo] protein binding GO ATP binding [Amigo] ATP binding GO nucleus [Amigo] nucleus GO cytoplasm [Amigo] cytoplasm GO protein amino acid phosphorylation [Amigo] protein amino acid phosphorylation GO cell cycle [Amigo] cell cycle GO cell cycle arrest [Amigo] cell cycle arrest GO transferase activity [Amigo] transferase activity GO manganese ion binding [Amigo] manganese ion binding PubGene STK11 Other databases Probes Probe STK11 Related clones (RZPD - Berlin) PubMed PubMed 71 Pubmed reference(s) in LocusLink Bibliography

Atlas Genet Cytogenet Oncol Haematol 2007; 2 202 A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, et al. Nature. 1998; 391: 184-187. Medline 9428765

Peutz-Jeghers syndrome is caused by mutations in a novel serine/threonine kinase. Jenne DE, Reimann H, Nezu J, Friedel W, Loffe S, Jeschke R, Muller O, et al. Nat Genet. 1998; 18: 38-43. Medline 9425897

Growth suppression by Lkb1 is mediated by a G(1) cell cycle arrest. Tiainen M, Ylikorkala A, Makela TP. Proc Natl Acad Sci USA. 1999; 96: 9248-9251. Medline 10430928

Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome. Esteller M, Avizienyte E, Corn PG, Lothe RA, Baylin SB, Aaltonen LA, Herman JG. Oncogene. 2000; 19: 164-168. Medline 10644993

The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death. Karuman P, Gozani O, Odze RD, Zhou XC, Zhu H, Shaw R, Brien TP, Bozzuto CD, Ooi D, Cantley LC, Yuan J. Mol Cell. 2001; 7: 1307-1319. Medline 11430832

LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest. AUTHORS Marignani PA, Kanai F, Carpenter CL. J Biol Chem. 2001; 276: 32415-32418. Medline 11445556

Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell growth. Sapkota GP, Kieloch A, Lizcano JM, Lain S, Arthur JS, Williams MR, Morrice N, Deak M, Alessi DR. J Biol Chem. 2001; 276: 19469-19482. Medline 11297520

LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1. Smith DP, Rayter SI, Niederlander C, Spicer J, Jones CM, Ashworth A. Hum Mol Genet. 2001; 10: 2869-2877. Medline 11741830

Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice. Ylikorkala A, Rossi DJ, Korsisaari N, Luukko K, Alitalo K, Henkemeyer M, Makela TP. Science. 2001; 293: 1323-1326. Medline 11509733

Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Bardeesy N, Sinha M, Hezel AF, Signoretti S, Hathaway NA, Sharpless NE, Loda M, Carrasco DR, DePinho RA. Nature 2002; 419:162167.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 203 Medline 12226664

Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD. Baas AF, Boudeau J, Sapkota GP, Smit L, Medema R, Morrice NA, Alessi DR, Clevers HC. EMBO J. 2003; 22: 3062-3072. Medline 12805220

Regulation of the Wnt signalling component PAR1A by the PeutzJeghers syndrome kinase LKB1. Spicer J, Rayter S,Young N, Elliott R, Ashworth A, Smith D. Oncogene. 2003; 22: 47524756. Medline 12879020

Genotype-phenotype correlations in Peutz-Jeghers syndrome. Amos CI, Keitheri-Cheteri MB, Sabripour M, Wei C, McGarrity TJ, Seldin MF, Nations L, Lynch PM, Fidder HH, Friedman E, Frazier ML. J. Med. Genet. 2004; 41: 327-333. REVIEW articles Medline 15121768

Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Baas AF, Kuipers J, Van der Wel NN, Batlle E, Koerten HK, Peters PJ, Clevers HC. Cell. 2004; 116: 457-466. Medline 15016379

LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. Lizcano JM, Goransson O, Toth R, Deak M, Morrice NA, Boudeau J, Hawley SA, Udd L, Makela TP, Hardie DG, Alessi DR. Embo J. 2004; 23:833-843. Medline 14976552

LKB1 kinase: master and commander of metabolism and polarity. Spicer J, Ashworth A. Curr Biol. 2004; 14:R383-5. Medline 15186763

LKB1, the multitasking tumour suppressor kinase. Marignani PA. J Clin Pathol. 2005 Jan;58(1):15-19. Review. Medline 15623475

The tumor suppressor LKB1 induces p21 expression in collaboration with LMO4, GATA-6, and Ldb1. Setogawa T, Shinozaki-Yabana S, Masuda T, Matsuura K, Akiyama T. Biochem Biophys Res Commun. 2006; 434: 1186-1190. Medline 16580634

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Contributor(s)

Atlas Genet Cytogenet Oncol Haematol 2007; 2 204 Written 02-2002 Jean-Loup Huret Updated 01-2007 Bharati Bapat, Sheron Perera Citation This paper should be referenced as such : Huret JL . STK11 (serine/threonine kinase 11). Atlas Genet Cytogenet Oncol Haematol. February 2002 . URL : http://AtlasGeneticsOncology.org/Genes/STK11ID292.html Bapat B, Perera S . STK11 (serine/threonine kinase 11). Atlas Genet Cytogenet Oncol Haematol. January 2007 . URL : http://AtlasGeneticsOncology.org/Genes/STK11ID292.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 2 205 Atlas of Genetics and Cytogenetics in Oncology and Haematology

RTN4 (reticulon 4)

Identity Other names ASY NI220/250 NOGO NOGO-A NSP NSP-CL Nbla00271 Nbla10545 RTN-X RTN4-A RTN4-B1 RTN4-B2 RTN4-C Hugo RTN4 Location 2p16.3 Local_order Between FLJ42562 and FLJ31438.

Local order.

DNA/RNA

Atlas Genet Cytogenet Oncol Haematol 2007; 2 206

Genomic structure and transcriptional isoforms.

Description The RTN4 gene spans about 75kb, and contains 9 major exons and several different cap sites (Fig. 2a). Transcription Three major, RTN4-A, B1 and C, (Fig. 2b) and several minor transcriptional isoforms result from alternative splicing and/or differential promoter usage. Although RTN4 mRNA is ubiquitously expressed, the expression of isoforms is tissue-specific, for example, RTN4-A and C in brain, RTN4-C in muscle, and RTN4-B1 in many other tissues. Protein

Description Proteins with different sizes are synthesized from different mRNA isoforms: RTN4-A, 129.9 kDa (1192 amino acids); RTN4-B1, 40.3 kDa (373 amino acids); RTN4-B2, 42.3 kDa (392 amino acids); RTN4-C, 22.4 kDa (199 amino acids). All RTN4 protein isoforms retain a common C-terminal domain containing two trans-membrane domains and an endoplasmic reticulum (ER)-retrieval motif. Expression Ubiquitously expressed (see Transcription). Localisation RTN4 protein localizes predominantly in the ER and, to a lesser extent, in cytoplasmic membrane. Function Although definitive functional mechanisms of RTN4 have not yet been clarified, RTN4 protein interacts with several other proteins, including RTN1, RTN3, DP1/Yop1p, BACE1, and Nogo receptor (NogoR). Interaction with DP1/Yop1p, an ER membrane protein, may be necessary for maintenance or stabilization of tubular ER. Binding with BACE1 (beta-amyloid converting enzyme 1) results in reduction in BACE1 activity and production of amyloid-beta. RTN4 also interacts with NogoR, and may lead to activation of RhoA and inhibition of neuronal regeneration in central nervous system. Further, overexpression of RTN4 may cause ER stress and apoptosis in certain cells. Homology Four reticulon family members (RTN1, RTN2, RTN3 and RTN4) have been identified. They possess a highly conserved C-terminal domain named reticulon homology domain. Implicated in Entity Various cancers. Note Down-regulation of RTN4 expression was observed in small cell lung carcinomas and adult T-cell leukemia/lymphomas, and RTN3, one of RTN4 interacting proteins, was over-expressed in astrocytomas, suggesting involvement of RTN4 (and RTN3) in certain types of tumorigenesis. However, increased incidence of tumor formation has

Atlas Genet Cytogenet Oncol Haematol 2007; 2 207 not been observed in RTN4 knock out mice. RTN4 is also suspected to involve in schizophrenia and neuronal degenerative diseases.

External links Nomenclature Hugo RTN4 GDB RTN4 Entrez_Gene RTN4 57142 reticulon 4 Cards Atlas RTN4ID42182ch2p16 GeneCards RTN4 Ensembl RTN4 Genatlas RTN4 GeneLynx RTN4 eGenome RTN4 euGene 57142 Genomic and cartography GoldenPath RTN4 - 2p16.3 chr2:55052833-55090974 - 2p16.3 (hg18-Mar_2006) Ensembl RTN4 - 2p16.3 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene RTN4 Gene and transcription Genbank AB015639 [ ENTREZ ] Genbank AB020693 [ ENTREZ ] Genbank AB040462 [ ENTREZ ] Genbank AB040463 [ ENTREZ ] Genbank AB073351 [ ENTREZ ] RefSeq NM_007008 [ SRS ] NM_007008 [ ENTREZ ] RefSeq NM_020532 [ SRS ] NM_020532 [ ENTREZ ] RefSeq NM_153828 [ SRS ] NM_153828 [ ENTREZ ] RefSeq NM_207520 [ SRS ] NM_207520 [ ENTREZ ] RefSeq NM_207521 [ SRS ] NM_207521 [ ENTREZ ] RefSeq AC_000045 [ SRS ] AC_000045 [ ENTREZ ] RefSeq NC_000002 [ SRS ] NC_000002 [ ENTREZ ] RefSeq NT_022184 [ SRS ] NT_022184 [ ENTREZ ] RefSeq NW_927719 [ SRS ] NW_927719 [ ENTREZ ] AceView RTN4 AceView - NCBI Unigene Hs.645283 [ SRS ] Hs.645283 [ NCBI ] HS645283 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q16799 [ SRS] Q16799 [ EXPASY ] Q16799 [ INTERPRO ] Prosite PS50845 RETICULON [ SRS ] PS50845 RETICULON [ Expasy ] Interpro IPR003388 Reticulon [ SRS ] IPR003388 Reticulon [ EBI ]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 208 CluSTr Q16799 PF02453 Reticulon [ SRS ] PF02453 Reticulon [ Sanger ] pfam02453 [ NCBI-CDD Pfam ] Blocks Q16799 HPRD Q16799 Protein Interaction databases DIP Q16799 IntAct Q16799 Polymorphism : SNP, mutations, diseases OMIM 604475 [ map ] GENECLINICS 604475 SNP RTN4 [dbSNP-NCBI] SNP NM_007008 [SNP-NCI] SNP NM_020532 [SNP-NCI] SNP NM_153828 [SNP-NCI] SNP NM_207520 [SNP-NCI] SNP NM_207521 [SNP-NCI] SNP RTN4 [GeneSNPs - Utah] RTN4] [HGBASE - SRS] HAPMAP RTN4 [HAPMAP] General knowledge Family RTN4 [UCSC Family Browser] Browser SOURCE NM_007008 SOURCE NM_020532 SOURCE NM_153828 SOURCE NM_207520 SOURCE NM_207521 SMD Hs.645283 SAGE Hs.645283 GO protein binding [Amigo] protein binding GO nuclear envelope [Amigo] nuclear envelope GO endoplasmic reticulum [Amigo] endoplasmic reticulum GO endoplasmic reticulum [Amigo] endoplasmic reticulum GO membrane [Amigo] membrane GO integral to membrane [Amigo] integral to membrane GO negative regulation of anti-apoptosis [Amigo] negative regulation of anti-apoptosis integral to endoplasmic reticulum membrane [Amigo] integral to endoplasmic GO reticulum membrane GO negative regulation of axon extension [Amigo] negative regulation of axon extension GO regulation of apoptosis [Amigo] regulation of apoptosis PubGene RTN4 Other databases Probes Probe RTN4 Related clones (RZPD - Berlin)

Atlas Genet Cytogenet Oncol Haematol 2007; 2 209 PubMed PubMed 43 Pubmed reference(s) in LocusLink Bibliography Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L, Spillmann AA, Christ F, Schwab ME. Nature. 2000; 403: 434-439. Medline 10667796

Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. GrandPre T, Nakamura F, Vartanian T, Strittmatter SM. Nature. 2000; 403: 439-444. Medline 10667797

Inhibitor of neurite outgrowth in humans. Prinjha R, Moore SE, Vinson M, Blake S, Morrow R, Christie G, Michalovich D, Simmons DL, Walsh FS. Nature. 2000; 403: 383-384. Medline 10667780

A novel protein, RTN-XS, interacts with both Bcl-XL and Bcl-2 on endoplasmic reticulum and reduces their anti-apoptotic activity. Tagami S, Eguchi Y, Kinoshita M, Takeda M, Tsujimoto Y. Oncogene. 2000; 19: 5736-5746. Medline 11126360

Assignment of the human reticulon 4 gene (RTN4) to chromosome 2p14---2p13 by radiation hybrid mapping. Yang J, Yu L, Bi AD, Zhao SY. Cytogenet Cell Genet. 2000; 88: 101-102. Medline 10773680

Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Fournier AE, GrandPre T, Strittmatter SM. Nature. 2001; 409: 341-346. Medline 11201742

Link of a new type of apoptosis-inducing gene ASY/Nogo-B to human cancer. Li Q, Qi B, Oka K, Shimakage M, Yoshioka N, Inoue H, Hakura A, Kodama K, Stanbridge EJ, Yutsudo M. Oncogene. 2001; 20: 3929-3936. Medline 11494121

Nogo provides a molecular marker for diagnosis of amyotrophic lateral sclerosis. Dupuis L, Gonzalez de Aguilar JL, di Scala F, Rene F, de Tapia M, Pradat PF, Lacomblez L, Seihlan D, Prinjha R, Walsh FS, Meininger V, Loeffler JP. Neurobiol Dis. 2002; 10: 358-365. Medline 12270696

Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a homozygous CAA insert. Novak G, Kim D, Seemen P, Tallerico T. Brain Res Mol Brain Res. 2002; 107: 183-189.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 210 Medline 12425946

Axon regeneration in young adult mice lacking Nogo-A/B. Kim JE, Li S, GrandPre T, Qiu D, Strittmatter SM. Neuron. 2003; 38: 187-190. Medline 12718854

Genomic structure and functional characterization of the promoters of human and mouse nogo/rtn4. Oertle T, Huber C, van der Putten H, Schwab ME. J Mol Biol. 2003; 325: 299-323. Medline 12488097

Nogo and its partners. Oertle T, Schwab ME. Trends Cell Biol. 2003; 13: 187-194. (REVIEW) Medline 12667756

Pro-apoptotic ASY/Nogo-B protein associates with ASYIP. Qi B, Qi Y, Watari A, Yoshioka N, Inoue H, Minemoto Y, Yamashita K, Sasagawa T, Yutsudo M. J Cell Physiol. 2003; 196: 312-318. Medline 12811824

Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Simonen M, Pedersen V, Weinmann O, Schnell L, Buss A, Ledermann B, Christ F, Sansig G, van der Putten H, Schwab ME. Neuron. 2003; 38: 201-211. Medline 12718855

Multi-functional gene ASY/Nogo/RTN-X/RTN4: Apoptosis, tumor suppression, and inhibition of neuronal regeneration. Watari A, Yutsudo M. Apoptosis. 2003; 8: 5-9. (REVIEW) Medline 12510146

Lack of enhanced spinal regeneration in Nogo-deficient mice. Zheng B, Ho C, Li S, Keirstead H, Steward O, Tessier-Lavigne M. Neuron. 2003; 38: 213-224. Medline 12718856

A new role for Nogo as a regulator of vascular remodeling. Acevedo L, Yu J, Erdjument-Bromage H, Miao RQ, Kim JE, Fulton D, Tempst P, Strittmatter SM, Sessa WC. Nat Med. 2004; 10: 382-388. Medline 15034570

Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation. He W, Lu Y, Oahwash I, Hu XY, Chang A, Yan R. Nat Med. 2004; 10: 959-965. Medline 15286784

Overexpression of human reticulon 3 (hRTN3) in astrocytoma. Huang X, Yang H, Zhou Y, Liu J, Yin B, Peng X, Qiang B, Yuan J.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 211 Clin Neuropathol. 2004; 23: 1-7. Medline 14986927

Mutations of the Nogo-66 receptor (RTN4R) gene in schizophrenia. Sinibaldi L, De Luca A, Bellacchio E, Conti E, Pasini A, Paloscia A, Spalletta G, Caltagirone C, Pizzuti A, Dallapiccola B. Human Mutat. 2004; 24: 534-535. Medline 15532024

Nogo-B is a new physiological substrate for MAPKAP-K2. Rousseau S, Peggie M, Campbell DG, Nebreda AR, Cohen P. Biochem J. 2005; 391: 433-440. Medline 16095439

Genetic deletion of the Nogo receptor does not reduce neurite inhibition in vitro or promote corticospinal tract regeneration in vivo. Zheng B, Atwal J, Ho C, Case L, He XL, Garcia KC, Steward O, Tessier-Lavigne M. Proc Natl Acad Sci USA. 2005; 102: 1205-1210. Medline 15647357

Human Nogo-C overexpression induces HEK293 cell apoptosis via a mechanism that involves JNK-c-Jun pathway. Chen Y, Tang X, Cao X, Chen H, Zhang X. Biochem Biophys Res Commun. 2006; 348: 923-928. Medline 16905119

ER stress triggers apoptosis induced by Nogo-B/ASY overexpression. Kuang E, Wan Q, Li X, Zou T, Qi Y. Exp Cell Res 2006; 312: 1983-1988. Medline 16687140

Reticulons RTN3 and RTN4-B/C interact with BACE1 and inhibit its ability to produce amyloid beta-protein. Murayama KS, Kametani F, Saito S, Kume H, Akiyama H, Araki W. Eur J Neurosci. 2006; 24: 1237-1244. Medline 16965550

Nogo A, B and C expression in schizophrenia, depression and bipolar cortex, and correlation of Nogo expression with CAA/TATC polymorphism in 3-UTR. Novak G, Tallerico T. Brain Res. 2006; 1120: 161-171. Medline 17022955

The Nogo receptor complex: confining molecules to molecular mechanisms. Schwab JM, Tuli SK, Failli V. Trends Mol Med. 2006; 12: 293-297. (REVIEW) Medline 16723274

Down-regulation of ASY/Nogo transcription associated with progression of adult T-cell leukemia/lymphoma. Shimakage M, Inoue N, Ohshima K, Kawahara K, Oka T, Yasui K, Matsumoto K, Inoue H, Watari A, Higashiyama S, Yutsudo M. Int J Cancer. 2006; 119: 1648-1653. Medline 16646068

Atlas Genet Cytogenet Oncol Haematol 2007; 2 212

A class of membrane proteins shaping the tubular endoplasmic reticulum. Voeltz GK, Prinz WA, Shibata Y, Rist JM, Rapoport TA. Cell. 2006; 124: 573-586. Medline 16469703

Reticulon proteins: emerging players in neurodegenerative diseases. Yan R, Shi Q, Hu X, Zhou X. Cell Mol Life Sci. 2006; 63: 877-889. (REVIEW) Medline 16505974

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Contributor(s) Written 01-2007 Masuo Yutsudo Citation This paper should be referenced as such : Yutsudo M . RTN4 (reticulon 4). Atlas Genet Cytogenet Oncol Haematol. January 2007 . URL : http://AtlasGeneticsOncology.org/Genes/RTN4ID42182ch2p16.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 2 213 Atlas of Genetics and Cytogenetics in Oncology and Haematology

RHOA (ras homolog gene family, member A)

Identity Other names ARH12 ARHA H12 RHO12 RHOH12 Hugo RHOA Location 3p21.31 DNA/RNA Description This gene can be found on Chromosome 3 at location: 49,371,585-49,424,530. Transcription The DNA sequence contains 5 exons and the transcript length is of 1919 bps translated to a 193 residues protein. Protein

