Atlas of Genetics and Cytogenetics in Oncology and Haematology


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WWOX (WW domain containing oxidoreductase)

Identity

Other namesFOR
murine name WOX1
Hugo WWOX
Location 16q23.1

DNA/RNA

Description WWOX is comprised of 9 coding exons in a region of approximately one million base pairs that includes the common fragile site FRA16D.
Transcription RT-PCR amplification of Wwox in normal and tumor cDNA samples has shown products apparently originating from alternative transcripts or transcript variants, respectively. Expressed truncated proteins have not been detected.
Pseudogene None reported.

Protein

 
  Alignment of human (hWwox), mouse (Mwwox), fly (fWwox), mosquito (moWwox) and worm (ceWwox) Wwox proteins. The locations of the WW1 and WW2 domains are shown, as well as the predicted sites for nuclear localization, NADP binding, mitochondrial targeting, substrate binding and a proton acceptor.
Description WWOX is a 414 amino acid protein that contains two WW domains and a short-chain dehydrogenase/reductase (SDR) domain.
Expression WWOX is highly expressed in secretory epithelial cells of reproductive, endocrine and exocrine organs and is expressed in all or most other tissues at a lower level. The protein is not expressed or is expressed at low level in many tumor types, including breast, pancreatic, gastric, hepatocellular, ovarian, lung and prostate cancers. Loss of WWOX expression can be due to inactivation by promoter methylation, allelic deletion or a combination of these mechanisms.
Localisation Cytoplasm, mitochondria.
Function Contains an N-terminal group 1 WW domain that binds proteins with a PPXY motif. Reportedly interacts with p53, p73, JUN, ERBB4, Ap2alpha, Ap2gamma, Ezrin/VIL2, Ack1/TNK2. Probably involved in apoptosis, steroid (estrogen) metabolism and signaling pathways. Mice carrying a targeted deletion of the Wwox gene develop osteosarcomas in juvenile Wwox(-/-) and lung papillary carcinomas in adult Wwox(+/-) mice spontaneously. Wwox(+/-) mice develop significantly more ethyl nitrosourea-induced lung tumors and lymphomas than wild-type littermates.

Mutations

Somatic Cancer cell lines from various tumor types, including ovarian, gastric and pancreatic, exhibit deletions within the WWOX gene, frequently in the introns surrounding exon 8.

Implicated in

Entity Breast cancer, esophageal and non-small cell lung cancer.
Disease Breast, esophageal and non-small cell lung cancer show high LOH rates and low mutation rates. 27% of ER+ breast carcinomas versus 46% for ER- cases were completely negative for WWOX expression; when weakly WWOX expressing cases were included with negative cases the significance increased. Methylation of regulatory sequences in WWOX exon 1 distinguish breast cancer DNA from normal DNA and DNA from adjacent tissue. Treatment with 5'-Aza-2'-deoxycytidine to demethylate the WWOX promoter successfully restored WWOX expression in WWOX-deficient breast cancer cells.
Prognosis In a sampling of 132 breast cancer tissues, high level WWOX expression was associated with better disease free survival.
  

Breakpoints

 
  Location of the t(14;16)(q32.3;q23) translocation breakpoints falling within the WWOX gene in 3 multiple myeloma cell lines.