Description RhoA encodes a 21-kDa, 193 amino acids, small Rho GTPase; it displays potent oncogenic activity when overexpressed. RhoA structure: The N-terminal half of RhoA contains the majority of the amino acids involved in GTP binding and hydrolysis, together with the Switch 1 and 2 regions that change conformation between the GTP-bound and GDP-bound states. Several X-ray crystallographic structures of RhoA have been solved at high resolution. Amino acids essential for catalytic function are conserved in other Rho proteins, including Gly14, Thr19, Phe30, and Gln63, which are involved in binding, stabilization or regulation of GTP hydrolysis. RhoA protein is target for several bacterial toxins, which modify key conserved amino acids involved in their regulation. These include Clostridium botulinum exoenzyme C3 transferase, which modifies Asn41, and Toxin B, which acts on Thr37. The C-terminus of RhoA is essential for correct localization of the protein. RhoA is post-translationally modified by prenylation of a conserved C-terminal cysteine followed by methylation and proteolytic removal of the last three amino acids. The prenyl group (geranylgeranyl) anchors the GTPase into membranes and this modification is essential for its stability, cell growth, transformation, and cytoskeletal organization. Expression RhoA protein is expressed in all tissues tested. Localisation RhoA is found in the cytoplasm or at the plasma membrane. RhoA activity regulation: RhoA has intrinsic GTPase activity and shuttle between an inactive GDP-bound state and active GDP-bound state. In vitro, the exchange of GDP to GTP occurs very slowly, and is catalyzed by guanine nucleotide exchange factors (GEFs), which exchange GDP for GTP. GTPase activating proteins (GAPs) catalyze hydrolysis of the gamma phosphate of GTP. There are over 80 GEFs and 70 GAPs for Rho GTPases, whose activity is tightly regulated and can be highly specific. RhoA can be sequestered in the

Atlas Genet Cytogenet Oncol Haematol 2007; 2 214 cytoplasm by guanine nucleotide dissociation inhibitors (RhoGDIs). These remove the Rho protein from the membrane by binding to the prenyl group and prevent its interaction with downstream effectors. RhoA effectors binding: To date, at least 11 proteins have been identified which directly interact with RhoA (ROCK1, ROCK2, PRK1/2 PKN, Rhotekin, Rhophilin, kinectin, Citron Kinase, MBS, p76RBE, PKC epsilon and DB1 transcription factor). Some of these have been shown to contribute to specific responses downstream of RhoA. Similarly to GEFs and GAPs, effectors bind to Rho both through the Switch 1 and 2 regions, but the amino acids involved in interaction with each target differ. Function RhoA regulates a diverse set of biological activities including actin organization, cell motility, cell polarity, gene transcription and cell-cycle progression. Role in actin organization: RhoA protein plays a central role in regulating cell shape, polarity and locomotion through their effects on actin polymerization, actomyosin contractility, cell adhesion, and microtubule dynamics. RhoA is believed to act primarily at the rear of migrating cells to promote detachment. RhoA directly stimulates actin polymerization through activiation of diaphanous-related formins (DRFs, also known as Dia proteins). These stimulate addition of actin monomers to the fast-growing end of actin filaments. DRFs act together with ROCKs to mediate Rho-induced stress fiber formation. ROCK-mediated phosphorylation of LIMK and consequent inhibition of cofilin also contributes to the increase in actin filaments in response to Rho. In addition, ROCKs induce actomyosin-based contractility and phosphorylate several proteins involved in regulating myosins and other actin-binding proteins. Actomyosin contractility is important in migrating cells for detachment of the rear. Microtubules are essential for determining cell polarity as well as for vesicular locomotion and intracellular transport. The concerted action of ROCK and Dia is essential for the regulation of cell polarity and organization of microtubules. ROCK phosphorylates TAU and MAP2, proteins that regulate microtubule stability. RhoA plays a key role in regulating the integrity of cell-extracellular matrix and cell-cell adhesions, the latter including both adherens junctions and tight junctions. Loss of cell- cell junctions is required form the migration of epithelial cells and may be regulated reciprocally by ROCKs and DRFs. Role in cytokinesis: Cytokinesis requires actomyosin-based contraction. Inhibition of ROCK or citron kinase causes defects in cytokinesis resulting in multinucleate cells. Diaphanous- related formins (DRFs) are also implicated in this process, the DRF mDia1 localizes to the cleavage furrow during cytokinesis. DRFs could contribute to cytokinesis by stimulating local actin polymerization and/or by coordinating microtubules with actin filaments at the site of the contractile ring. Role in cell cycle regulation: RhoA plays a pivotal role in G1 cell cycle progression, primarily through regulation of both cyclin D1 expression, and the levels of the cyclin-dependent kinase inhibitors p21 and p27. Multiple pathways seem to link Rho proteins to the control of cyclin D1 levels. Many of these involve the activation of protein kinases, leading to the subsequent modulation of transcription factor activity. RhoA suppresses p21 levels in multiple normal and transformed cell lines. This effect appears to occur through a transcriptional mechanism but is independent of p53, a major transcriptional regulator of p21. RhoA plays an important role in determining the levels of p27 through a pathway involving its effector, the Rho-associated kinases. Role in development: RhoA protein is required for processes involving cell migration in development including: neurite outgrowth, dorsal closure, bone formation, and myogenesis. Rho- loss of function is embryonically lethal in mouse development by E7. This is attributed to failure in gastrulation and an inability of cells to migrate. Role in transcriptional control: The relationship between many of the cellular functions mediated by RhoA with transcriptional regulation has been described. RhoA modulates the activity of SRF, NF-kappaB, c/EBPb, Stat3, Stat5, FHL-2, PAX6, GATA-4, E2F, Estrogen Receptor alpha, Estrogen Receptor beta, CREB, and transcription factors that depend on the

Atlas Genet Cytogenet Oncol Haematol 2007; 2 215 JNK and p38 MAP kinase pathways. Substrates to these kinases include c-Jun, ELK, PEA3, ATF2, MEF2A, Max and CHOP/2GADD153. Mutations Note Several types of human cancers have been analyzed for RhoA mutations. Thus, breast, ovarian, renal, lung and colon specimens were surveyed for RhoA gene mutations and performed chromosomal analysis on 3p21. No mutations in RhoA were found, nor there a correlation between RhoA mRNA expression and the presence or absence of 3p21 deletions. Implicated in Entity Breast carcinoma Oncogenesis RhoA protein levels were significantly increased in breast cancer compared with the corresponding normal tissue. Of particular note, protein levels of RhoA were barely detectable in normal mammary tissue, but were highly expressed in all breast tumors tested. Interestingly, RhoA protein levels correlated with increasing breast tumor grade.

Entity Ovarian carcinoma Oncogenesis RhoA mRNA is higher in ovarian carcinoma, especially of serous histological type, than in benign tumors. The expression of the protein is further upregulated in tumors of stages III/IV when compared to those of stages I/II. Analysis of matched pairs of primary and metastatic lesions showed that expression of both RhoA mRNA was significantly higher in metastatic lesions of peritoneal dissemination than in the respective primary tumors.

Entity Testicular cancer Oncogenesis Protein expression of RhoA and its two major downstream effectors ROCK-I and ROCK-II, was significantly higher in tumor tissue than in nontumor tissue from 57 patients with testicular germ cell tumors. The expression was greater in tumors of higher stages than lower stages, thus RhoA correlates with tumor stage and aggressiveness.

Entity Pelvic/ureteric cancer Oncogenesis Both mRNA and protein level of RhoA are elevated in pelvic/ureteric cancer with an increase in lymph node metastasis. The expression levels of RhoA were related to poorly differentiated grade and muscle invasion and associated with a shorter disease- free and overall survival. These findings suggest that RhoA is involved in the invasion and metastasis of upper urinary tract cancer, indicating that RhoA may be a useful prognostic factor in this disease.

Entity Bladder cancer Oncogenesis A similar deregulation of RhoA is observed in bladder cancer. In this sense, RhoA and ROCK protein levels are elevated in tumors, again with higher expression in less differentiated tumors and metastatic lymph nodes compared to normal bladder. Interestingly, the levels of expression of RhoA and ROCK correlated positively with one another suggesting that the GTPase and its effector synergize to promote tumor progression.

Entity Lung tumors Oncogenesis Of the two major forms of lung cancer, small cell lung carcinoma (SCLC) and non- small cell lung carcinoma (NSCLC), the former has a greater metastatic potential. The expression and activation of RhoA is greater in SCLC than NSCLC cell lines. It has been observed that RhoA repress the expression of nitric oxide synthase-2 (NOS-2) in

Atlas Genet Cytogenet Oncol Haematol 2007; 2 216 a lung cancer-derived cell line. Since NOS-2 activity is related to reduced proliferation, RhoA could be eliminating this antiproliferative signal in lung carcinogenesis. In addition, inhibition of RhoA by C3 exoenzyme or through ADP-ribosylation leads to an increase in cadherin-based adhesion and loss of motility of SCLC.

Entity Oesophageal squamous cell carcinoma Oncogenesis There were significant correlations among RhoA overexpression and TNM clinical classification, lymphatic invasion, and blood-vessel invasion. The five-year survival rates for ESCC patients with RhoA overexpression were significantly lower than those in patients with RhoA under-expression. The expression of RhoA protein appeared to be correlated with tumour progression of ESCC. Patients with RhoA overexpression tended to have poor prognosis compared with patients with RhoA under-expression.

Entity Gastric cancer Oncogenesis RhoA was found frequently overexpressed in gastric cancer tissues compared with normal tissues, suggesting that RhoA may play a critical role in the carcinogenesis of this type of cancer. The interference of RhoA expression and/or activity could significantly inhibit the proliferation and tumorigenicity of gastric cancer cells and enhance the chemosensitivity to therapeutic agents such as Adriamycin and 5- fluorouracil.

Entity Hepatocellular carcinoma Oncogenesis Invasiveness of hepatocellular carcinoma is facilitated by the Rho/Rho-kinase pathway and likely to be relevant to tumor progression. The Rho/Rho-kinase may be useful as a prognostic indicator and in the development of novel therapeutic strategies.

Entity Pancreatic tumor Oncogenesis Although overexpression of RhoA has not been detected in any pancreatic tumor tissue to date, it might nevertheless also be involved in pancreatic tumors. Two 3- hydroxy 3methylgultaryl coenzyme A (HMG- CoA) reductase inhibitors, fluvastatin and lovastatin inhibit human pancreatic cancer ell invasion and metastasis in a Rho- dependent manner. These inhibitors prevent the synthesis of cholesterol precursors necessary for proper membrane translocation of Rho protein.

Entity Colorectal cancer Oncogenesis A high proportion of colon cancers overexpress RhoA and several aspects of colon tumor biology have been related to Rho GTPases. Leptin receptor and leptin-induced migration of colonic epithelial cancer cells is dependent on RhoA, since inhibition of the activity of the GTPase through introduction of dominant negative mutants completely abolishes the invasive capacity of the tumor cells.

External links Nomenclature Hugo RHOA GDB RHOA Entrez_Gene RHOA 387 ras homolog gene family, member A Cards Atlas RHOAID42107ch3p21 GeneCards RHOA Ensembl RHOA

Atlas Genet Cytogenet Oncol Haematol 2007; 2 217 Genatlas RHOA GeneLynx RHOA eGenome RHOA euGene 387 Genomic and cartography GoldenPath RHOA - 3p21.31 chr3:49371585-49424530 - 3p21.3 (hg18-Mar_2006) Ensembl RHOA - 3p21.3 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene RHOA Gene and transcription Genbank AF498970 [ ENTREZ ] Genbank AK130066 [ ENTREZ ] Genbank AK130808 [ ENTREZ ] Genbank AK222556 [ ENTREZ ] Genbank BC000946 [ ENTREZ ] RefSeq NM_001664 [ SRS ] NM_001664 [ ENTREZ ] RefSeq AC_000046 [ SRS ] AC_000046 [ ENTREZ ] RefSeq NC_000003 [ SRS ] NC_000003 [ ENTREZ ] RefSeq NT_022517 [ SRS ] NT_022517 [ ENTREZ ] RefSeq NW_921651 [ SRS ] NW_921651 [ ENTREZ ] AceView RHOA AceView - NCBI Unigene Hs.247077 [ SRS ] Hs.247077 [ NCBI ] HS247077 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P08100 [ SRS] P08100 [ EXPASY ] P08100 [ INTERPRO ] PS00237 G_PROTEIN_RECEP_F1_1 [ SRS ] PS00237 Prosite G_PROTEIN_RECEP_F1_1 [ Expasy ] PS50262 G_PROTEIN_RECEP_F1_2 [ SRS ] PS50262 Prosite G_PROTEIN_RECEP_F1_2 [ Expasy ] Prosite PS00238 OPSIN [ SRS ] PS00238 OPSIN [ Expasy ] Interpro IPR000276 GPCR_Rhodpsn [ SRS ] IPR000276 GPCR_Rhodpsn [ EBI ] Interpro IPR001760 Opsin [ SRS ] IPR001760 Opsin [ EBI ] Interpro IPR000732 Rhodopsin [ SRS ] IPR000732 Rhodopsin [ EBI ] CluSTr P08100 Pfam PF00001 7tm_1 [ SRS ] PF00001 7tm_1 [ Sanger ] pfam00001 [ NCBI-CDD ] Blocks P08100 HPRD P08100 Protein Interaction databases DIP P08100 IntAct P08100 Polymorphism : SNP, mutations, diseases OMIM 165390 [ map ] GENECLINICS 165390 SNP RHOA [dbSNP-NCBI]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 218 SNP NM_001664 [SNP-NCI] SNP RHOA [GeneSNPs - Utah] RHOA] [HGBASE - SRS] HAPMAP RHOA [HAPMAP] General knowledge Family RHOA [UCSC Family Browser] Browser SOURCE NM_001664 SMD Hs.247077 SAGE Hs.247077 GO nucleotide binding [Amigo] nucleotide binding GO magnesium ion binding [Amigo] magnesium ion binding GO GTPase activity [Amigo] GTPase activity GO signal transducer activity [Amigo] signal transducer activity GO protein binding [Amigo] protein binding GO GTP binding [Amigo] GTP binding GO intracellular [Amigo] intracellular GO cytoskeleton [Amigo] cytoskeleton small GTPase mediated signal transduction [Amigo] small GTPase mediated signal GO transduction GO Rho protein signal transduction [Amigo] Rho protein signal transduction GO membrane [Amigo] membrane actin cytoskeleton organization and biogenesis [Amigo] actin cytoskeleton GO organization and biogenesis positive regulation of NF-kappaB import into nucleus [Amigo] positive regulation of GO NF-kappaB import into nucleus positive regulation of I-kappaB kinase/NF-kappaB cascade [Amigo] positive GO regulation of I-kappaB kinase/NF-kappaB cascade BIOCARTA CCR3 signaling in Eosinophils [Genes] BIOCARTA Thrombin signaling and protease-activated receptors [Genes] BIOCARTA Influence of Ras and Rho proteins on G1 to S Transition [Genes] Rho-Selective Guanine Exchange Factor AKAP13 Mediates Stress Fiber BIOCARTA Formation [Genes] BIOCARTA Protein Kinase A at the Centrosome [Genes] BIOCARTA Role of EGF Receptor Transactivation by GPCRs in Cardiac Hypertrophy [Genes] Role of PI3K subunit p85 in regulation of Actin Organization and Cell BIOCARTA Migration [Genes] Erk and PI-3 Kinase Are Necessary for Collagen Binding in Corneal BIOCARTA Epithelia [Genes] BIOCARTA Phospholipids as signalling intermediaries [Genes] BIOCARTA Integrin Signaling Pathway [Genes] BIOCARTA Role of MAL in Rho-Mediated Activation of SRF [Genes] BIOCARTA Ras Signaling Pathway [Genes] BIOCARTA Rho cell motility signaling pathway [Genes] BIOCARTA Trefoil Factors Initiate Mucosal Healing [Genes] BIOCARTA uCalpain and friends in Cell spread [Genes] PubGene RHOA

Atlas Genet Cytogenet Oncol Haematol 2007; 2 219 Other databases Probes Probe RHOA Related clones (RZPD - Berlin) PubMed PubMed 203 Pubmed reference(s) in LocusLink Bibliography Rho GTPases are over-expressed in human tumors. Fritz G, Just I, Kaina B. Int J Cancer. 1999; 81: 682-687. Medline 10328216

Cell motility mediated by rho and Rho-associated protein kinase plays a critical role in intrahepatic metastasis of human hepatocellular carcinoma. Genda T, Sakamoto M, Ichida T, Asakura H, Kojiro M, Narumiya S, Hirohashi S. Hepatology. 1999; 30: 1027-1036. Medline 10498656

Leptin promotes invasiveness of kidney and colonic epithelial cells via phosphoinositide 3- kinase-, rho-, and rac-dependent signaling pathways. Attoub S, Noe V, Pirola L, Bruyneel E, Chastre E, Mareel M, Giman MP, Gespach C. FASEB J. 2000; 14: 2329-2338. Medline 11053255

Rho GTPases and their effector proteins. Bishop AL, Hall A. Biochem J. 2000; 348: 241-255. Medline 10816416

Ras and RhoA suppress whereas RhoB enhances cytokine-induced transcription of nitric oxide synthase-2 in human normal liver AKN-1 cells and lung cancer A-549 cells. Delarue FL, Taylor BS, Sebti SM. Oncogene. 2001; 20: 6531-6537. Medline 11641777

Rho GTPases in human breast tumours: expression and mutation analyses and correlation with clinical parameters. Fritz G, Brachetti C, Bahlmann F, Schmidt M, Kaina B. Br J Cancer. 2002; 87: 635-644. Medline 12237774

3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors reduce human pancreatic cancer cell invasion and metastasis. Kusama T, Mukai M, Iwasaki T, Tatsuta M, Matsumoto Y, Akedo H, Inoue M, Nakamura H. Gastroenterology. 2002; 122: 308-317. Medline 11832446

RhoA is associated with invasion and lymph node metastasis in upper urinary tract cancer. Kamai T, Kawakami S, Koga F, Arai G, Takagi K, Arai K, Tsujii T, Yoshida KI. BJU Int. 2003; 91: 234-238. Medline 12581011

Rho regulates the hepatocyte growth factor/scatter factor-stimulated cell motility of human oral squamous cell carcinoma cells.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 220 Kitajo H, Shibata T, Nagayasu H, Kawano T, Hamada J, Yamashita T, Arisue M. Oncol Rep. 2003; 10: 1351-1356. Medline 12883706

Cell migration: integrating signals from front to back. Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, Borisy G, Parsons JT, Horwitz AR. Science. 2003; 302: 1704-1709.

The small GTPase RhoA has greater expression in small cell lung carcinoma than in non-small cell lung carcinoma and contributes to their unique morphologies. Varker KA, Phelps SH, King MM, Williams CL. Int J Oncol. 2003; 22: 671-681. Medline 12579323

Rho GTPases in human cancer: an unresolved link to upstream and downstream transcriptional regulation. Benitah SA, Valeron PF, van Aelst L, Marshall CJ, Lacal JC. Biochim Biophys Acta. 2004; 1705: 121-132. Medline 15588766

Overexpression of RhoA, Rac1, and Cdc42 GTPases is associated with progression in testicular cancer. Kamai T, Yamanishi T, Shirataki H, Takagi K, Asami H, Ito Y, Yoshida K. Clin Cancer Res. 2004; 10: 4799-4805. Medline 15269155

Rho-family GTPases: it's not only Rac and Rho (and I like it). Wennerberg K, Der CJ. J Cell Sci. 2004; 117: 1301-1312. Medline 15020670

Correlation between RhoA overexpression and tumour progression in esophageal squamous cell carcinoma. Faried A, Nakajima M, Sohda M, Miyazaki T, Kato H, Kuwano H. Eur J Surg Oncol. 2005; 31: 410-414. Medline 15837049

Rho GTPase expression in tumourigenesis: evidence for a significant link. Gómez del Pulgar T, Benitah SA, Valeron PF, Espina C, Lacal JC. Bioessays. 2005; 27: 602-613. Medline 15892119

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Contributor(s) Written 01-2007 Teresa Gomez del Pulgar, Juan Carlos Lacal Citation This paper should be referenced as such :

Atlas Genet Cytogenet Oncol Haematol 2007; 2 221 Gomez del Pulgar T, Lacal JC . RHOA (ras homolog gene family, member A). Atlas Genet Cytogenet Oncol Haematol. January 2007 . URL : http://AtlasGeneticsOncology.org/Genes/RHOAID42107ch3p21.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

Atlas Genet Cytogenet Oncol Haematol 2007; 2 222 Atlas of Genetics and Cytogenetics in Oncology and Haematology

RARRES1 (retinoic acid receptor responder (tazarotene induced) 1)

Identity Other names TIG1 Hugo RARRES1 Location 3q25.32 Local_order Telomeric to MFSD1 and centromeric to GFM1 and LXN Note RARRES1 (retinoic acid receptor responder 1) is also known as TIG1 (Tazarotene- induced gene 1). The gene was initially identified as a target gene that was induced by the synthetic retinoid tazarotene (AGN 190168) in human skin raft cultures. It is upregulated by retinoic acid receptorspecific but not by retinoid X receptor-specific retinoids. As noted in the early published articles, the authors mentioned that RARRES1 (TIG1) is located at 3p12-13. The location was subsequently confirmed to be incorrect. UCSC Genome Browser on Human Mar. 2006 Assembly shows that the RARRES1 should be located between 3q25.32 and 3q25.33. DNA/RNA

Two transcript variants (isoform 1: NM_206963.1 and isoform 2: NM_002888.2) are shown. Black boxes represent the exons of RARRES1. CpG: location of CpG island.

Description The RARRES1 gene contains 6 exons and spans 35377 bases. Transcription Two alternatively spliced transcripts were identified (isoform 1 and isoform 2). Exons 1 to 4 are common to both isoforms. Exon 5 and 6 are present in isoform 1 (NM_206963.1) only. The cDNA of isoform 1 is 1545 bp while isoform 2 is 886 bp. Pseudogene No known pseudogenes Protein

Atlas Genet Cytogenet Oncol Haematol 2007; 2 223

The gray box indicates the single membrane-spanning hydrophobic region. Lataxin domain for 2 RARRES1 isoforms is shown as black box.

Description Called Retinoic acid receptor responder protein 1 (synonyms: Tazarotene-induced gene 1 protein/RAR-responsive protein TIG1); Two isoform, isoform 1 (NP_996846) and isoform 2 (NP_002879), produced by alternative splicing were reported. Isoforms 1 and 2 contain 294 and 228 amino acids respectively. Molecular weight of Isoform 1 is 33258 Da. The two isoforms show difference in the 3'end-region. RARRES1 is predicted to be a transmembrane protein with a small N-terminal intracellular regions, a single membrane-spanning hydrophobic region, and a large C-terminal extracellular region containing a glycosylation signal. Expression High level of RARRES1 transcripts was detected in multiple tissues including prostate, heart, lung, liver, colon and small intestine. Expression of RARRES1 protein was demonstrated in colorectal tissues. Localisation Based on the predicted amino acid sequence, RARRES1 is suspected to be a transmembrane protein. However, immunohistochemical analysis showed that RARRES1 protein localizes at the supranuclear regions of colorectal adenocarcinoma, adenoma and adjacent normal epithelial cells. The precise localization of RARRES1 protein needed to be further investigated. Function RARRES1 was suggested to be a tumor suppressor of a variety of human cancers. Inactivation of RARRES1 is involved in the malignant progression of prostate cancer. Restoration of RARRES1 expression in malignant prostate cell lines led to a decrease of invasiveness and tumorigenicity in nude mice. It is speculated that RARRES1 may function as a cell adhesion molecule. Since the protein shows sequence similarity to Latexin, the only known mammalian carboxypeptidase inhibitor, RARRES1 may also have protease inhibitor activity and inhibit the degradation of extracellular matrix. Homology RARRES1 belongs to the proteinase inhibitor I47 (latexin) family, its c-terminal region shows 30% sequence similarity with Latexin. Mutations Note No germline or somatic mutation associated with disease is reported. Implicated in Entity A variety of human cancers Note The association of RARRES1 with human cancer was first revealed by the subtractive differential gene display analysis of benign and malignant prostate cell lines. The gene was expressed in benign prostate cell lines and not in malignant ones. It is now considered as a putative tumor suppressor gene in a variety of human cancers

Atlas Genet Cytogenet Oncol Haematol 2007; 2 224 although its function remains unclear. Its expression is commonly suppressed in prostate carcinoma, lung cancer, nasopharyngeal carcinoma, and leukemia by promoter hypermethylation. Restoring RARRES1 expression in prostate cancer cells resulted in decrease of in vitro invasiveness and in vivo tumorigenicity. RARRES1 also implicated in therapeutic effects of retinoic acid in psoriasis. Disease prostate carcinoma, nasopharyngeal carcinoma, head and neck cancer, lung cancer, gastric carcinoma, colorectal adenocarcinoma, endometrial cancer, breast cancer, acute myeloid leukemia, Chronic myeloid leukemia. Prognosis down-regulation of RARRES1 is significantly related with the late stage colorectal adenocarcinoma (Dukes's stage D). However, no difference in survival was found comparing patient with negative, weak and strong RARRES1 expression in tumors. Cytogenetics No translocations and amplifications of this gene have been reported Hybrid/Mutated No hybrid gene involving RARRES1 has been described. Gene

Breakpoints Note No breakpoints involving this gene have been described. External links Nomenclature Hugo RARRES1 GDB RARRES1 Entrez_Gene RARRES1 5918 retinoic acid receptor responder (tazarotene induced) 1 Cards Atlas RARRES1ID42050ch3q25 GeneCards RARRES1 Ensembl RARRES1 Genatlas RARRES1 GeneLynx RARRES1 eGenome RARRES1 euGene 5918 Genomic and cartography RARRES1 - 3q25.32 chr3:159905134-159932969 - 3q25.32-q25.33 (hg18- GoldenPath Mar_2006) Ensembl RARRES1 - 3q25.32-q25.33 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene RARRES1 Gene and transcription Genbank AK130079 [ ENTREZ ] Genbank AW514087 [ ENTREZ ] Genbank BC029640 [ ENTREZ ] Genbank BM919188 [ ENTREZ ] Genbank CR595342 [ ENTREZ ] RefSeq NM_002888 [ SRS ] NM_002888 [ ENTREZ ] RefSeq NM_206963 [ SRS ] NM_206963 [ ENTREZ ] RefSeq AC_000046 [ SRS ] AC_000046 [ ENTREZ ]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 225 RefSeq NC_000003 [ SRS ] NC_000003 [ ENTREZ ] RefSeq NT_005612 [ SRS ] NT_005612 [ ENTREZ ] RefSeq NW_921807 [ SRS ] NW_921807 [ ENTREZ ] AceView RARRES1 AceView - NCBI Unigene Hs.131269 [ SRS ] Hs.131269 [ NCBI ] HS131269 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt P13631 [ SRS] P13631 [ EXPASY ] P13631 [ INTERPRO ] PS00031 NUCLEAR_REC_DBD_1 [ SRS ] PS00031 NUCLEAR_REC_DBD_1 [ Prosite Expasy ] PS51030 NUCLEAR_REC_DBD_2 [ SRS ] PS51030 NUCLEAR_REC_DBD_2 [ Prosite Expasy ] Interpro IPR001628 Hrmn_rcpt_DNA_bd [ SRS ] IPR001628 Hrmn_rcpt_DNA_bd [ EBI ] Interpro IPR000536 Hrmn_rcpt_lig_bd [ SRS ] IPR000536 Hrmn_rcpt_lig_bd [ EBI ] Interpro IPR008946 Nucl_rcpt_lig_bd [ SRS ] IPR008946 Nucl_rcpt_lig_bd [ EBI ] Interpro IPR003078 Rtnoid_rcpt [ SRS ] IPR003078 Rtnoid_rcpt [ EBI ] Interpro IPR001723 Str_hrmn_rcpt [ SRS ] IPR001723 Str_hrmn_rcpt [ EBI ] CluSTr P13631 PF00104 Hormone_recep [ SRS ] PF00104 Hormone_recep [ Sanger Pfam ] pfam00104 [ NCBI-CDD ] Pfam PF00105 zf-C4 [ SRS ] PF00105 zf-C4 [ Sanger ] pfam00105 [ NCBI-CDD ] Smart SM00430 HOLI [EMBL] Smart SM00399 ZnF_C4 [EMBL] Prodom PD000035 Znf_C4steroid[INRA-Toulouse] P13631 RARG1_HUMAN [ Domain structure ] P13631 RARG1_HUMAN [ Prodom sequences sharing at least 1 domain ] Blocks P13631 PDB 1FCX [ SRS ] 1FCX [ PdbSum ], 1FCX [ IMB ] 1FCX [ RSDB ] PDB 1FCY [ SRS ] 1FCY [ PdbSum ], 1FCY [ IMB ] 1FCY [ RSDB ] PDB 1FCZ [ SRS ] 1FCZ [ PdbSum ], 1FCZ [ IMB ] 1FCZ [ RSDB ] PDB 1FD0 [ SRS ] 1FD0 [ PdbSum ], 1FD0 [ IMB ] 1FD0 [ RSDB ] HPRD P13631 Protein Interaction databases DIP P13631 IntAct P13631 Polymorphism : SNP, mutations, diseases OMIM 605090 [ map ] GENECLINICS 605090 SNP RARRES1 [dbSNP-NCBI] SNP NM_002888 [SNP-NCI] SNP NM_206963 [SNP-NCI] SNP RARRES1 [GeneSNPs - Utah] RARRES1] [HGBASE - SRS] HAPMAP RARRES1 [HAPMAP] General knowledge Family RARRES1 [UCSC Family Browser] Browser

Atlas Genet Cytogenet Oncol Haematol 2007; 2 226 SOURCE NM_002888 SOURCE NM_206963 SMD Hs.131269 SAGE Hs.131269 GO negative regulation of cell proliferation [Amigo] negative regulation of cell proliferation GO membrane [Amigo] membrane GO integral to membrane [Amigo] integral to membrane PubGene RARRES1 Other databases Probes Probe RARRES1 Related clones (RZPD - Berlin) PubMed PubMed 8 Pubmed reference(s) in LocusLink Bibliography Tazarotene-induced gene 1 (TIG1), a novel retinoic acid receptor responsive gene in skin. Nagpal S, Patel S, Asano AT, Johnson AT, Duvic M, Chandraratna RA. J Invest Dermatol. 1996; 106(2): 269-274. Medline 8601727

Molecular mechanisms of tazarotene action in psoriasis. Duvic M, Nagpal S, Asano AT, Chandraratua RA. J Am Acad Dermatol. 1997; 37(2 Pt 3): S18-24. Medline 9270552

Ovocalyxin-32, a novel chicken eggshell matrix protein. isolation, amino acid sequencing, cloning, and immunocytochemical localization. Gautron J, Hincke MT, Mann K, Panheleux M, Bain M, McKee MD, Solomon SE, Nys Y. J Biol Chem. 2001; 276(42): 39243-39252. Medline 11493603

Tazarotene-induced gene 1 (TIG1) expression in prostate carcinomas and its relationship to tumorigenicity. Jing C, EI-Ghany MA, Beesley C, Foster CS, Rudland PS, Smith P, Ke Y. J Natl Cancer Inst. 2002; 94(7): 482-490. Medline 11929948

Is TIG1 a new tumor suppressor in prostate cancer? Lotan R. J Natl Cancer Inst. 2002; 94(7): 469-470. Medline 11929940

Purification of ovocalyxin-32, a novel chicken eggshell matrix protein. Hincke MT, Gantron J, Mann K, Panheleux M, McKee MD, Bain M, Solomon SE, Nys Y. Connect Tissue Res. 2003 ;44 Suppl 1: 16-19. Medline 12952168

Re: Is TIG1 a new tumor suppressor in prostate cancer? Tokumaru Y, Sun DI, Nomoto S, Yamashita K, Sidransky D. J Natl Cancer Inst. 2003; 95(12): 919-920. Medline 12813179

Atlas Genet Cytogenet Oncol Haematol 2007; 2 227

Microdissection, mRNA amplification and microarray: a study of pleural mesothelial and malignant mesothelioma cells. Mohr S, Bottin MC, Lannes B, Neuville A, Bellocq JP, Keith G, Rihn BH. Biochimie. 2004; 86(1): 13-19. Medline 14987796

Optimal use of a panel of methylation markers with GSTP1 hypermethylation in the diagnosis of prostate adenocarcinoma. Tokumaru Y, Harden SV, Sun DI, Yamashita K, Epstein JI, Sidransky D. Clin Cancer Res. 2004; 10(16): 5518-5522. Medline 15328191

DNA microarray analysis of vitamin D-induced gene expression in a human colon carcinoma cell line. Wood RJ, Tchack L, Angelo G, Pratt RE, Sonna LA. Physiol Genomics. 2004; 17(2): 122-129. Medline 14996990

Hypermethylation and silencing of the putative tumor suppressor Tazarotene-induced gene 1 in human cancers. Youssef EM, Chen XQ, Higuchi E, Kondo Y, Garcia-Manero G, Lotan R, Issa JP. Cancer Res. 2004; 64(7): 2411-2417. Medline 15059893

Methylation of the retinoid response gene TIG1 in prostate cancer correlates with methylation of the retinoic acid receptor beta gene. Zhang J, Liu L, Pfeifer GP. Oncogene. 2004; 23(12): 2241-2249. Medline 14691453

An inflammatory role for the mammalian carboxypeptidase inhibitor latexin: relationship to cystatins and the tumor suppressor TIG1. Aagaard A, Listwan P, Cowieson N, Huber T, Ravasi T, Wells CA, Flanagan JU, Kellie S, Hume DA, Kobe B, Martin JL. Structure. 2005; 13(2): 309-317 Medline 15698574

Silencing of the retinoid response gene TIG1 by promoter hypermethylation in nasopharyngeal carcinoma. Kwong J, Lo KW, Chow LS, Chan FL, To KF, Huang Dp. Int J Cancer. 2005; 113(3): 386-392. Medline 15455391

DNA methylation of genes linked to retinoid signaling in squamous cell carcinoma of the esophagus: DNA methylation of CRBP1 and TIG1 is associated with tumor stage. Mizuiri H, Yoshida K, Toge T, Oue N, Aung PP, Noguchi T, Yasui W. Cancer Sci. 2005; 96(9): 571-577. Medline 16128742

Promoter hypermethylation as an independent prognostic factor for relapse in patients with prostate cancer following radical prostatectomy. Rosenbaum E, Hoque MO, Cohen Y, Zahurak M, Eisenberger MA, Epstein JI, Partin AW, Sidransky D. Clin Cancer Res. 2005; 11(23): 8321-5325.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 228 Medline 16322291

DNA methylation of genes linked with retinoid signaling in gastric carcinoma: expression of the retinoid acid receptor beta, cellular retinol-binding protein 1, and tazarotene-induced gene 1 genes is associated with DNA methylation. Shutoh M, Oue N, Aung PP, Noguchi T, Kuraoka K, Nakayama H, Kawahara K, Yasui W. Cancer. 2005; 104(8): 1609-1619. Medline 16134180

Discovery of epigenetically masked tumor suppressor genes in endometrial cancer. Takai N, Kawamata N, Walsh CS, Gery S, Desmond JC, Whittaker S, Said JW, Popoviciu LM, Jones PA, Miyakawa I, Koeffler HP. Mol Cancer Res. 2005; 3(5): 261-269. Medline 15886297

All-trans retinoic acid treatment of Wilms tumor cells reverses expression of genes associated with high risk and relapse in vivo. Zirn B, Samans B, Spangenberg C, Graf N, Eilers M, Gessler M. Oncogene. 2005; 24(33): 5246-5251. Medline 15897880

Multiple tumor suppressor genes are increasingly methylated with age in non-neoplastic gastric epithelia. So K, Tamura G, Honda T, Homma N, Waki T, Togawa N, Nishizuka S, Motoyama T. Cancer Sci. 2006; 97(11): 1155-1158. Medline 16952303

Effects of oestrogen on gene expression in epithelium and stroma of normal human breast tissue. Wilson CL, Sims AH, Howell A, Miller CJ, Clarke RB. Endocr Relat Cancer. 2006; 13(2): 617-628. Medline 16728587

RARRES1 expression is significantly related to tumour differentiation and staging in colorectal adenocarcinoma. Wu CC, Shyu RY, Chou JM, Jao SW, Chao PC, Kang JC, Wu ST, Huang SL, Jiang SY Eur J Cancer. 2006; 42(4): 557-565. Medline 16426842 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

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Contributor(s) Written 01-2007 Kwok-Wai Lo, Grace TY Chung Citation This paper should be referenced as such : Lo KW, Chung GTY . RARRES1 (retinoic acid receptor responder (tazarotene induced) 1). Atlas Genet Cytogenet Oncol Haematol. January 2007 . URL : http://AtlasGeneticsOncology.org/Genes/RARRES1ID42050ch3q25.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

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DDX43 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 43)

Identity Other names HAGE (for AntiGEn) DKFZp434H2114 Hugo DDX43 Location 6q13 Local_order between markers GATA11B08 and D6S284 Note This gene was isolated as a cDNA by applying a subtraction approach named representational difference analysis (RDA). Rhabdomyosarcoma LB23-SAR was used as the source of tester cDNA that was subtracted with driver cDNA, a mixture of human uterus, breast, heart, and colon cDNA. DNA/RNA Transcription The transcript is about 2.2 kb. Gene HAGE is weakly transcribed in normal tissues: the level of expression was estimated to represent only 0.2% of the level found in the LB23-SAR reference cell line. The only exception is testis, which shows a level of expression comparable to that of LB23-SAR. Gene HAGE was found to be expressed in 90 out of 383 tumor samples of different histological types, well above the level in normal tissues; about 5% of the positive samples showed a level of expression above 10% of the level of LB23-SAR, and 7% showed a level of expression between 1-10%. Expression of HAGE was induced in fibroblasts after treatment with the demethylating agent, 5-aza-2¹-deoxycytidine. Protein

Description The largest open reading frame comprises 1,944 nucleotides and encodes a protein of 648 amino acids (72,871 Da). The pKi of the protein is 9.29. Function Comparison with databases revealed that HAGE shows 55% similarity with the human p68 protein, an ATP-dependent RNA helicase that is a member of the DEAD-box proteins. Four motifs that are present in members of the DEAD box family are conserved in the HAGE protein. However, ATPase and helicase activities of HAGE were not demonstrated. Mutations Note No mutation was observed in the HAGE cDNA isolated from LB23-SAR. Implicated in Entity Tumors Note HAGE expression can be induced by demethylating agent 5-azadeoxycytidine, suggesting that demethylation plays a role in the activation of these genes in tumors. Activation of HAGE in tumor cells most likely results therefore from the genome-wide demethylation process that is known to occur in these cells. Oncogenesis HAGE is not the first case of a DEAD-box protein that is overexpressed in tumors. Moreover, it worth noting that one out of 42 discovered mutated human tumor antigens

Atlas Genet Cytogenet Oncol Haematol 2007; 2 230 is produced by a point mutation in a gene named MUM-3. This gene encodes a protein with homology with members of the RNA helicase family. These observations suggest that mutated or overexpressed may contribute to tumoral transformation or progression.

External links Nomenclature Hugo DDX43 GDB DDX43 Entrez_Gene DDX43 55510 DEAD (Asp-Glu-Ala-Asp) box polypeptide 43 Cards Atlas DDX43ID40288ch6q13 GeneCards DDX43 Ensembl DDX43 Genatlas DDX43 GeneLynx DDX43 eGenome DDX43 euGene 55510 Genomic and cartography GoldenPath DDX43 - 6q13 chr6:74161192-74183791 + 6q12-q13 (hg18-Mar_2006) Ensembl DDX43 - 6q12-q13 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene DDX43 Gene and transcription Genbank AJ278110 [ ENTREZ ] Genbank AL136751 [ ENTREZ ] Genbank BC056879 [ ENTREZ ] Genbank BC066938 [ ENTREZ ] RefSeq NM_018665 [ SRS ] NM_018665 [ ENTREZ ] RefSeq AC_000049 [ SRS ] AC_000049 [ ENTREZ ] RefSeq NC_000006 [ SRS ] NC_000006 [ ENTREZ ] RefSeq NT_007299 [ SRS ] NT_007299 [ ENTREZ ] RefSeq NW_923184 [ SRS ] NW_923184 [ ENTREZ ] AceView DDX43 AceView - NCBI Unigene Hs.125507 [ SRS ] Hs.125507 [ NCBI ] HS125507 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt O00571 [ SRS] O00571 [ EXPASY ] O00571 [ INTERPRO ] PS00039 DEAD_ATP_HELICASE [ SRS ] PS00039 DEAD_ATP_HELICASE [ Prosite Expasy ] PS51192 HELICASE_ATP_BIND_1 [ SRS ] PS51192 HELICASE_ATP_BIND_1 [ Prosite Expasy ] Prosite PS51194 HELICASE_CTER [ SRS ] PS51194 HELICASE_CTER [ Expasy ] Prosite PS51195 Q_MOTIF [ SRS ] PS51195 Q_MOTIF [ Expasy ]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 231 Interpro IPR001410 DEAD [ SRS ] IPR001410 DEAD [ EBI ] Interpro IPR011545 DEAD/DEAH_N [ SRS ] IPR011545 DEAD/DEAH_N [ EBI ] Interpro IPR000629 DEAD_box [ SRS ] IPR000629 DEAD_box [ EBI ] Interpro IPR001650 Helicase_C [ SRS ] IPR001650 Helicase_C [ EBI ] CluSTr O00571 Pfam PF00270 DEAD [ SRS ] PF00270 DEAD [ Sanger ] pfam00270 [ NCBI-CDD ] PF00271 Helicase_C [ SRS ] PF00271 Helicase_C [ Sanger ] pfam00271 [ NCBI- Pfam CDD ] Smart SM00487 DEXDc [EMBL] Smart SM00490 HELICc [EMBL] Blocks O00571 HPRD O00571 Protein Interaction databases DIP O00571 IntAct O00571 Polymorphism : SNP, mutations, diseases OMIM 606286 [ map ] GENECLINICS 606286 SNP DDX43 [dbSNP-NCBI] SNP NM_018665 [SNP-NCI] SNP DDX43 [GeneSNPs - Utah] DDX43] [HGBASE - SRS] HAPMAP DDX43 [HAPMAP] General knowledge Family DDX43 [UCSC Family Browser] Browser SOURCE NM_018665 SMD Hs.125507 SAGE Hs.125507 Enzyme 3.6.1.- [ Enzyme-SRS ] 3.6.1.- [ Brenda-SRS ] 3.6.1.- [ KEGG ] 3.6.1.- [ WIT ] GO nucleotide binding [Amigo] nucleotide binding y GO RNA binding [Amigo] RNA binding GO ATP-dependent RNA helicase activity [Amigo] ATP-dependent RNA helicase activity GO ATP binding [Amigo] ATP binding GO intracellular [Amigo] intracellular GO hydrolase activity [Amigo] hydrolase activity PubGene DDX43 Other databases Probes Probe DDX43 Related clones (RZPD - Berlin) PubMed PubMed 4 Pubmed reference(s) in LocusLink Bibliography Identification on a human sarcoma of two new genes with tumor-specific expression.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 232 Martelange V, De Smet C, De Plaen E, Lurquin C, Boon T. Cancer Res. 2000; 60(14): 3848-3855. Medline 10919659

High frequency of autologous anti-melanoma CTL directed against an antigen generated by a point mutation in a new helicase gene. Baurain JF, Colau D, van Baren N, Landry C, Martelange V, Vikkula M, Boon T, Coulie PG. J Immunol. 2000; 164(11): 6057-6066. Medline 10820291

Frequent expression of HAGE in presentation chronic myeloid leukaemias. Adams SP, Sahota SS, Mijovic A, Czepulkowski B, Padua RA, Mufti GJ, Guinn BA. Leukemia. 2002; 16(11): 2238-2242. Medline 12399967

Analysis of the tumour suppressor genes, FHIT and WT-1, and the tumour rejection genes, BAGE, GAGE-1/2, HAGE, MAGE-1, and MAGE-3, in benign and malignant neoplasms of the salivary glands. Nagel H, Laskawi R, Eiffert H, Schlott T. Mol Pathol. 2003; 56(4): 226-231. Medline 12890744

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Contributor(s) Written 01-2007 Etienne De Plaen Citation This paper should be referenced as such : De Plaen E . DDX43 (DEAD (Asp-Glu-Ala-Asp) box polypeptide 43). Atlas Genet Cytogenet Oncol Haematol. January 2007 . URL : http://AtlasGeneticsOncology.org/Genes/DDX43ID40288ch6q13.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

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CDK4 (cyclin-dependent kinase 4)

Identity Other names CMM3 MGC14458 PSK-J3 Hugo CDK4 Location 12q14 Telomeric to the OS9 (amplified in osteosarcoma 9), CENTG1 (centaurin, gamma 1) and TSPAN31 (tetraspanin 31, SAS) genes. Centromeric to the MARCH9 (membrane- Local_order associated ring finger (C3HC4) 9), CYP27B1 (cytochrome P450, family 27, subfamily B, polypeptide 1) and METTL1 (methyltransferase like 1) genes. These seven genes are clustered within a genomic region of about 75 kb. DNA/RNA

Genomic organization of the CDK4 gene on .

Description CDK4 is a relatively compact gene that spans 4.16 kb of genomic DNA on the long arm of chromosome 12, in the telomere-to-centromere orientation. The gene consists of eight exons of which the first exon is non-coding. The start codon is located in the beginning of exon 2 and the stop codon in the beginning of exon 8. Transcription The CDK4 mRNA is 1.44 kb. In the Ensembl database, also a shorter, alternatively spliced transcript (Q96BE9_HUMAN) is listed, but there is no biological evidence for a function of this transcript or the polypeptide it may encode. Pseudogene The Ensembl database lists OTTHUMG00000011002 (Vega gene RP11-414B7.1) on chromosome 1 as a processed pseudogene of CDK4. Protein Description The open reading frame encodes a 303 amino acid protein with an estimated molecular weight of 33.7 kDa. CDK4 is member of the Ser-Thr protein kinase family and its catalytic domain extends from amino acid 6 to 295. Expression CDK4 is expressed in a variety of normal cells and tissues as well as in cancer cells. The protein is often overexpressed in human tumors (e.g. malignant melanoma, glioma, sarcoma and carcinomas of the breast, colon, lung, ovary and oral cavity). Localisation Nuclear or nuclear/cytoplasmic Function CDK4 constitutes the catalytic subunit of a heterodimeric Ser/Thr protein kinase which is involved in controlling progression through the G1 phase of the cell cycle. The activating partner of CDK4 (the regulatory subunit) is one of the D-type cyclins:

Atlas Genet Cytogenet Oncol Haematol 2007; 2 234 CCND1, CCND2 or CCND3. Once activated, the CDK4-cyclin D complex phosphorylates members of the retinoblastoma protein family ( pRb, p107, p130). The activity of CDK4 is inhibited by the p16 (INK4A) protein, which interferes with the cyclin D-binding region. Homology CDK4 belongs to the mammalian Cdk family, which includes about 20 members. The cyclin-binding domain of CDK4 has the amino acid sequence PISTVRE. The overall identity of CDK4 to CDK1 is 42%. Mutations Germinal Germ-line mutations in the CDK4 gene have so far only been found in families with inherited malignant melanoma and multiple atypical nevi. There are six such families reported. The mutations affect the Arg encoded by codon 24, changing it either to Cys (two families) or to His (four families). Somatic Amplification of the chromosomal region that includes CDK4 is commonly seen in gliomas and several subgroups of sarcomas, and may also occur in other tumors such a malignant melanomas. Point mutations have only rarely been observed and are of unknown biological significance. Implicated in Entity Familial cutaneous malignant melanoma 3 (CMM3)

Entity Sporadic malignant melanoma Note Cases with wild-type BRAF and NRAS genes

Entity Glioma Disease Anaplastic astrocytoma and glioblastoma multiforme

Entity Sarcoma Disease In particular liposarcoma, alveolar rhabdomyosarcoma and osteosarcoma

External links Nomenclature Hugo CDK4 GDB CDK4 Entrez_Gene CDK4 1019 cyclin-dependent kinase 4 Cards Atlas CDK4ID238ch12q14 GeneCards CDK4 Ensembl CDK4 Genatlas CDK4 GeneLynx CDK4 eGenome CDK4 euGene 1019 Genomic and cartography GoldenPath CDK4 - 12q14 chr12:56428272-56432431 - 12q14 (hg18-Mar_2006) Ensembl CDK4 - 12q14 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 235 HomoloGene CDK4 Gene and transcription Genbank BC003644 [ ENTREZ ] Genbank BC005864 [ ENTREZ ] Genbank BC010153 [ ENTREZ ] Genbank BC015669 [ ENTREZ ] Genbank CR407668 [ ENTREZ ] RefSeq NM_000075 [ SRS ] NM_000075 [ ENTREZ ] RefSeq AC_000055 [ SRS ] AC_000055 [ ENTREZ ] RefSeq NC_000012 [ SRS ] NC_000012 [ ENTREZ ] RefSeq NT_029419 [ SRS ] NT_029419 [ ENTREZ ] RefSeq NW_925395 [ SRS ] NW_925395 [ ENTREZ ] AceView CDK4 AceView - NCBI Unigene Hs.95577 [ SRS ] Hs.95577 [ NCBI ] HS95577 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt Q00526 [ SRS] Q00526 [ EXPASY ] Q00526 [ INTERPRO ] PS00107 PROTEIN_KINASE_ATP [ SRS ] PS00107 PROTEIN_KINASE_ATP [ Prosite Expasy ] PS50011 PROTEIN_KINASE_DOM [ SRS ] PS50011 PROTEIN_KINASE_DOM [ Prosite Expasy ] Prosite PS00108 PROTEIN_KINASE_ST [ SRS ] PS00108 PROTEIN_KINASE_ST [ Expasy ] Interpro IPR011009 Kinase_like [ SRS ] IPR011009 Kinase_like [ EBI ] Interpro IPR000719 Prot_kinase [ SRS ] IPR000719 Prot_kinase [ EBI ] Interpro IPR008271 Ser_thr_pkin_AS [ SRS ] IPR008271 Ser_thr_pkin_AS [ EBI ] Interpro IPR002290 Ser_thr_pkinase [ SRS ] IPR002290 Ser_thr_pkinase [ EBI ] CluSTr Q00526 Pfam PF00069 Pkinase [ SRS ] PF00069 Pkinase [ Sanger ] pfam00069 [ NCBI-CDD ] Smart SM00220 S_TKc [EMBL] Prodom PD000001 Prot_kinase[INRA-Toulouse] Q00526 CDK3_HUMAN [ Domain structure ] Q00526 CDK3_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks Q00526 PDB 1LFN [ SRS ] 1LFN [ PdbSum ], 1LFN [ IMB ] 1LFN [ RSDB ] HPRD Q00526 Protein Interaction databases DIP Q00526 IntAct Q00526 Polymorphism : SNP, mutations, diseases OMIM 123829;609048 [ map ] GENECLINICS 123829;609048 SNP CDK4 [dbSNP-NCBI] SNP NM_000075 [SNP-NCI] SNP CDK4 [GeneSNPs - Utah] CDK4] [HGBASE - SRS] HAPMAP CDK4 [HAPMAP]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 236 General knowledge Family CDK4 [UCSC Family Browser] Browser SOURCE NM_000075 SMD Hs.95577 SAGE Hs.95577 2.7.11.22 [ Enzyme-SRS ] 2.7.11.22 [ Brenda-SRS ] 2.7.11.22 [ KEGG ] 2.7.11.22 [ Enzyme WIT ] regulation of progression through cell cycle [Amigo] regulation of progression through GO cell cycle GO G1/S transition of mitotic cell cycle [Amigo] G1/S transition of mitotic cell cycle GO nucleotide binding [Amigo] nucleotide binding cyclin-dependent protein kinase holoenzyme complex [Amigo] cyclin-dependent protein GO kinase holoenzyme complex GO protein kinase activity [Amigo] protein kinase activity GO cyclin-dependent protein kinase activity [Amigo] cyclin-dependent protein kinase activity GO protein binding [Amigo] protein binding GO ATP binding [Amigo] ATP binding GO nucleus [Amigo] nucleus GO transcription factor complex [Amigo] transcription factor complex GO protein amino acid phosphorylation [Amigo] protein amino acid phosphorylation GO cell cycle [Amigo] cell cycle GO signal transduction [Amigo] signal transduction GO transferase activity [Amigo] transferase activity GO regulation of cell proliferation [Amigo] regulation of cell proliferation GO cell division [Amigo] cell division BIOCARTA Influence of Ras and Rho proteins on G1 to S Transition [Genes] BIOCARTA Cyclins and Cell Cycle Regulation [Genes] BIOCARTA Cell Cycle: G1/S Check Point [Genes] BIOCARTA p53 Signaling Pathway [Genes] BIOCARTA RB Tumor Suppressor/Checkpoint Signaling in response to DNA damage [Genes] PubGene CDK4 Other databases Probes Probe CDK4 Related clones (RZPD - Berlin) PubMed PubMed 112 Pubmed reference(s) in LocusLink Bibliography Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Khatib ZA, Matsushime H, Valentine M, Shapiro DN, Sherr CJ, Look AT. Cancer Res. 1993; 53: 5535-5541. Medline 8221695

Amplification of multiple genes from chromosomal region 12q13-14 in human malignant gliomas: preliminary mapping of the amplicons shows preferential involvement of CDK4, SAS, and MDM2.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 237 Reifenberger G, Reifenberger J, Ichimura K, Meltzer PS, Collins VP. Cancer Res. 1994; 54: 4299-4303. Medline 8044775

Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, Hayward N, Dracopoli NC. Nat Genet. 1996; 12: 97-99. Medline 8528263

Molecular changes during the genesis of human gliomas. Sehgal A. Semin Surg Oncol. 1998; 14: 3-12. Review. Medline 9407626

Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. Soufir N, Avril MF, Chompret A, Demenais F, Bombled J, Spatz A, Stoppa-Lyonnet D, Benard J, Bressac-de Paillerets B. Hum Mol Genet. 1998; 7:209-216. Medline 9425228

Distinct sets of genetic alterations in melanoma. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Brocker EB, LeBoit PE, Pinkel D, Bastian BC. N Engl J Med. 2005; 353: 2135-2147. Medline 16291983

Mammalian cyclin-dependent kinases. Malumbres M, Barbacid M. Trends Biochem Sci. 2005; 30:630-641. Review. Medline 16236519

A large Norwegian family with inherited malignant melanoma, multiple atypical nevi, and CDK4 mutation. Molven A, Grimstvedt MB, Steine SJ, Harland M, Avril MF, Hayward NK, Akslen LA. Genes Chromosomes Cancer. 2005; 44:10-18. Medline 15880589 REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed

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Contributor(s) Written 01-2007 Anders Molven Citation This paper should be referenced as such : Molven A . CDK4 (cyclin-dependent kinase 4). Atlas Genet Cytogenet Oncol Haematol. January 2007 URL : http://AtlasGeneticsOncology.org/Genes/CDK4ID238ch12q14.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

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AXIN2 (axin 2)

Identity Other names axil (mostly in rat) conductin DKFZp781B0869 (single database entry only) MGC126582 (single database entry only) Hugo AXIN2 Location 17q24.1 DNA/RNA

The 5' end of the human AXIN2 gene. An alignment of human genomic DNA (top line) with the 5' end of different Axin2 mRNA variants. Exons are shown as boxes (non- coding: filled; coding: open) and the translational start codon is marked (ATG).

Description The AXIN2 gene spans about 35 kbp including 10 coding exons and 3 non-coding 5' exons (E0a, 0b and 0c; see above). Nearby genes: about 70 kbp upstream is CCDC46 (coiled-coil domain containing 46), about 300 kbp downstream is RGS9 (regulator of G-protein signalling 9). In addition, there is a putative gene that overlaps the AXIN2 non-coding 5' exons and coding exon 1 (E1) and is transcribed from the same strand (Gnomon model hmm119498); there is no published data on whether this is actually expressed. Transcription Transcription occurs from three separate promoters leading to initiation at each of the three non-coding 5' exons. mRNAs are spliced so that that each non-coding exon is expressed separately, rather than in combinations. It is unclear whether transcription can initiate at the first coding exon (E1). Promoters can be activated by TCF transcription factors binding at multiple sites and by E2F1 binding at up to 4 sites, although E2F1 can also induce transcription in the absence of consensus sites. It has been reported that exon 6 can be omitted in an alternatively-spliced form. Pseudogene None identified Protein

Atlas Genet Cytogenet Oncol Haematol 2007; 2 239

Description Human Axin2 is an 843 amino acids protein (777 amino acids from delta exon 6 mRNAs) containing an RGS domain (regulator of G protein signalling; amino acids 81- 200), a GSK-3 beta binding domain (amino acids 327-413), a beta- binding domain (amino acids 413-476), and a DIX domain (domain in dishevelled and axin; amino acids 761-843). Expression Expression appears to be ubiquitous in adult tissues (although at differing levels), but is limited to specific regions during embryonic development. Expression is regulated at multiple levels including transcription, mRNA stability, translation and protein stability. Localisation Axin2 protein has been localised to the cytoplasm, the nucleus and the mitotic spindle. Function Molecular functions : 1) Axin2 acts as a negative regulator of canonical Wnt/TCF signalling by enhancing formation of the beta-catenin destruction complex. Since expression of Axin2 is itself activated by canonical Wnt/TCF signalling, this results in a negative feedback-loop that restricts TCF activity. 2) Axin2 may influence TCF activity by re-localising beta-catenin to the cytoplasm. 3) Activity of the GSK-3 beta target snail1 can be regulated by Axin2's ability to influence the nucleo-cytoplasmic localisation of GSK-3 beta. 4) Axin2 binds polo-like kinase 1 (PLK1) during mitosis and influences the accuracy of chromosome segregation. Cellular/physiological functions : 1) Axin2 expression oscillates during early embryogenesis in response to Wnt3a • this is required to achieve correct the temporal TCF activity to allow somatogenesis. 2) A requirement for Axin2 for correct calvarial morphogenesis and craniosynostosis has been revealed in Axin2 -/- mice. 3) Axin2 appears to act as a tumour suppressor, and somatic mutations have been seen in many different tumour types (see below). Homology Axin2 is 44% identical to axin in mice and knock-in experiments suggest that the proteins can be functionally equivalent. Mutations Note A large number of different mutations in the AXIN2 gene have been identified. In many cases (but not all) these lead to premature translational termination and protein truncation. Truncated Axin2 protein is more stable than the wild type, while there has been speculation that the mRNA may be less stable. Germinal Heterozygous germ line mutations in exon 7 that lead to premature termination are associated with familial tooth agenesis and a predisposition to colorectal cancer. Further germ line polymorphisms associated with familial tooth agenesis have been identified in exons 2 and 7. A polymorphism within exon 1 has been identified that is associated with risk of lung cancer. Many other polymorphisms that have yet to be associated with any function have been detected. Somatic The genomic region containing the AXIN2 gene shows loss of heterozygosity and re- arrangements in a variety of cancers. In addition somatic point mutations and deletions have been identified in colorectal cancer, hepatocellular carcinomas, ovarian endometrioid adenocarcinomas and hepatoblastomas. Many of these

Atlas Genet Cytogenet Oncol Haematol 2007; 2 240 mutations/deletions result in translation of truncated proteins that are likely to be functionally inactive, although one report has suggested that these truncated proteins have a dominant negative activity. Implicated in Entity Colorectal cancer (CRC) Oncogenesis Axin2 is often over-expressed in CRC as a result of the deregulation of canonical Wnt/beta-catenin signalling that is an early event in CRC development (usually caused by mutations/deletions in APC or beta-catenin). Somatic inactivating mutations within Axin2 have been reported in CRC and theoretically these could contribute to further deregulation of Wnt/beta-catenin • suggesting that Axin2 is a tumour suppressor. However mutations have only been seen in microsatellite unstable tumours and often within regions of mono-nucleotide repeats (exon 7), hence whether Axin2 mutations are cause or effect in these tumours remains undetermined. In support of Axin2's role as a tumour suppressor are observations that Axin2 is silenced by promoter methylation in many microsatellite unstable tumours. As discussed above, heterozygotes for some germ line mutations in AXIN2 are predisposed to CRC although this seems to be involved with only a very small proportion of familial colorectal cancer.

Entity Other cancers (hepatocellular carcinomas, hepatoblastomas, ovarian endometrioid adenocarcinomas) Oncogenesis Somatic mutations in Axin2 have been detected in a range of cancer types. It is usually assumed that these lead to partial inactivation of Axin2 function thereby deregulation of canonical Wnt/beta-catenin signalling. In most cases this has not formally been demonstrated, and the contribution of Axin2 mutations to any putative change in Wnt/beta-catenin activity and to the development of these cancers remains mostly unclear.

Entity Familial Tooth Agenesis (see above)

External links Nomenclature Hugo AXIN2 GDB AXIN2 Entrez_Gene AXIN2 8313 axin 2 (conductin, axil) Cards Atlas AXIN2ID456ch17q24 GeneCards AXIN2 Ensembl AXIN2 Genatlas AXIN2 GeneLynx AXIN2 eGenome AXIN2 euGene 8313 Genomic and cartography GoldenPath AXIN2 - 17q24.1 chr17:60955147-60988227 - 17q23-q24 (hg18-Mar_2006) Ensembl AXIN2 - 17q23-q24 [CytoView] NCBI Genes Cyto Gene Seq [Map View - NCBI] OMIM Disease map [OMIM] HomoloGene AXIN2

Atlas Genet Cytogenet Oncol Haematol 2007; 2 241 Gene and transcription Genbank AB052751 [ ENTREZ ] Genbank AF078165 [ ENTREZ ] Genbank AF205888 [ ENTREZ ] Genbank AK025718 [ ENTREZ ] Genbank BC101533 [ ENTREZ ] RefSeq NM_004655 [ SRS ] NM_004655 [ ENTREZ ] RefSeq AC_000060 [ SRS ] AC_000060 [ ENTREZ ] RefSeq NC_000017 [ SRS ] NC_000017 [ ENTREZ ] RefSeq NT_010783 [ SRS ] NT_010783 [ ENTREZ ] RefSeq NW_926918 [ SRS ] NW_926918 [ ENTREZ ] AceView AXIN2 AceView - NCBI Unigene Hs.156527 [ SRS ] Hs.156527 [ NCBI ] HS156527 [ spliceNest ] Protein : pattern, domain, 3D structure SwissProt O15169 [ SRS] O15169 [ EXPASY ] O15169 [ INTERPRO ] Prosite PS50841 DIX [ SRS ] PS50841 DIX [ Expasy ] Prosite PS50132 RGS [ SRS ] PS50132 RGS [ Expasy ] Interpro IPR001158 DIX [ SRS ] IPR001158 DIX [ EBI ] Interpro IPR000342 RGS [ SRS ] IPR000342 RGS [ EBI ] CluSTr O15169 Pfam PF00778 DIX [ SRS ] PF00778 DIX [ Sanger ] pfam00778 [ NCBI-CDD ] Pfam PF00615 RGS [ SRS ] PF00615 RGS [ Sanger ] pfam00615 [ NCBI-CDD ] Smart SM00021 DAX [EMBL] Smart SM00315 RGS [EMBL] Prodom PD003639 DIX[INRA-Toulouse] O15169 AXN1_HUMAN [ Domain structure ] O15169 AXN1_HUMAN [ sequences Prodom sharing at least 1 domain ] Prodom PD003639[INRA-Toulouse] O15169 AXN1_HUMAN [ Domain structure ] O15169 AXN1_HUMAN [ sequences Prodom sharing at least 1 domain ] Blocks O15169 PDB 1DK8 [ SRS ] 1DK8 [ PdbSum ], 1DK8 [ IMB ] 1DK8 [ RSDB ] PDB 1EMU [ SRS ] 1EMU [ PdbSum ], 1EMU [ IMB ] 1EMU [ RSDB ] HPRD O15169 Protein Interaction databases DIP O15169 IntAct O15169 Polymorphism : SNP, mutations, diseases OMIM 114500;604025;608615 [ map ] GENECLINICS 114500;604025;608615 SNP AXIN2 [dbSNP-NCBI] SNP NM_004655 [SNP-NCI] SNP AXIN2 [GeneSNPs - Utah] AXIN2] [HGBASE - SRS] HAPMAP AXIN2 [HAPMAP]

Atlas Genet Cytogenet Oncol Haematol 2007; 2 242 General knowledge Family AXIN2 [UCSC Family Browser] Browser SOURCE NM_004655 SMD Hs.156527 SAGE Hs.156527 GO somitogenesis [Amigo] somitogenesis GO intramembranous ossification [Amigo] intramembranous ossification GO signal transducer activity [Amigo] signal transducer activity GO protein binding [Amigo] protein binding GO intracellular [Amigo] intracellular GO nucleus [Amigo] nucleus GO signal transduction [Amigo] signal transduction GO multicellular organismal development [Amigo] multicellular organismal development GO negative regulation of cell proliferation [Amigo] negative regulation of cell proliferation regulation of Wnt receptor signaling pathway [Amigo] regulation of Wnt receptor GO signaling pathway negative regulation of osteoblast differentiation [Amigo] negative regulation of GO osteoblast differentiation PubGene AXIN2 Other databases Probes Probe AXIN2 Related clones (RZPD - Berlin) PubMed PubMed 19 Pubmed reference(s) in LocusLink Bibliography Four regions of allelic imbalance on 17q12-qter associated with high-grade breast tumors. Plummer SJ, Paris MJ, Myles J, Tubbs R, Crowe J, Casey G. Genes Chromosomes Cancer 1997; 20:354-62. Medline 9408751

Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Behrens J, Jerchow BA, Wurtele M, Grimm J, Asbrand C, Wirtz R, Kuhl M, Wedlich D, Birchmeier W. Science 1998; 280:596-9. Medline 9554852

Consortium study on 1280 breast carcinomas: allelic loss on targets subregions associated with family history and clinical parameters. Phelan CM, Borg A, Cuny M, Crichton DN, Baldersson T, Andersen TI, Caligo MA, Lidereau R, Lindblom A, Seitz S, Kelsell D, Hamann U, Rio P, Thorlacius S, Papp J, Olah E, Ponder B, Bignon YJ, Scherneck S, Barkardottir R, Borresen-Dale AL, Eyfjord J, Theillet C, Thompson AM, Larsson C. Cancer Res 1998; 58:1004-12. Medline 9500463

Axil, a member of the Axin family, interacts with both glycogen synthase kinase 3beta and beta-catenin and inhibits axis formation of Xenopus embryos. Yamamoto H, Kishida S, Uochi T, Ikeda S, Koyama S, Asashima M, Kikuchi A. Mol Cell Biol 1998; 18:2867-75. Medline 9566905

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Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta- catenin/TCF signalling. Liu W, Dong X, Mai M, Seelan RS, Taniguchi K, Krishnadath KK, Halling KC, Cunningham JM, Boardman LA, Qian C, Christensen E, Schmidt SS, Roche PC, Smith DI, Thibodeau SN Nat Genet 2000; 26:146-7. Medline 11017067

Genomic structure, chromosome mapping and expression analysis of the human AXIN2 gene. Dong X, Seelan RS, Qian C, Mai M, Liu W. Cytogenet Cell Genet 2001; 93:26-8. Medline 11474173

Diverse mechanisms of beta-catenin deregulation in ovarian endometrioid adenocarcinomas. Wu R, Zhai Y, Fearon ER, Cho KR. Cancer Res 2001; 61:8247-55. Medline 11719457

Subcellular distribution of Wnt pathway proteins in normal and neoplastic colon. Anderson CB, Neufeld KL, White RL. Proc Natl Acad Sci U S A 2002; 99:8683-8. Medline 12072559

Wnt/beta-catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Jho EH, Zhang T, Domon C, Joo CK, Freund JN, Costantini F. Mol Cell Biol 2002; 22:1172-83. Medline 11809808

Activation of AXIN2 expression by beta-catenin-T cell factor. A feedback repressor pathway regulating Wnt signaling. Leung JY, Kolligs FT, Wu R, Zhai Y, Kuick R, Hanash S, Cho KR, Fearon ER. J Biol Chem 2002; 277:21657-65. Medline 11940574

Negative feedback loop of Wnt signaling through upregulation of conductin/Axin2 in colorectal and liver tumors. Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U, van de Wetering M, Clevers H, Schlag PM, Birchmeier W, Behrens J. Mol Cell Biol 2002; 22:1184-93. Medline 11809809

Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Taniguchi K, Roberts LR, Aderca IN, Dong X, Qian C, Murphy LM, Nagorney DM, Burgart LJ, Roche PC, Smith DI, Ross JA, Liu W. Oncogene 2002; 21:4863-71. Medline 12101426

Wnt3a plays a major role in the segmentation clock controlling somitogenesis. Aulehla A, Wehrle C, Brand-Saberi B, Kemler R, Gossler A, Kanzler B, Herrmann BG. Dev Cell 2003; 4:395-406. Medline 12636920

Atlas Genet Cytogenet Oncol Haematol 2007; 2 244 Immunohistochemical analysis and mutational analyses of beta-catenin, Axin family and APC genes in hepatocellular carcinomas. Ishizaki Y, Ikeda S, Fujimori M, Shimizu Y, Kurihara T, Itamoto T, Kikuchi A, Okajima M, Asahara T. Int J Oncol 2004; 24:1077-83. Medline 15067328

Mutations and elevated transcriptional activity of conductin (AXIN2) in hepatoblastoma. Koch A, Weber N, Waha A, Hartman W, Denkhaus D, Behren J, Birchmeier W, Schweinitz D, Pietsch T J Pathology 2004; 204:546-554. Medline 15538750

Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Lammi L, Arte S, Somer M, Jarvinen H, Lahermo P, Thesleff I, Pirinen S, Nieminen P. Am J Hum Genet 2004; 74:1043-50. Medline 15042511

Mouse axin and Axin2/conductin proteins are functionally equivalent in vivo. Chia IV, Costantini F. Mol Cell Biol 2005; 25:4371-6. Medline 15899843

Cross-talk between pRb/E2F and Wnt/b-catenin pathways: E2F1 induces Axin2 leading to repression of Wnt signalling and to increased cell death. Hughes TA, Brady HJM. Exp Cell Res 2005a; 303:32-46. Medline 15572025

E2F1 up-regulates Axin2 both by direct activation of transcription and by stabilisation of Axin2 mRNA. Hughes TA, Brady HJM. Biochem. Biophys. Res. Commun. 2005b; 329:1267-1274. Medline 15766563

Expression of Axin2 is regulated by the alternative 5' untranslated regions of its mRNA. Hughes TA, Brady HJM. J Biol Chem 2005c; 280:8581-8588. Medline 15611123

Germline mutations of AXIN2 are not associated with nonsyndromic colorectal cancer. Peterlongo P, Howe LR, Radice P, Sala P, Hong YJ, Hong SI, Mitra N, Offit K, Ellis NA. Hum Mutat 2005; 25:498-500. Medline 15841489

The links between axin and carcinogenesis. Salahshor S, Woodgett JR. J Clin Pathol 2005; 58:225-36. Medline 15735151

Genetic and epigenetic changes of components affecting the WNT pathway in colorectal carcinomas stratified by microsatellite instability. Thorstensen L, Lind GE, Lovig T, Diep CB, Meling GI, Rognum TO, Lothe RA. Neoplasia 2005; 7:99-108. Medline 15802015

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The role of Axin2 in calvarial morphogenesis and craniosynostosis. Yu HM, Jerchow B, Sheu TJ, Liu B, Costantini F, Puzas JE, Birchmeier W, Hsu W. Development 2005; 132:1995-2005. Medline 15790973

Aberrant Wnt/beta-catenin signaling can induce chromosomal instability in colon cancer. Hadjihannas MV, Bruckner M, Jerchow B, Birchmeier W, Dietmaier W, Behrens J Proc Natl Acad Sci U S A 2006; 103:10747-52. Medline 16815967

Regulation of Axin2 expression at the levels of transcription, translation and protein stability in lung and colon cancer. Hughes TA, Brady HJM. Cancer Lett 2006; 233:338-47. Medline 15885887

Single nucleotide polymorphism of the AXIN2 gene is preferentially associated with human lung cancer risk in a Japanese population. Kanzaki H, Ouchida M, Hanafusa H, Yano M, Suzuki H, Aoe M, Imai K, Shimizu N, Nakachi K, Shimizu K. Int J Mol Med 2006; 18:279-84. Medline 16820935

Epigenetic silencing of AXIN2 in colorectal carcinoma with microsatellite instability. Koinuma K, Yamashita Y, Liu W, Hatanaka H, Kurashina K, Wada T, Takada S, Kaneda R, Choi YL, Fujiwara SI, Miyakura Y, Nagai H, Mano H. Oncogene 2006; 25:139-46. Medline 16247484

Nucleo-cytoplasmic distribution of beta-catenin is regulated by retention. Krieghoff E, Behrens J, Mayr B. J Cell Sci 2006; 119:1453-63. Medline 16554443

Axis inhibition protein 2 (AXIN2) polymorphisms may be a risk factor for selective tooth agenesis. Mostowska A, Biedziak B, Jagodzinski PP. J Hum Genet 2006; 51:262-6. Medline 16432638

Mutations within Wnt pathway genes in sporadic colorectal cancers and cell lines. Suraweera N, Robinson J, Volikos E, Guenther T, Talbot I, Tomlinson I, Silver A Int J Cancer 2006; 119:1837-42. Medline 16708370

A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Yook JI, Li XY, Ota I, Hu C, Kim HS, Kim NH, Cha SY, Ryu JK, Choi YJ, Kim J, Fearon ER, Weiss SJ. Nat Cell Biol 2006; 8:1398-406. Medline 17072303

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Atlas Genet Cytogenet Oncol Haematol 2007; 2 246 BiblioGene - INIST Search in all EBI

Contributor(s) Written 01-2007 Thomas A Hughes Citation This paper should be referenced as such : Hughes TA . AXIN2 (axin 2). Atlas Genet Cytogenet Oncol Haematol. January 2007 . URL : http://AtlasGeneticsOncology.org/Genes/AXIN2ID456ch17q24.html

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t(2;12)(q31;p13)

Clinics and Pathology Disease Non Hodgkin lymphoma (NHL) and myelodysplastic syndrome (chronic myelomonocytic leukemia (CMML) Epidemiology Only 2 cases to date (male patients): 1 NHL aged 30 yrs and 1 CMML aged 78 yrs Prognosis The CMML case died 2 yrs 9 mths after diagnosis Cytogenetics Additional del(11q) in the NHL case and +21 in the CMML case anomalies Genes involved and Proteins Note ETV6 was found involved in the NHL case

External links Other t(2;12)(q31;p13) Mitelman database (CGAP - NCBI) database Other t(2;12)(q31;p13) CancerChromosomes (NCBI) database To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Case Report Reciprocal translocation t(2;12)(q31;p13) in a case of CMML Bibliography Heterogeneity in the breakpoints in balanced rearrangements involving band 12p13 in hematologic malignancies identified by fluorescence in situ hybridization: TEL (ETV6) is involved in only one half. Sato Y, Bohlander SK, Kobayashi H, Reshmi S, Suto Y, Davis EM, Espinosa III R, Hoopes R, Montgomery KT, Kucherlapati RS, Le Beau MM, Rowley JD, Blood 1997; 90: 4886-4893 Medline 9389705

Contributor(s) Written 11-2006 Jean Loup Huret Citation This paper should be referenced as such : Huret JL . t(2;12)(q31;p13). Atlas Genet Cytogenet Oncol Haematol. November 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t0212q31p13ID1459.html © Atlas of Genetics and Cytogenetics in Oncology and Haematology

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t(12;17)(p11;q11) in AML

Clinics and Pathology Disease Acute myeloid leukaemia (AML) Note The appearance of the translocation may resemble the rare non-random t(12;17)(p13;q11-21) associated with ALL. Epidemiology Very rare translocation reported in three adults and one child with secondary AML following an ALL. The four published cases have been female. Prognosis Insufficient data to indicate a prognostic significance. Cytogenetics Additional All reported cases have additional aberrations. In two cases the translocation is part of anomalies a complex karyotype. Three of the four cases are reported to have loss of the second chromosome 17. Genes involved and Proteins Note No report of any molecular or FISH data to elucidate exact breakpoint or genes.

External links Other t(12;17)(p11;q11) in AML Mitelman database (CGAP - NCBI) database Other t(12;17)(p11;q11) in AML CancerChromosomes (NCBI) database Other http://cgap.nci.nih.gov/Chromosomes/Mitelman database

To be noted Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. Bibliography Use of conditioned media in cell culture can mask cytogenetic abnormalities in acute leukaemia. Sun G, Koeffler HP, Gale RP, Sparkes RS, Schreck RR. Cancer Genet Cytogenet 1990; 46: 107-113. Medline 2331674

Translocations involving 12p in acute myeloid leukemia: association with prior myelodysplasia and exposure to mutagenic agents. UKCCG (United Kingdom Cancer Cytogenetics Group) Genes Chromosom Cancer 1992; 5: 252-254. Medline 1384679

Acute leukemia cytogenetics: an evaluation of combining G-band karyotyping with multi-color spectral karyotyping.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 249 Kerndrup GB, Kjeldsen E. Cancer Genet Cytogenet 2001; 124: 7-11. Medline 11165315

Cytogenetic analysis and clinical significance of aberrations in acute leukaemia. Brozek I, Babinska M, Kardas I, Wozniak A, Balcerska A, Hellmann A, Limon J. J Appl Genet 2003; 44: 401-412. Medline 12923315

Contributor(s) Written 11-2006 David Betts Citation This paper should be referenced as such : Betts D . t(12;17)(p11;q11) in AML. Atlas Genet Cytogenet Oncol Haematol. November 2006 . URL : http://AtlasGeneticsOncology.org/Anomalies/t1217p11q11ID1437.html

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Stiff-person syndrome

Identity Other names Stiff-man syndrome Inheritance none known Clinics Note Stiff-person syndrome is a rare neurological disorder characterized by stiffness of skeletal muscles with superimposed spasms. The syndrome is a putative autoimmune disease occurring as an idiopathic or paraneoplastic condition. It is often associated with antibodies to glutamic acid decarboxylase (GAD) or, less commonly, to the 128 kD synaptic protein later amphiphysin (AMPH) and few other autoantigens. Phenotype Diagnosis of GAD-antibody associated stiff-person syndrome is made according to the and clinics following criteria: Prodrome of stiffness and rigidity in axial muscles Progression to include stiffness of limbs, making walking difficult Increased lumbar lordosis Presence of superimposed painful spasm, often precipitated by external stimuli (auditory stimulation like hand clapping) Normal sensation, no paresis An EMG finding of continuous motor unit activity (CMUA) at rest Response to benzodiazepines including clinical response and reduction on CMUA High levels of GAD antibodies Other features: Less frequently, stiff-person syndrome is associated with antibodies to the 128 kDa synaptic protein amphiphysin. It is then a paraneoplastic condition, most often occurring with breast cancer. The pathogenic role of the antibodies directed against the 128 kDa synaptic protein amphiphysin has been shown by transmission of disease symptoms by passive transfer to rats. One case of stiff-person syndrome associated with antibodies to the synaptic protein gephyrin has been described.

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Western blots of brain homogenates showing protein antigens recognized by serum and cerebrospinal fluid samples from patients 1,2 and 3, affected by stiff-man syndrome and breast cancer (lane 1,2 and 3) and by serum samples from control patients and normal subjects. The sera from the three patients affected by affected by stiff-man syndrome and breast cancer did not react with the Gad band, which was recognized by a human serum positive for GAD antibodies (lane 4). Lane 5, serum from a control patient with the stiff-man syndrome who did not have GAD antibodies; and lane 6 serum of a normal subject. A band with an apparent molecular mass of 128 kd was recognized by the serum samples of patient 1, 2 and 3. Lane 7 and 8 were both loaded with 20 ug of protein from a homogenate of a rat brain and were labelled with serum and cerebrospinal fluid, respectively, from patient 3. (Reprinted with permission from F. Folli et al, Autoantibodies to a 128 kd protein in three women with the stiff-man syndrome and breast cancer. N Engl J Med 1993; 328: 546-551. Copyright 1993 Massachusetts Medical Society. All rights reserved). Photomicrographs of Sections of Rat Cerebellum and Brain Stem Stained with Serum Samples (Diluted 1:20) from Patients 1, 2, and 3 affected by stiff-man syndrome and breast cancer, and a Control Patient affected by stiff-man syndrome with autoantibodies against glutamic acid decarboxilase and with Rabbit Antibodies to

Atlas Genet Cytogenet Oncol Haematol 2007; 2 253 Synaptic-Vesicle Proteins. Anti-amphiphysin antibody titers during two series of plasma exchanges (filled squares: anti-amphysin titer, arrows: days of plasma exchange) in a patient with anti- amphiphysin associated stiff-person syndrome. Clinical improvement closely correlated with drop in titer.

Neoplastic risk GAD-antibody positive stiff-person syndrome has not been described as a paraneoplastic condition. Most cases of amphiphysin antibody associated stiff-person syndrome are paraneoplastic. Cancers described are breast cancer, small-cell lung, and ovarian carcinoma. The one case with anti-gephyrin antibodies was associated with an undifferentiated carcinoma of the mediastinum. Treatment Patients may respond to symptomatic treatment with benzodiazepines, and to a certain extent baclofen, valproic acid, tiagabine, and other drugs enhancing GABAergic transmission. Given the autoimmune pathogenesis immunosuppression, plasmapheresis, and high dose intravenous immunoglobulins (IVIG) seem to be treatments of choice. The only randomized controlled trial in this disorder showed that IVIG was an efficient treatment in GAD-antibody positive stiff-person syndrome. In the paraneoplastic forms, removal of the cancer is essential. Anti-amphiphysin associated stiff-person syndrome has been successfully treated with plasmapheresis. Evolution GAD-antibody positive stiff-person syndrome is usually slowly progressive, but can make patients bed-bound in the end. The paraneoplastic types are usually rapidly progressive and may be associated with encephalitis and other paraneoplastic syndromes. The prognosis of the neurological disorder depends on tumor treatment. Genes involved and Proteins

Gene Name GAD2 (Glutamate decarboxylase 2) Location 10p12 Note GAD2 isthe rate limiting enzyme of GABA synthesis. Stiff-person syndrome with autoantibodies directed against GAD is associated with type 1 diabetes mellitus and polyendocrine autoimmune diseases, including Grave¹s disease, hypothyroidism, Addison¹s disease and atrophic gastritis.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 254 Gene Name AMPH (Amphiphysin) Location 7p14 Note AMPH is a 128 kd synaptic protein. It supports endocytosis at synapses by the formation of dynamin-rings around clathrin vesicles. Stiff.person syndrome, with autoantibodies directed against Amphiphysin, is associated with breast cancer.

Gene Name GPHN (Gephyrin) Location 14q24 Note GPHN is a postsynaptic protein needed for the clustering of glycine receptors.

External links Orphanet ORPHA3198 Bibliography The synaptic vesicle-associated protein amphiphysin is the 128-kD autoantigen of Stiff-Man syndrome with breast cancer. De Camilli P, Thomas A, Cofiell R, Folli F, Lichte B, Piccolo G, Meinck HM, Austoni M, Fassetta G, Bottazzo G, Bates D, Cartlidge N, Solimena M, Kilimann MW. J Exp Med 1993; 178: 2219-2223. Medline 8245793

Autoantibodies to a 128-kd synaptic protein in three women with the stiff-man syndrome and breast cancer. Folli F, Solimena M, Cofiell R, De CAmilli P. N Engl J Med 1993; 328: 546-551. Medline 8381208

The amphiphysin family of proteins and their role in endocytosis at the synapse. Wigge P, McMahon HT. Trends Neurosci 1998; 21: 339-344. Medline 9720601

Anti-amphiphysin antibodies are associated with various paraneoplastic neurological syndromes and tumors. Antoine JC, Absi L, Honnorat J, Boulesteix JM, de Brouker T, Vial C, Butler M, De Camilli P, Michel D. Arch Neurol 1999; 56: 172-177. Medline 10025422

Autoimmunity to gephyrin in Stiff-Man syndrome. Butler MH, Hayashi A, Ohkoshi N, Villmann C, Becker CM, Feng G, De Camilli P, Solimena M. Neuron 2000; 26: 307-312. Medline 10839351

High-dose intravenous immune globulin for stiff-person syndrome. Dalakas MC, Fujii M, Li M, Lutfi B, Kyhos J, McElroy B. N Engl J Med 2001; 345: 1870-1876.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 255 Medline 11756577

Stiff man syndrome and related conditions. Meinck HM, Thompson PD. Mov Disord 2002; 17: 853-866. Medline 12360534

Neuropathology and antibody-binding studies in anti-amphiphysin-associated stiff-person syndrome with encephalopathy. Wessig C, Klein R, Schneider M, Toyka KV, Naumann M, Sommer C. Neurology 2003; 61: 195-198. Medline 12874398

Stiff-person syndrome. Murinson BB. Neurologist 2004; 10: 131-137. Medline 15140273

Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin. Sommer C, Weishaupt A, Brinkhoff J, Biko L, Wessig C, Gold R, Toyka KV. Lancet 2005; 365: 1406-1411. Medline 15836889

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 12-2006 Franco Folli, Claudia Sommer Citation This paper should be referenced as such : Folli F, Sommer C . Stiff-person syndrome. Atlas Genet Cytogenet Oncol Haematol. December 2006 . URL : http://AtlasGeneticsOncology.org/Kprones/StiffpersonID10103.html

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Perlman syndrome (renal hamartomas, nephroblastomatosis and fetal gigantism)

Identity Note The Perlman syndrome is characterized by polyhydramnios, fetal overgrowth, neonatal macrosomia, high neonatal mortality, macrocephaly, dysmorphic facial features, visceromegaly, nephroblastomatosis and a predisposition for Wilms tumor at very early age. Inheritance Inheritance is of an autosomal recessive nature. Etiology: The genetic basis of the Perlman syndrome is unknown and there is no conclusive laboratory test to confirm the diagnosis. Although both sexes are affected, the sex ratio is 2M:1F. The diagnosis is based on characteristic features and confirmed by histological renal evidence. The syndrome has been described in both consanguineous and non-consanguineous couplings.

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Figure 1,2 : Macrocephaly, hypertelorism, epicanthus, broad flat nasal bridge, anteverted upper lip, axial hypotonia. Figure 3 : Abdominal ultrasound scan at 6 months of age: nephromegaly with lobulated contoured kidneys and loss of corticomedullary differentiation.

Clinics Phenotype Abnormalities : and clinics Growth: oversize already evident in the prenatal and postnatal period. Craniofacial: macrocephaly, prominent forehead, deep-set eyes, hypertelorism, epicantal folds, broad flat nasal bridge, everted upper lip, high arched palate, low-set ears (figure 1,2). Visceral: nephromegaly, nephroblastomatosis, Wilms tumor (figure 3). Occasional

Atlas Genet Cytogenet Oncol Haematol 2007; 2 258 abnormalities (table1): Central nervous system abnormalities : agenesis of the corpus callosum; large cisterna magna; retrocerebellar and perichiasmatic leptomeningeal cysts, white matter hypoplasia and grey matter heterotopia involving the cerebellum and superior colliculi; choroid plexus hemangiomas; generalized cerebral atrophy with a marked deficit in the myelinization of the white matter; left periventricular ovoid cystic formation. Cardiomegaly . Congenital heart disease : interrupted aortic arch and anomalous coronary vessels and the dextroposition of the heart , muscular ventricular septal defect . Intestinal malformations : intestinal malrotation and distal ileal atresia and volvulus and intestinal malrotation with caecum located on the midline, while most of the small intestine was located on the right ; Hemangiomas : Capillary hemangioma in the left antecubital fossa, choroids plexus hemangioma and superficial cutaneus capillary hemangioma around the umbilicus. Cryptorchidism. Skeletal abnormalities : the absence of the normal widening of the lumbar interpediculate distances, rounded iliac wings, small sacrosciatic notches in a patient, and in patients showing crowded toes and bilateral calcaneovalgus deformity, genua recurvata, left metatarsus varus, right hallux varus, severe right convex dorsal and left convex lumbar scoliosis, lumbar hyperlordosis and crest iliac asymmetry, prominent xiphisternum . Hypotonia . Developmental delay.

Prenatal diagnosis is possible for families at risk for Perlman syndrome. The fetal overgrowth and particularly the OFC greater than the 90th centile for gestational age, that is associated with polyhydramnios, may be the first signs of Perlman syndrome. A prompt recognition and an accurate follow-up are recommended to offer these patients clinical assistance and to prevent the high morbidity and mortality in Perlman syndrome.

Table1 : Characteristic clinical features of Perlman syndrome Table 2: Comparison of Perlman, Beckwith-Wiedemann, Sotos, Weaver and Simpson-Golabi-Behmel syndromes.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 259 Differential It is a clinical overlap with other overgrowth syndromes associated with Wilms tumor. diagnosis Wilms tumor is also associated with Beckwith-Wiedemann syndrome, Sotos syndrome, Weaver syndrome and Simpson-Golabi-Behemel syndrome (table 2).

Evolution Pre and postnatal nephromegaly is evident. In a lot of the cases described neonatal nephromegaly is present at birth. In a patient, the neonatal nephromegaly is not evaluated and a patient described at birth had not organomegaly. Nephromegaly is associated with fetal lobulation. Nephroblastomatosis is characteristic. Histopathologic findings show cytodifferentiated nodular renal blastema and nests of immature glomeruli together with sclerotic glomeruli and primitive structures. Foci of hamartomatous tissue can be found in the medulla. Nephroblastomatosis predisposes to the development of Wilms tumor, which is frequent and has been found in 7 of the 23 reported patients . Renal biopsy is necessary to evaluate the presence of Wilms tumor. Wilms tumor was diagnosed at the ages of 4 days, 8 months, 10 months, 10 months, 4 years and 6 months and 1 year and 8 months of age. Organomegaly is frequent ( cardiomegaly, nephromegaly and hepato/splenomegaly). In the few patients who survived beyond neonatal age, a psychomotor delay of various degree was reported. A 12 year old girl is referred was moderately retarded, partly due to chemotherapy and radiation ; a 1 year-old patient had a development quotient (DQ) of 50, a nine-year-old patient had a normal cognitive level and the neurological examination was normal. Prognosis The prognosis is severe with neonatal death in most children ; only 5 cases have been described with a survival beyond the first year of life. Cytogenetics Note No chromosomal abnormalities have been found thus far, except for the case of Chernos et al , with a ³de novo² extraG-positive band on the tip of the short arm of chromosome 11 Bibliography Metanephric hamartomas and nephoblastomatosis in siblings.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 260 Liban E, Kozenitzsky Il. Cancer. 1970; 25: 885-888. Medline 4315293

Renal hamartomas and nephroblastomatosis with fetal gigantism:a familial syndrome. Perlman M, Goldberg GM, Bar-Ziv J, Danovitch G. J Pediatr. 1973; 83: 414-418. Medline 4353457

Syndrome of fetal gigantism, renal hamartomas and nephroblastomatosis with Wilms¹ tumor. Perlman M, Levin M, Witels B. Cancer. 1975; 35: 1212-1217. Medline 163679

The Perlman Syndrome of Familial Renal Dysplasia with Wilms tumor, fetal gigantism and multiple congenital anomalies. Neri G, Martini-Neri ME, Katz Ben E, Optiz JM. American Journal of Medical Genetics. 1984; 19: 195-207. Medline 6093533

Perlman syndrome: familial renal dysplasia with Wilms tumor, fetal gigantism and multiple congenital anomalies. Perlman M. Am J Med Genet. 1986; 25: 793-795. Medline 3024486

The Perlman familial nephroblastomatosis syndrome. Greenberg F, Stein F, Gresik V, Finegold MJ, Carpenter RJ, Riccardi VM, Beaudet AL. American Journal of Medical Genetics. 1986; 24: 101-110. Medline 3010722

Expanding the spectrum of Perlman syndrome. Greenberg F, Copeland K, Gresik MV. Am J Med Genet. 1988; 29: 773-779. Medline 2840828

Perlman syndrome: report of a case and results of molecular studies. Hamel BCJ, Mannens M., Bokkerink JPM. Am J Hum Genet. 1989; 45 (suppl.): A48.(Abstract)

A case of Perlman syndrome associated with a cytogenetic abnormality of chromosome 11. Chernos JE, Fowlow SB, Cox DM. Am J Hum Genet. 1990; 47 (suppl.)A28. (Abstract)

Perlman and Wiedemann-Beckwith syndromes: two distinct conditions associated with Wilms tumour. Grundy RG, Pritchard J, Baraitser M, Risdon A, Robards M. Eur J pediatr. 1992; 151: 895-898. Medline 1361910

Perlman syndrome: report of a case with additional radiographic findings. Herman TE, McAlister WH. Pediatr Radiol. 1995; 25: S70-S72. Medline 8577560

Atlas Genet Cytogenet Oncol Haematol 2007; 2 261

Extending the overlap of three congenital overgrowth syndromes. Coppin B, Moore I, Hatchwell E. Clin Genet. 1997; 51: 375-378. Medline 9237499

Perlman syndrome: a cause of enlarged, hyperechogenic kidneys. Chitty LS, Clark T, Maxwell D. Prenat Diagn. 1998; 18:1163-1168. Medline 9854726

Perlman syndrome: a case report emphasizing the similarity to and distinction from Beckwith- Wiedemann and prune-belly syndromes. Fahmy J, Kaminsky C, Parisi MT. Pediatr radiol. 1998; 28: 179-182. Medline 9561541

Prenatal ultrasound observations in subsequent pregnancies with Perlman syndrome. Van der Stege JG, van Eyck J, Arabin B. Ultrasound Obstet Gynecol. 1998; 11:149-151. Medline 9549846

Perlman syndrome: four additional cases and review. Henneveld HT, van Lingen RA, Hamel BCJ, Stolte-Dijkstra I, van Hessen AJ. Am J Med Genet. 1999; 86: 439-446. Medline 10508986

A case of Perlman syndrome: Fetal gigantism, renal dysplasia, and severe neurological deficits. Schilke K, Schaefer F, Waldherr R, Rohrschneider W, John C, Himbert U, Mayatepek E, Tariverdian G. Am J Med Genet. 2000; 91: 29-33. Medline 10751085

Overgrowth syndromes. Cohen MM jr, Neri G, Weksberg R. Oxford University Press. 2002; 47-50.

Antenatal Sonographic Features of Perlman Syndrome. DeRoche M, Craffey A, Greenstein R, Borgida A. J Ultrsound Med. 2004; 23.561-564. Medline 15098877

Perlman syndrome: clinical report and nine-years follow-up. Piccione M, Cecconi M, Giuffrè M , Lo Curto M, Malacarne M , Piro E, Riccio A, Corsello G. Am J Med Genet A. 2005; 139(2):131-135. Medline 16278893

A case of Perlman syndrome presenting with hemorrhagic hemangioma. Pirgon O, Atabek ME, Akin F, Sert A. J Pediatr Hematol Oncol. 2006; 28(8):531-533. Medline 16912594

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Atlas Genet Cytogenet Oncol Haematol 2007; 2 262 Last year publications automatic search in PubMed Contributor(s) Written 12-2006 Maria Piccione, Giovanni Corsello Citation This paper should be referenced as such : Piccione M, Corsello G. . Perlman syndrome (renal hamartomas, nephroblastomatosis and fetal gigantism). Atlas Genet Cytogenet Oncol Haematol. December 2006 . URL : http://AtlasGeneticsOncology.org/Kprones/PerlmanID10117.html

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Atlas Genet Cytogenet Oncol Haematol 2007; 2 263 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Pallister Hall Syndrome (PHS)

Identity Inheritance Autosomal dominant; rare with unknown incidence. Clinics Phenotype Major findings : Hypothalamic hamartoma: a non-enhancing mass in the floor of the and clinics third ventricle posterior to the optic chiasm that is isointense to grey matter on T1 and T2 pulse sequences of an MRI, but may have distinct intensity on FLAIR. (Neither cranial CT examination nor cranial ultrasound examination is adequate for diagnosis of hypothalamic hamartoma). Central polydactyly : The presence of six or more well-formed digits with a ³Y² shaped metacarpal or metatarsal bone. Postaxial polydactyly : Can be either PAP-A with a well shaped digit on the ulnar or fibular aspect of the limb, or PAP-B with a rudimentary digit or nubin in the same position. Bifid epiglottis : A midline anterior-posterior cleft of the epiglottis that involves at least two-thirds of the epiglottic leaf. It is a useful feature for clinical diagnosis because it appears to be very rare in syndromes other than PHS and is also rare as an isolated malformation. Other : Imperforate anus, renal abnormalities including cystic malformations, renal hypoplasia, ectopic ureteral implantation, and pulmonary segmentation anomalies such as bilateral bilobed lungs.

Image A : MRI showing hypothalamic hamartoma in PHS patient. Image B : Hand film showing central polydactyly, note ³Y² shaped metarcarpal.

Neoplastic risk No increased risk of cancer has been reported for individuals with PHS. Hypothalamic hamartomas, a benign growth, are found in a majority of patients. Treatment Treatment of individuals with PHS depends on their individual manifestations. Management of epiglottic abnormalities depends on the type of abnormality and extent of respiratory compromise. Seizures are treated symptomatically. Treatment for

Atlas Genet Cytogenet Oncol Haematol 2007; 2 264 endocrine abnormalities, especially for cortisol deficiency, is urgent. Repair of polydactyly can be undertaken on an elective basis and anal atresia or stenosis treated in the standard manner. Hypothalamic hamartomas should not be removed or biopsied because of the risk of surgical complications and need for hormone supplements during the individual's remaining life. Prognosis The prognosis for an individual with PHS and no known family history of PHS is based on the malformations present in the individual. Literature surveys are not useful for this purpose because reported cases tend to show bias of ascertainment to more severe involvement. Although PHS has been categorized as a member of the CAVE (cerebro- acro-visceral early lethality) group of disorders, few affected individuals have an early lethality phenotype. This early lethality is most likely attributable to panhypopituitarism that is caused by pituitary or hypothalamic dysplasia or severe airway malformations such as laryngotracheal clefts. In addition, imperforate anus can cause serious complications if not recognized promptly. Thus, in the absence of life-threatening malformations, the prognosis should be assumed to be excellent for individuals with the nonfamilial occurrence of PHS. For individuals with a family history of affected family members, the prognosis is based on the degree of severity present in the family. Several large families have been reported as having a mild form of PHS with excellent general health and normal longevity. Genes involved and Proteins

Gene Name GLI3 Location 7p14 DNA/RNA Description GLI3 has 15 exons, 14 of which are coding exons, and extends over approximately 300 kb of genomic DNA. Protein Description 1580 amino acids; GLI3 contains a C2H2 zinc finger and six additional domains conserved between GLI family members. Function GLI3 functions as both an activator and repressor of transcription, playing a central role in the Sonic Hedgehog pathway. In the presence of Sonic Hedgehog GLI3 enters the nucleus and activates transcription of downstream genes. In the absence of Sonic Hedgehog full length GLI3 is retained in the cytoplasm where it is cleaved into a repressor form. The repressor form is free to move into the nucleus and downregulate transcription. Homology GLI family of transcription factors, C2H2 zinc finger domain. Mutations

Schematic of GLI3 protein showing seven conserved domains between the GLI family members, the C2H2 zinc finger is shown in red. Positions of thirty distinct PHS mutations are marked by lines above the protein.

Germinal Over 36 mutations have been identified in individuals with PHS. All mutations identified to date predict a truncated protein. Mutations that cause PHS are thought to result in the production of a constituitive

Atlas Genet Cytogenet Oncol Haematol 2007; 2 265 repressor protein. The majority of truncating mutations in the middle third of the protein cause PHS. These mutations retain the C2H2 zinc finger but are missing the last third of the protein. External links Other Pallister Syndrome - GeneClinics database

Bibliography GLI3 encodes a 190-kilodalton protein with multiple regions of GLI similarity. Ruppert JM, Vogelstein B, Arheden K, Kinzler KW. Mol Cell Biol. 1990; 10: 5408-5415. Medline 2118997

Polysyndactyly and asymptomatic hypothalamic hamartoma in mother and son: A variant of Pallister-Hall syndrome. Low M, Moringlane JR, Reif J, Barbier D, Beige G, Kolles H, Kujat C, Zang KD, Henn W. Clin Genet. 1995; 48: 209-212. Medline 8591673

Stringent delineation of Pallister-Hall syndrome in two long surviving patients: Importance of radiological anomalies of the hands. Verloes A, David A, Ngo L, Bottani A. J Med Genet. 1995; 32: 605-611. Medline 7473651

Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome. Kang S, Allen J, Graham JM, Jr., Grebe T, Clericuzio C, Patronas N, Ondrey F, Green E, Schaffer A, Abbott M, Biesecker LG. J Med Genet. 1997a; 34: 441-446. Medline 9192261

GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Kang S, Graham JM, Jr., Olney AH, Biesecker LG. Nat Genet. 1997b; 15: 266-268. Medline 9054938

Asymptomatic laryngeal malformations are common in patients with Pallister-Hall syndrome. Ondrey F, Griffith A, Van Waes C, Rudy S, Peters K, McCullagh L, Biesecker LG. Am J Med Genet. 2000; 94: 64-67. Medline 10982485

Overlap of PIV syndrome, VACTERL and Pallister-Hall syndrome: Clinical and molecular analysis. Killoran CE, Abbott M, McKusick VA, Biesecker LG. Clin Genet. 2000; 58: 28-30. Medline 10945658

Long-term treatment with growth hormone improves final height in a patient with Pallister-Hall syndrome. Galasso C, Scire G, Fabbri F, Spadoni GL, Killoran CE, Biesecker LG, Boscherini B. Am J Med Genet. 2001; 99: 128-131. Medline 11241471

Atlas Genet Cytogenet Oncol Haematol 2007; 2 266 Hirschprung's disease and imperforate anus in Pallister-Hall syndrome: A new association. Haynes JH, Bagwell CE. J Pediatr Surg. 2003; 38: 1411-1412. Medline 14523835

Epilepsy and hypothalamic hamartoma: Look at the hand Pallister-Hall syndrome. Kremer S, Minotti L, Thiriaux A, Grand S, Satre V, Le Bas JF, Kahane P. Epileptic Disord. 2003; 5: 27-30. Medline 12773293

Gonadal mosaicism in severe Pallister-Hall syndrome. Ng D, Johnston JJ, Turner JT, Boudreau EA, Wiggs EA, Theodore WH, Biesecker LG. Am J Med Genet. 2004; 124A: 296-302. Medline 14708104

Hypothalamic hamartomas and seizures: distinct natural history of isolated and Pallister-Hall syndrome cases. Boudreau EA, Liow K, Frattali CM, Wiggs E, Turner JT, Feuillan P, Sato S, Patsalides A, Patronas N, Biesecker LG, Theodore WH. Epilepsia. 2005; 46(1): 42-47. Medline 15660767

Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: Robust phenotype prediction from the type and position of GLI3 mutations. Johnston JJ, Olivos-Glander I, Killoran C, Elson E, Turner JT, Peters KF, Abbott MH, Aughton DJ, Aylsworth AS, Bamshad MJ, Booth C, Curry CJ, David A, Dinulos MB, Flannery DB, Fox MA, Graham JMJr, Grange K, Guttmacher AE, Hannibal MC, Henn W, Hennekam RCM, Holmes LB, Hoyme HE, Leppig KA, Lin AE, MacLeod P, Manchester DK, Marcelis C, Mazzanti L, McCann E, McDonald MM, Mendelsohn NJ, Moeschler JB, Moghaddam B, Neri G, Newbury-Ecob R, Pagon RA, Phillips JAIII, Sadler LS, Stoler JM, Tilstra D, Walsh Vockley CM, Zackai EH, Zadeh TM, Brueton L, Black GCM,2 Biesecker LG. Am. J. Hum. Genet. 2005; 76: 609-622. Medline 15739154

Genitourinary malformations as a feature of the Pallister-Hall syndrome. McCann E, Fryer AE, Craigie R, Baillie C, Ba'ath ME, Selby A, Biesecker LG. Clin Dysmorphol. 2006; 15(2): 75-79.

REVIEW articles automatic search in PubMed Last year publications automatic search in PubMed Contributor(s) Written 01-2007 Jennifer J Johnston, Leslie G Biesecker Citation This paper should be referenced as such : Johnston JJ, Biesecker LG . Pallister Hall Syndrome (PHS). Atlas Genet Cytogenet Oncol Haematol. January 2007 . URL : http://AtlasGeneticsOncology.org/Kprones/PallisterHallID10126.html

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Atlas Genet Cytogenet Oncol Haematol 2007; 2 267 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Genetic Instability in Cancer

Sheron Perera, BSc and Bharati Bapat, PhD

Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Department of Lab Medicine and Pathobiology, University of Toronto, Canada .

January 2007

Cancer is a complex disease, with multiple genes in diverse pathways involved in its initiation, progression, invasion and metastasis. In fact, it is widely accepted that the sequential accumulation of mutations that activate oncogenes and disrupt tumour suppressor genes, combined with multiple cycles of clonal selection and evolution facilitate the process of carcinogenesis. It has been estimated that disruption of about six cellular processes are required for transformation[1]. However, a recent comprehensive sequence evaluation of colon and breast cancer genomes hints that this number may be even higher (9 for breast, 12 for colon) than previously estimated[2]. If this model holds true then the rate-limiting step in the process of carcinogenesis would be the rate at which new mutations occur and any factor that influences this rate should have an effect on the rate of carcinogenesis.

Genetic instability refers to a set of events capable of causing unscheduled alterations, either of a temporary or permanent nature, within the genome. This term encompasses diverse genetic changes, which can be classified in a variety of ways. For simplicity we will categorize them into two major groups, instability occurring at the chromosomal level and at the nucleotide level. Instability at the nucleotide level occurs due to faulty DNA repair pathways such as base excision repair and nucleotide excision repair and includes instability of microsatellite repeat sequences (MSI) caused by defects in the mismatch repair pathway. The second form or chromosomal instability (CIN), defines the existence of accelerated rate of chromosomal alterations, which result in gains or losses of whole chromosomes as well as inversions, deletions, duplications and translocations of large chromosomal segments. Aneuploidy, which refers to an abnormal karyotype is a hallmark of many cancer cells and is thought to develop as a result of CIN. The observation that cancer cells harbour an abnormal number of chromosomes was made almost a century ago[3, 4] since then we have come a long way in understanding the causes behind this type of instability. To date several pathways and processes have been implicated in CIN including :

a) pathways involved in telomere and centromere stability, b) cell cycle checkpoint pathways and kinases, c) pathways regulating diverse proteins via post-translational modifications, d) sister chromatid cohesion and chromosome segregation, and e) centrosome duplication[5]. Genetic instability is a very broad topic that encompasses varied fields of biology. Hence, in this article we will focus on nucleotide instability including microsatellite instability; the role of epigenetic modifications, telomeres and the environment in genetic instability; and the role of genetic instability in

Atlas Genet Cytogenet Oncol Haematol 2007; 2 268 cancer stem cells. For further details on chromosomal instability please refer to the Deep Insight article titled Chromosomal instability by David Gisselsson.

DNA repair defects

Cells are exposed to many damaging insults capable of causing aberrations in DNA. These include environmental insults such as ultraviolet (UV) light, X-rays and genotoxic chemicals, as well the by- products of endogenous processes such as reactive oxygen species (ROS) and lipid peroxides. In addition, some chemical bonds in DNA tend to spontaneously break down under physiologic conditions, such as when spontaneous hydrolysis of nucleotides occurs resulting in abasic sites[6]. In order to repair these errors and restore the integrity of the genome, the cell has in place a range of overlapping DNA repair networks. Some of the best evidence for the role of genetic instability in tumourigenesis comes from examples where mutations that cause defects in dna repair mechanisms lead to syndromes of cancer susceptibility. Some of the common examples studied to date will be discussed below.

Mismatch Repair and Microsatellite Instability

Mismatch repair (MMR) has a central role in maintaining genomic stability by repairing DNA replication errors and inhibiting recombination between homologous sequences[7]. It is a post-replicative mechanism capable of eliminating base-base mismatches and insertion/deletion loops that arise during DNA synthesis. In the mammalian MMR system two heterodimeric complexes recognize mispaired bases; the hMSH2-hMSH3 (MutSs) complex, which preferentially recognizes insertion/ deletion loops; and the hMSH2-hMSH6 (MutSa) complex, which recognizes both base-base mispairs and insertion/ deletion loops. Two other proteins, hMLH1 and hPMS2, form a heterodimer (MutLa) that is then able to bind to the previously mentioned hMSH2 heterodimers. This complex is thought to interact with and recruit other proteins required for the repair process including Exo1, PCNA, RPA and Polg. In addition, a recent report demonstrated that MutLa is a latent endonuclease that is activated in the presence of a mismatch, MutSa, RFC, PCNA and ATP[8]. hMLH1 has been shown to form two other heterodimers, MutLs and MutLg, with the hPMS1 and hMLH3 proteins respectively. The roles of these two complexes in post-replicative error repair remains largely inconclusive, although it is believed that each could act as a "backup" for MutLa if the need arose. MMR improves the fidelity of DNA biosynthesis 100-1000 fold and reduces the error rate to one error per 1010 bases[9]. Defective MMR results in mirosatellite instability (MSI), characterized by the expansion or contraction of the number of tandem repeats, due to polymerase slippage at the many microsatellite loci that occur throughout the genome.

Germline mutations in the MMR genes are associated with the inherited cancer syndrome, hereditary non-polyposis colorectal cancer (HNPCC). Instability of microsatellite repeats is seen in tumours of as many as 85% of patients with HNPCC, making it a hallmark feature of this syndrome[10, 11]. HNPCC, which accounts for about 2% of all CRC cases, is one of the most common cancer predisposition syndromes. It is an autosomal dominant disorder characterized by the development of cancer in the colon as well as in extra-colonic sites including the endometrium, stomach, urinary tract, ovaries, small bowel and brain. MMR deficiency has also been shown to give rise to sporadic colorectal, endometrial and gastric cancers. Defective mismatch repair increases the likelihood of mutations in genes containing repeat sequences that regulate growth, differentiation or apoptosis. Somatic mutations of several genes including BAX, TCF4, AXIN2, and PTEN are found in MSI positive cancers.

To date there have been reports of families with individuals who have homozygous mutations in the mismatch repair genes MLH1, MSH2, MSH6 and PMS2. Such individuals develop several congenital abnormalities including haematopoietic malignancies, pediatric brain cancers, childhood leukemia, and HNPCC-related cancers and multiple cafe-au-lait spots, a common characteristic of neurofibromatosis type 1 [12-17]. This phenotype manifests in an autosomal recessive fashion, because a mutant allele is inherited from each parent. In addition, there have been reports of individuals carrying compound heterozygous PMS2 mutations who develop Turcot syndrome[18]. This syndrome is defined by the presence of brain tumors and multiple adenomas/colorectal cancers that occur at an early age and is associated with mutations in the APC and MMR genes.

Nucleotide Excision Repair

Atlas Genet Cytogenet Oncol Haematol 2007; 2 269 Nucleotide excision repair (NER) has a broader specificity in that it is able to recognize lesions as diverse as disturbances in the double helix conformation that are caused by UV light, to chemical damage that gives rise to DNA cross links/bulky adducts. The NER pathway is a multi-step process and as many as 30 proteins assemble at the damaged site in a stepwise fashion[19]. Individuals born with defects in the NER pathway develop a syndrome known as Xeroderma Pigmentosum (XP). Inherited defects in any one of the 7 nucleotide excision repair XPA-XPG genes as well as XPV (a non NER gene) have been implicated in this disease[20]. XP patients have a very high susceptibility to developing cancer in areas of skin exposed to the sun. The median age at which skin tumours arise in these patients is 8 years, compared with a average of 60 years observed in the normal population[21]. In addition a subset of XP patients show neurological defects and emerging evidence appears to indicate that the immune system of XP patients is impaired due to UV exposure[22-26]. This may indicate defective immune surveillance or increased susceptibility to UV-induced immunomodulation, which may contribute to the increased susceptibility to skin cancer[19]. Two other syndromes have been associated with defective NER, the first being Cockayne syndrome characterized by neurological defects and sun sensitivity but no predisposition to skin cancer[27]. The second syndrome trichothiodystrophy is defined by patients with brittle hair caused by a sulphur deficiency, in addition to other features such as mental retardation and small stature[28, 29].

Base Excision Repair

Base excision repair (BER) is mainly responsible for repairing damage induced by endogenous metabolic processes such as methylation, deamination, reactive oxygen species (ROS) and hydrolysis[30]. Multiple proteins contribute to BER pathway and enable it to correct non-bulky damaged nucleotides, abasic sites as well as single-strand breaks. The process is initiated by DNA glycosylases specific for various types of damage, which recognize and cleave the N-glycosylic bond that connects the damaged base to the DNA backbone[31]. To date, 11 such DNA glycosylases have been identified in mammals[32]. Reactive oxygen species can modify the C8 position of Guanine to form 7, 8-dihydro-8-oxoguanine (8-oxoG), a major product of such damage. 8-oxoG is highly mutagenic and is able with adenine and cause G:C->T:A transversions[33]. The glycosylases most commonly involved in the removal of 8-oxoG are OGG1, MYH and MTH1. It was discovered recently that biallelic inactivation of MYH can lead to an autosomal recessive form of inherited colorectal cancer known as MYH-associate polyposis (MAP)[34]. This came as a surprise to many, as unlike MMR and NER, no inherited defects in these genes had been reported prior to this[34].

Role of Epigenetic Modifications in Genetic Instability

In addition to the sequence alterations and chromosomal aberrations discussed above, epigenetic modifications that affect both DNA and the associated chromatin are capable of influencing gene expression and the stability of the genome. An important point to bear in mind is that although epigenetic modifications are mitotically heritable, they are in a state of constant flux within the lifetime of an individual. The possible contribution of the best-studied epigenetic mechanisms to genetic instability will be discussed below.

Methylation in Tumourigenesis

DNA methylation or the covalent modification of the C-5 position of cytosine residues occurs primarily at the short stretches of CG dinucleotides known as CpG islands. Recent estimates suggest that there are at least 29,000 such regions in the , many of which surround the 5' ends of genes [35]. In bacteria, methylation is thought to have evolved as a defense against foreign DNA. On the contrary, in eukaryotes methylation is thought to play a role in regulating gene expression and in silencing repeat elements in the genome[36]. In normal cells the pattern of expression is stably maintained following DNA replication and cell division by a maintenance enzyme, DNA methyltransferase, (DNMT1). The establishment of DNA modifications is thought to be a highly random event[37], and could be instrumental in contributing to genetic instability. This is illustrated by the example of DNMT1, which has an estimated error rate of 5%, as well as a small rate of de novo methylation[38, 39].

Atlas Genet Cytogenet Oncol Haematol 2007; 2 270 The first epigenetic mechanism implicated in carcinogenesis was DNA hypomethylation[40]. In addition, there have been reports of age related decreases in DNA methylation levels that occur in a tissue specific manner[41, 42]. It is likely that these changes contribute to the age-related increase in incidence of illnesses, such as carcinogenesis and autoimmunity[43]. Examples of genes hypomethylated in cancer include cyclin d2 in gastric carcinoma[44], Ha-RAS in lung and colon cancer[45] and Maspin and S100P in pancreatic cancer[46]. Several studies have implicated genomic hypomethylation in the genetic instability seen in many cancers. In a recent study of colorectal carcinomas it was shown that genome-wide hypomethylation is strongly correlated with chromosomal instability[47], indicating the potential role of hypomethylation in destabilizing the genome.

CpG islands commonly occur in the promoter regions, thus hypermethylation of this region has been shown to silence gene expression[48]. This was first identified in the retinoblastoma protein (Rb) followed by promoter hypermethylation of several other tumour suppressor and cell-cycle regulatory genes[49]. It is believed that hypermethylation too is an early event that may precede the neoplastic process[50, 51]. A prime example of the role of hypermethylation in contributing to genetic instability is hMLH1 inactivation, where promoter hypermethylation is thought to be primarily responsible for approximately 15% of sporadic colorectal cancers associated with microsatellite instability [52, 53]. In a study by Costello et al.[35], 1184 unselected CpG islands were screened in 98 primary human tumours using restriction landmark genomic scanning (RLGS). This study found that on average about 600 CpG islands were aberrantly methylated in tumours, indicating the potentially vast number of genes likely to be aberrantly expressed due to this mechanism.

Methylation also plays an important role in inactivating one copy of the X chromosome, so that equal gene dosage is maintained in the somatic cells of males and females[54]. Imprinting refers to the phenomenon by which only the maternal or paternal allele of certain genes are expressed and the second allele is suppressed via methylation[55]. Therefore demethylation of such imprinted genes can lead to a situation where both alleles are expressed [56, 57]. This has been shown to contribute to malignancies by activating a normally silent copy of the gene as in the case of IGF2[58]. Aberrant imprinting can also silence a normally active copy of a gene involved in growth inhibition as shown with p57kip [59]. Loss of imprinting has also been shown to contribute to certain congenital syndromes such as the Beckwith-Wiedemann Syndrome , Prader-Willi Syndrome (PWS) and Angelman's Syndrome (AS) [60, 61]. Beckwith-Wiedmann syndrome occurs due to loss of imprinting on chromosome 11p, and is characterized by pre- and post-natal overgrowth syndrome, often accompanied by exomphalos and a predisposition for childhood tumours[62]. Loss of imprinting on chromosome 15q of the paternal and maternal alleles, lead to PWS and AS respectively. PWS is characterized by mild mental retardation, short stature and obesity, while AS is characterized by ataxia, severe mental retardation accompanied by a lack of speech, hyperactivity and a predisposition for inappropriate bouts of laughter[62].

Histone modification

Chromatin, which consists of repeating units called nucleosomes, is the packaged form of DNA present in the eukaryotic cell. Each nucleosome consists of DNA that is wrapped tightly around a group of conserved, highly basic proteins known as histones. Histones can be covalently modified by acetylation, methylation, phosphorylation, ubiquitination and Poly-ADP ribosylation, which ultimately influence the tightness of the protein-DNA interaction and can create a code that can be recognized by chromatin remodeling complexes[63, 64]. This idea of a histone code suggests that specific patterns of modifications are read like a molecular bar code, resulting in the recruitment of cellular machinery that alter the chromatin state [65]. The role of histone modification and chromatin remodeling in the carcinogenic process is a rapidly evolving field. To date histone acetylation and methylation have been implicated in cancer.

It is the interplay between histone acteylases (HATs) and histone deacetylates (HDACs) that determine the precise balance of acetylation within the nucleus. Abnormal HDAC activity has been commonly observed in haemotological malignancies[66]. Studies done in these cancers have shown that fusion proteins such as RAR-PML and RAR-PLZF can recruit HDACs, which in turn lead to aberrant transcriptional repression that halts differentiation[67, 68]. It has been proposed that a dynamic relationship exists between histone modifications, chromatin structure and DNA methylation[69, 70]. For example it has been shown that histone acetylation and gene activation,

Atlas Genet Cytogenet Oncol Haematol 2007; 2 271 results in DNA demethylation[69], while the opposite situation where low steady state level of histone acetylation and methylation, results in the recruitment of DNMT1 and DNA methylation of regulatory regions[66]. Thus, it is mechanistically possible that skewed regulation of this inter-relationship could lead to genetic instability.

The role of the environment in genetic instability

Despite the many checkpoints and repair processes the cell has in place to prevent the occurrence and propagation of errors, genetic instability is a widespread phenomenon observed in many cancers. Thus, it appears likely that the environment in which these cancers arise somehow selects for and facilitates the clonal expansion of cells that show instability in their genome. This point is supported by the observation that colorectal tumours, which show an MSI or CIN phenotype exclusively, are located in anatomically distinct regions. MSI tumours are localized in the proximal section of the intestine, while CIN tumours are more frequently seen in the distal colon and rectum[71, 72]. This review will therefore briefly summarize what is currently known about the role of the macroenvironment, specifically dietary factors and the microenvironment, specifically hypoxia in the development of genetic instability.

It is possible that environmental agents are able to instigate the process of instability, as illustrated by work done in colorectal carcinogenesis. Heterocyclic amines (HAA) are carcinogens that are a common product of cooking beef, pork, poultry and fish at high temperatures. A study by Wu et al., demonstrated that patients with MSI positive cancers had significantly higher dietary exposure to heterocyclic amines, as determined by the preference for well-done meat and the frequent use of techniques that produces HAA[73]. 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine or PhIP, the most abundant heterocyclic amine in the western diet, is a bulky adduct forming agent that is able to cause a variety of cancers in experimental animals[74-77]. Another powerful rodent carcinogen is MNNG (N-methyl-N'-nitro-N-nitrosoguanidine)[78]. An alkylating agent, it is able to preferentially methylate the O6 position of deoxyguanosine residues in DNA. Gastrointestinal cells are continually exposed to both PhIP and MNNG at varying concentrations. In a study undertaken to determine if carcinogen exposure can influence the type of instability seen in cells, it was found that cells resistant to PhIP, developed a chromosomal instability or CIN phenotype, while cells resistant to MNNG exhibited MSI and associated mismatch repair defects[79]. This data suggests that exposure to certain dietary carcinogens, may in fact select for cancer cells with distinct types of genetic instability and vice versa[79].

Role of tumour microenvironment in genetic instability

The tumour microenvironment has been proposed to contribute to the increased genetic instability seen in cancer cells. Several studies have lent support to this notion, including a study that demonstrated a higher rate of genomic instability of mouse cells when grown in vivo as subcutaneous tumour implants in syngeneic mice, as measured using an EGFP reporter gene and a genomic minisatellite locus[80]. More specifically, hypoxia has been singled out as a major microenvironmental factor. Hypoxia, which appears to occur transiently within the tumour microenvironment, has been shown to lead to cycles of hypoxia and reoxygenation[81]. This is thought to lead to DNA damage as a result of reactive oxygen species (ROS) and the enzyme superoxide dismutase. In addition to ROS leading to the formation of 8-oxoG, and accumulating evidence suggest a role for oxygen and ROS in causing single and double strand breaks[81]. In addition to its ability to cause aberrations in DNA, these cycles of hypoxia and reoxygenation have been shown to affect DNA synthesis, by both interrupting this process and by leading to over-replication after reoxygenation[81-84]. Other studies have found that it is hypoxia induced gene amplification of p-Glycoprotein that is responsible for the observed resistance to adriamycin and doxorubicin[85, 86], indicating that gene amplification may also be caused by hypoxia. Furthermore, emerging evidence suggests that hypoxia can influence the integrity of the genome by impacting upon DNA repair pathways. As described above, MLH1 is one of the key genes involved in mismatch repair. It was shown that hypoxia downregulates the expression of the MLH1 gene at the transcriptional level and this was thought to occur via chromatin remodeling, as treatment with an histone deacteylase inhibitor prevented the aforementioned decrease[87]. It has also been demonstrated that hypoxia enriches for MMR deficient cells [88]. Thus, DNA damage, defective DNA synthesis, gene amplification and the deregulation of DNA repair pathways all appear to be mechanisms by which hypoxia contributes to genetic instability. Little is still known about other

Atlas Genet Cytogenet Oncol Haematol 2007; 2 272 microenvironmental factors that may lead to instability. However, it has been suggested that the tumour microenvironment may represent in mammalian cells a conserved evolutionary mechanism that increases the rate of mutation in response to cellular stresses, which preferentially gives cancer cells a survival advantage[81].

Telomeres and Genetic Instability

One mechanism that can bring about chromosomal instability (CIN) is telomere loss. Although CIN is not addressed in detail in this paper, the role of telomeres is briefly summarized to highlight the important role it may play in carcinogenesis and the implications it may have in the field of genetic instability.

Telomeres refer to the segments of DNA bound by specific proteins that cap the ends of chromosomes and in doing so acts as a buffer to prevent loss of valuable genomic sequence during replication[6], as well as to prevent chromosomes fusing at the ends[5]. A RNA primer is required for the process of DNA replication. Thus, when replication proceeds from the 5'->3' direction, it leaves a stretch of unreplicated DNA at the 5' end. This leads to a gradual loss of telomeric repeats and the consequent shortening of telomeres by about 50-200 base pairs, after each round of replication[5]. A specific enzyme, telomerase, maintains the telomere length. Telomerase consists of two main components; the reverse trancriptase component (hTERT), which is only expressed in cells where telomerase activity is present; and the ribonucleoprotein moiety (hTERC/hTR), which is expressed ubiquitously in all cells. In adults, telomerase activity has been observed only in immature germ cells, certain stem/progenitor cells and in a subset of somatic cells such as human fibroblasts.

Telomerase is suppressed in the majority of somatic cells leading to the continuing telomere attrition, which leads to irreversible cell-cycle arrest known as replicative cell senescence. It has been demonstrated that primary human fibroblasts that have lost the ability to senesce, display telomere shortening and eventually enter a crisis stage that culminates in chromosome fusion, aneuploidy and cell death[89]. It has been proposed that it is therefore important for cancer cells to regain the ability to maintain telomeres, in order to avoid senescence and extensive chromosome fusion during crisis[89, 90]. In fact it has been shown that about 85-90% of human cancers have reactivated telomerase and are able to maintain telomere length[5]. Interestingly cancer cells that are deficient for telomerase activity are able to maintain telomere length via a mechanism known as alternative lengthening of telomeres or ALT. It has been suggested that the ALT mechanism makes use of DNA repair pathways and recombination to maintain telomere length[91]. Thus, whichever mechanism employed by the cell, it appears that maintaining telomere length is critical for tumourigenesis and cellular immortalization[5]. Telomere maintenance is also required for chromosomal instability. Given that cancer cells inevitably display properties of telomere maintenance and genetic instability, it has been proposed that telomere loss could be either a cause or a consequence of genetic instability[5], or perhaps be involved in both.

However, conflicting with this view is the observation that the telomeres of invasive human cancers are often shorter than their normal counterparts[92]. Studies in telomerase deficient mice (mTERC-/-) provided a plausible explanation to this paradox[93]. In these mice telomere shortening induced chromosome instability and in doing so increased the rate of tumour initiation[94]. At the same time it was seen that telomere loss can inhibit tumour progression and the development of macroscopically advanced tumours[94-97]. This indicates that the timing at which the telomeres shortening occurs plays a crucial role in cancer development[98]. In fact it was found that 88.6% of precursor lesions known as intraepithelial neoplasia lesions display shortening of telomeres[98].

Cancer Stem Cells and Genetic instability

The stem cell model of carcinogenesis has been rapidly growing in popularity. The American Association for Cancer Research Stem Cell Workshop defined a cancer stem cell as a cell within the tumour that possesses the capacity to self-renew, and in doing so gives rise to the heterogeneous lineages that comprise the tumour. Cancer cells may arise therefore from tissue stem cells that have acquired mutations that render them cancerous, or it may be a more differentiated i.e. progenitor cell that may have "re-acquired" stem cell like properties due to mutations [99]. Either scenario is different

Atlas Genet Cytogenet Oncol Haematol 2007; 2 273 from the widely accepted stochastic model of carcinogenesis. Cancer stem cells or cancer initiating cells have been identified to date in acute myelogenous leukemia[100], breast tumours [101], brain tumours [102, 103] and most recently in a subset of colon tumours [104]. The discovery of the existence of cancer initiating cells raises some very important questions regarding whether genetic instability exists within these cells and what role if any it plays in these cells.

There is an increased likelihood that exogenous and endogenous environmental agents cause a greater degree of genetic and epigenetic changes in stem cells; as opposed to their differentiated counterparts, who by their very definition have shorter life spans. This is a fairly novel field, and much more research needs to be undertaken to determine the relationship between genetic instability and cancer stem cells. However some preliminary evidence comes from work done in haematological malignancies and telomere instability. Haematological neoplasia can be divided in to three stages, pre- malignant, chronic and acute, with the last being the most advanced stage. Telomere loss was shown to be rapid during the progression of chronic myeloid leukemia, in fact patients in the late chronic phase had shorter telomeres than those in early chronic phase[105]. In addition patients with pre- malignant disease with shorter telomeres had more cytogenetic abnormalities[106] and a poorer prognosis with increased rates of leukemic transformation[107]. These observations suggest that shortening telomeres can bring about genetic instability in cancer stem cells, which is further supported by the observation that telomere shortening occurs very early in carcinogenic cascade, indicating the likelihood that this process occurs in cancer stem cells. Additionally, progression of pre- malignant disease to acute stage was shown to correlate with telomerase activation[108]. Together these observation implicate telomere attrition and telomerase reactivation as risk factors for the malignant transformation of stem cells[93]. On a separate note, loss of heterozygosity of cancer related genes in mammary stem cells have been shown to contribute to genetic instability in progeny cells and result in subsequent breast cancer development[101, 109-111]. This observation also supports the notion that the theories of genetic instability and cancer stem cells are not mutually exclusive.

Summary and Conclusion

It is well documented that the sequential accumulation of mutations in tumour suppressors and oncogenes are required for the process of tumourigenesis to proceed. Any event(s) that accelerates the spontaneous rate of alterations in the cells supports this process, illustrated by the prevalence of genetic instability in cancer cells. DNA repair processes play a critical role in repairing damaged DNA, and in ensuring faithful transmission of genetic material. Thus, it comes as no surprise that inherited defects of genes in these pathways, lead to several disorders, most of which increase susceptibility to cancer by many fold, and maybe evident by the early age at diagnosis of cancer in these in patients. In addition to genetic alterations, epigenetic modifications such as methylation and histone modification have been shown to bring about genetic instability. In addition, it is likely that the prolonged exposure to environmental agents and/ or processes may, in concert with individual genetic factors determine the establishment of tumours. Despite these observations, the existence of subsets of tumours that lack an identifiable form of instability has led to skepticism regarding the need for genetic instability in the process of cellular transformation. However, this may indicate that the importance of genetic instability in carcinogenesis differs based on several factors including an individual's genetic background, tissue of interest, baseline mutation rate, environmental exposure, age and time of onset. There also remains the question of whether genetic instability is the driving force behind the process of tumourigenesis or if it is simply a bystander effect of the process. Thus the precise role of genetic instability in the various cancers needs to be defined further. An additional challenge is posed by the prospective identification of cancer stem cells, which call for theory of genetic instability to be reviewed in a new light.

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Contributor(s) Written 01-2007 Sheron Perera, Bharati Bapat Citation This paper should be referenced as such : Perera S, Bapat B . Genetic Instability in Cancer. Atlas Genet Cytogenet Oncol Haematol. January 2007 . URL : http://AtlasGeneticsOncology.org/Deep/GenetInstabilityCancerID20056.html

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Reciprocal translocation t(2;12)(q31;p13) in a case of CMML

Despina Iakovaki, Markos Fisfis, Katy Stefanoudaki, Georgia Bardi

Clinics Age and sex : 78 yrs old male patient Previous history : no preleukemia no previous malignant disease; no inborn condition of note Organomegaly : no hepatomegaly; splenomegaly; no enlarged lymph nodes; no central nervous system involvement Blood Hb : 5.7 g/dl; platelets : 86 x 109/l; Bone marrow : increased cellularity, hyperplastic granulocytic series with dysgranulopoiesis, polymorphous and dysplastic megakaryocytes, numerous micromegakaryocytes, depressed erythroid series. Blasts: 5%, Monocytes:17%. Note: WBC Differential: Neu:23, Lymph:31, Mono:41, Myelo- Metamyelocytes: 5%, granulocytic dysplasia. Absolute monocyte count: 1.3 x 109/l Cyto pathology classification Cytology and immunophenotype : ; Precise diagnosis : Chronic myelomonocytic leukemia (CMML) Survival Date of diagnosis: 02-2003 Treatment : Supportive; blood transfusions, steroids, platelets transfusions Complete remission : None Status : Dead 11-2005 Survival : 33 months Karyotype Sample : Bone marrow; culture time : Direct preparations (after 1 h in culture) and 24 H; banding : G- banding with Wright stain Results : 46,XY,t(2;12)(q31;p13)[22]/47,idem,+21[3].

Partial karyogram of the cytogenetically abnormal clone with the translocation t(2;12)(q31;p13). The arrows indicate the breakpoint in the abnormal chromosomes 2 and 12.

Atlas Genet Cytogenet Oncol Haematol 2007; 2 279 Comments Among the haematological malignancies with clonal chromosome aberrations reported in the world literature, there is only one case with the same translocation t(2;12)(q31;p13), a non Hodgkin lymphoma published by Sato et al., 1997. The karyotypic findings of the present case indicates a cytogenetic clonal evolution, since a second abnormal clone with the translocation t(2;12)(q31;p13) and trisomy of chromosome 21 was identified together with the clone displaying the t(2;12)(q31;p13) as the sole change. Internal links Atlas Card t(2;12)(q31;p13)>t(2;12)(q31;p13) Bibliography Heterogeneity in the breakpoints in balanced rearrangements involving band 12p13 in hematologic malignancies identified by fluorescence in situ hybridization: TEL (ETV6) is involved in only one half. Sato Y, Bohlander SK, Kobayashi H, Reshmi S, Suto Y, Davis EM, Espinosa III R, Hoopes R, Montgomery KT, Kucherlapati RS, Le Beau MM, Rowley JD, Blood 1997; 90: 4886-4893 Medline 9389705

Contributor(s) Written 11-2006 Despina Iakovaki, Markos Fisfis, Katy Stefanoudaki, Georgia Bardi Citation This paper should be referenced as such : Iakovaki D, Fisfis M, Stefanoudaki K, Bardi G . Reciprocal translocation t(2;12)(q31;p13) in a case of CMML. Atlas Genet Cytogenet Oncol Haematol. November 2006 . URL : http://AtlasGeneticsOncology.org/Reports/0212IakovakiID100017.html

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CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet) t(8;13)(p12;q12) in an atypical chronic myeloid leukaemia case

Valeria AS De Melo, Alistair G Reid

Clinics Age and sex : 43 yrs old male patient Previous history : no preleukemia ; Organomegaly : no hepatomegaly; no splenomegaly; enlarged lymph nodes; no central nervous system involvement Blood WBC : 9.8 x 109/l; Hb : 11.5 g/dl; platelets : 28 x 109/l; Cyto pathology classification Cytology and immunophenotype : ; Precise diagnosis : Atypical chronic myeloid leukaemia Survival Date of diagnosis: 02-1992 Treatment : Chemo/Radiation/bone marrow transplantation Complete remission was obtained Treatment related death : + Relapse : - Status : Dead 06-1994 Survival : 28 mths Karyotype Sample : Bone marrow; culture time : CM FUDR 48h; banding : G-banding Results : 46,XY,t(8;13)(p12;q12)[8]/46,XY[2]

Partial karyotype showing the t(8;13)(p12;q12) - G-banding Comments Eight of the metaphases examined showed a translocation between chromosomes 8 and 13. There was no evidence of a Philadelphia translocation. The t(8;13) is usually found in myeloproliferative

Atlas Genet Cytogenet Oncol Haematol 2007; 2 281 syndromes with FGFR1 involvement and a poor prognosis Internal links Atlas Card t(8;13)(p12;q12)>t(8;13)(p12;q12) Bibliography t(8;13)(p12;q12) - updated. Pebusque MJ, Cross NCP Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 97-100.

Contributor(s) Written 12-2006 Valeria AS De Melo, Alistair G Reid Citation This paper should be referenced as such : De Melo VAS, Reid AG . t(8;13)(p12;q12) in an atypical chronic myeloid leukaemia case. Atlas Genet Cytogenet Oncol Haematol. December 2006 . URL : http://AtlasGeneticsOncology.org/Reports/0813ReidID100018.html

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CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet)

A case of myeloproliferative disorder with t(5;10)(q33;q21.2)

Valeria AS De Melo, Alistair G Reid

Clinics Age and sex : 48 yrs old male patient Previous history : no preleukemia ; Organomegaly : no hepatomegaly; splenomegaly; no enlarged lymph nodes; no central nervous system involvement Blood WBC : 59.1 x 109/l; Hb : 11.1 g/dl; platelets : 58 x 109/l; blasts : less% than 1 Cyto pathology classification Cytology and immunophenotype : ; Precise diagnosis : Myeloproliferative disorder Survival Date of diagnosis: 03-1999 Treatment : HU,IS, BMT Complete remission was obtained Treatment related death : - Relapse : - Status : Alive Survival : 75 mths + Karyotype Sample : Bone marrow; culture time : FUDR; banding : G-banding Results : 46,XY,t(5;10)(q33;q21.2)[16]/46,XY[8] Other molecular studies technics : PCR (Ratio BCR-ABL/ABL) results : 11/2000: 0; 04/2001: 0; 03/2002: 0.18

Atlas Genet Cytogenet Oncol Haematol 2007; 2 283 Partial karyotype showing the t(5;10)(q33;q21.2) - G-banding Comments One third of the metaphases examined (8/24) were apparently normal male while the remaining majority of cells showed a balanced translocation between chromosomes 5 and 10. This translocation is poorly known: only 2 cases of atypical chronic myeloid leikemia of unknown prognosis. Further cases will help defining this rare entity. Internal links Atlas Card t(5;10)(q33;q21.2)>t(5;10)(q33;q21.2) Bibliography t(5;10)(q33;q21). Mecucci C. Atlas Genet Cytogenet Oncol Haematol 2001; 5 (1): 122-123.

Contributor(s) Written 12-2006 Valeria AS De Melo, Alistair G Reid Citation This paper should be referenced as such : De Melo VAS, Reid AG . A case of myeloproliferative disorder with t(5;10)(q33;q21.2). Atlas Genet Cytogenet Oncol Haematol. December 2006 . URL : http://AtlasGeneticsOncology.org/Reports/0510ReidID100019.html

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CASE REPORTS in HAEMATOLOGY (Paper co-edited with the European LeukemiaNet)

A novel chromosomal translocation (6;14) (p22;q32) in a case of precursor B- cell Acute Lymphoblastic Leukemia.

Siddharth G Adhvaryu, Alka Dwivedi, Peggy Stoll

Clinics Age and sex : 25 yrs old male patient Previous history : no preleukemia no previous malignant disease; no inborn condition of note Organomegaly : no hepatomegaly; no splenomegaly; no enlarged lymph nodes; no central nervous system involvement Blood WBC : 19.6 x 109/l; Hb : 12.3 g/dl; platelets : 15 x 109/l; blasts : 68% Bone marrow : The specimen was taken from the iliac crest and particle crush smears appeared cellular but dilute. The trephine imprints were cellular. No significant maturation of the myeloid series was present. The myeloid series were primarily composed of segmented neutrophils. No erythroid dyspoiesis was evident. Only a rare magakaryocyte was seen. Blasts were similar to those of the peripheral blood and appeared very delicate and easily crushed. No Auer rods were seen. Cyto pathology classification Cytology and immunophenotype : Precursor B-cell acute lymphoblastic Leukemia (WHO); Flow cytometric analysis of the marrow was performed at the Methodist Hospital. The blasts had a precursor B-lymphoblast phenotype: CD19 positive, CD20 positive, CD10 positive, CD79a positive (cytoplasmic) and TdT positive. Myeloid markers (CD13, CD33, CD14, CD117 and myeloperoxidase) are negative. T-cell markers (CD3, CD5, CD7, CD4 and CD8) are also negative. CD34 is positive (partial). Rearranged Ig Tcr : Not done Electron microscopy : Not done Precise diagnosis : Precursor B-cell Acute Lymphoblastic Leukemia Survival Date of diagnosis: 11/2006 Treatment : Asparaginase, Cyclophosphamide, Daunorubicin, Vineristine Complete remission was obtained Comments : marrow examination on 12/04/2006 is compatible with early remission. Treatment related death : No; Discharged from hospital on 12/06/2006 Relapse : - Status : Alive Survival : N/A Karyotype

Atlas Genet Cytogenet Oncol Haematol 2007; 2 285 Sample : Peripheral Blood; culture time : 24 h, 48 h; banding : GTW Results : 46-47, XY,del(5)(q34),t(6;14) (p22;q32),i(9)(q10),del(17)(p10),-20,+mar[cp6] Other molecular cytogenetics technics : Fluorescence In Situ Hybridization (FISH) Other molecular cytogenetics results : FISH was performed using Vysis LSI IGH dual color, break apart rearrangement probe. The analysis revealed an IgH rearrangement with the green signal on der (6).

Representative metaphase of case # 06-1570

Partial karyotype of case # 06-1570 showing the new t(6;14)(p22;q32) and other anomalies

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FISH results showing 14q32 translocation. Comments There are few reports documenting t(6;14)(p21.1;q32.3), in cases of multiple myeloma/plasma cell leukemia and diffuse large B cell non Hodgkin lymphoma. Our case report shows a karyotype with multiple abnormalities. One significant abnormality observed was the loss of 9 p in the form of i(9)(q10), which is a common finding in precursor B-cell lymphoblastic leukemia. Our case also showed partial deletions of 5q and 17p. We observed a novel translocation t(6;14) (p22;q32) in a patient with Precursor B-cell Acute Lymphoblastic Leukemia. FISH studies performed on the metaphases of this specimen confirmed the translocation of IGH (located on 14q32.3). E2F3 is a transcription factor located on 6p22 that is reported to play a critical role in regulating normal cellular proliferation and differentiation. Though the exact gene in 6p22 translocation is not yet known, it is speculated that E2F3 might be clinically significant in leukemia/MDS. However, involvement of Geminin, DNA replication inhibitor (GMNN) located on 6p22.2 cannot be ruled out. Call for collaboration Dr Siddharth G Adhvaryu, Director, Cytogenetics Laboratory, UTHSCSA, San Antonio, TX-78229, Ph: 210-567-4021, 210-567-4050/4051; E-mail: [email protected] Internal links Atlas Card t(6;14)(p22;q32) Bibliography E2F3 is critical for normal cellular proliferation. Humberto PO, Verona R, Trimarchi JM, Rogers C, Dandapani S, Lees JA. Medline 10733529

Cyclin D3 is a target of t(6;14)(p21.1;q32.3) of mature B-cell malignancies. Sonoki T, Harder L, Horsman DE, Karran L, Taniguchi I, Willis TG, Gesk S, Steinemann D, Zucca E, Schlegelberger B, Sole F, Mungall AJ, GAscoyne RD, Seibert R, Dyer MJ. Blood. 2001; 98(9): 2837-2844 Medline 11675358

Rereplication by depletion of geminin is seen regardless of p53 status and activates a G2/M checkpoint. Zhu W, Chen Y, Dutta A. Mol Cell Biol. 2004; 24(16): 7140-7150

Atlas Genet Cytogenet Oncol Haematol 2007; 2 287 Medline 15282313 t(6;14)(p21;q32). Viguié F. Atlas Genet Cytogenet Oncol Haematol 2005; 9 (3): 476-478. http://AtlasGeneticsOncology.org/Anomalies/t0614p21q32ID1306.html

E2F3 is the main target gene of the 6p22 amplicon with high specificity for human bladder cancer. Oeggerli M, Schraml P, Ruiz C, Bloch M, Novotny H, Mirlacher M, Sauter G, Simon R. Oncogene. 2006; 25(49): 6538-6543 Medline 16953223

Translocation (14;18)(q32;q21) in acute lymphoblastic leukemia: a study of 12 cases and review of literature. D¹Achille P, Seymour JF, Campbell, LJ. Cancer Genet Cytogenet. 2006; 171 (1): 52-56 Medline 17074591

Contributor(s) Written 01-2007 Siddharth G Adhvaryu, Alka Dwivedi, Peggy Stoll Citation This paper should be referenced as such : Adhvaryu SG, Dwivedi A, Stoll P . A novel chromosomal translocation (6;14) (p22;q32) in a case of precursor B-cell Acute Lymphoblastic Leukemia.. Atlas Genet Cytogenet Oncol Haematol. January 2007 . URL : http://AtlasGeneticsOncology.org/Reports/0614AdhvaryuID100020.html

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