External links

Nomenclature
HugoWWOX
GDBWWOX
Entrez_GeneWWOX  51741  WW domain containing oxidoreductase
Cards
AtlasWWOXID508ch16q23
GeneCardsWWOX
EnsemblWWOX [Search_View]   ENSG00000186153 [Gene_View]
GenatlasWWOX
GeneLynxWWOX
eGenomeWWOX
euGene51741
Genomic and cartography
GoldenPathWWOX  -  16q23.1   chr16:76691052-76870094 +  16q23.3-q24.1   [Description]    (hg18-Mar_2006)
EnsemblWWOX - 16q23.3-q24.1 [CytoView]
NCBIMapview
OMIMDisease map [OMIM]
HomoloGeneWWOX
Gene and transcription
GenbankAF187015 [ ENTREZ ]
GenbankAF211943 [ ENTREZ ]
GenbankAF227526 [ ENTREZ ]
GenbankAF227527 [ ENTREZ ]
GenbankAF227528 [ ENTREZ ]
RefSeqNM_016373 [ SRS ]    NM_016373 [ ENTREZ ]
RefSeqNM_130791 [ SRS ]    NM_130791 [ ENTREZ ]
RefSeqNM_130844 [ SRS ]    NM_130844 [ ENTREZ ]
RefSeqAC_000059 [ SRS ]    AC_000059 [ ENTREZ ]
RefSeqAC_000148 [ SRS ]    AC_000148 [ ENTREZ ]
RefSeqNC_000016 [ SRS ]    NC_000016 [ ENTREZ ]
RefSeqNT_010498 [ SRS ]    NT_010498 [ ENTREZ ]
RefSeqNW_001838328 [ SRS ]    NW_001838328 [ ENTREZ ]
RefSeqNW_926528 [ SRS ]    NW_926528 [ ENTREZ ]
AceViewWWOX AceView - NCBI
UnigeneHs.461453 [ SRS ]    Hs.461453 [ NCBI ]     HS461453 [ spliceNest ]
Fast-db11784 (alternative variants)
Protein : pattern, domain, 3D structure
SwissProtQ12953 [ SRS]    Q12953 [ EXPASY ]     Q12953 [ INTERPRO ]
InterproIPR002198 DHase_sc/Rdtase_SDR [ SRS ]    IPR002198 DHase_sc/Rdtase_SDR [ EBI ]
InterproIPR016040 NAD(P)-bd [ SRS ]    IPR016040 NAD(P)-bd [ EBI ]
CluSTrQ12953
BlocksQ12953
PDBWWOX [ SRS ]    WWOX [ PdbSum ],   WWOX [ IMB ]   WWOX [ RSDB ]
HPRD05501
Protein Interaction databases
DIPQ12953
IntActQ12953
Polymorphism : SNP, mutations, diseases
OMIM133239;605131    [ map ]   
GENECLINICS133239;605131
SNPWWOX [dbSNP-NCBI]  
SNPNM_016373 [SNP-NCI]  
SNPNM_130791 [SNP-NCI]  
SNPNM_130844 [SNP-NCI]  
SNPWWOX [GeneSNPs - Utah]  WWOX] [HGBASE - SRS]
HAPMAPWWOX [HAPMAP]  
TICdbWWOX [Translocation breakpoints In Cancer]  
HGMDWWOX
General knowledge
Family BrowserWWOX [UCSC Family Browser]
SOURCENM_016373
SOURCENM_130791
SOURCENM_130844
SMDHs.461453
SAGEHs.461453
GObinding [Amigo]  binding
GOnucleus [Amigo]  nucleus
GOcytoplasm [Amigo]  cytoplasm
GOmitochondrion [Amigo]  mitochondrion
GOGolgi apparatus [Amigo]  Golgi apparatus
GOmetabolic process [Amigo]  metabolic process
GOsteroid metabolic process [Amigo]  steroid metabolic process
GOoxidoreductase activity [Amigo]  oxidoreductase activity
GOoxidoreductase activity [Amigo]  oxidoreductase activity
GOoxidoreductase activity [Amigo]  oxidoreductase activity
GOnegative regulation of cell cycle [Amigo]  negative regulation of cell cycle
GOprotein dimerization activity [Amigo]  protein dimerization activity
GOcoenzyme binding [Amigo]  coenzyme binding
GOoxidation reduction [Amigo]  oxidation reduction
PubGeneWWOX
TreeFamWWOX
CTD51741 [Comparative ToxicoGenomics Database]
Other databases
Probes
ProbeWWOX Related clones (RZPD - Berlin)
PubMed
PubMed49 Pubmed reference(s) in LocusLink

Bibliography

Common chromosomal fragile site FRA16D sequence: identification of the FOR gene spanning FRA16D and homozygous deletions and translocation breakpoints in cancer cells.
Ried K, Finnis M, Hobson L, Mangelsdorf M, Dayan S, Nancarrow JK, Woollatt E, Kremmidiotis G, Gardner A, Venter D, Baker E, Richards RI
Human molecular genetics. 2000 ; 9 (11) : 1651-1663.
PMID 10861292
 
WWOX, the FRA16D gene, behaves as a suppressor of tumor growth.
Bednarek AK, Keck-Waggoner CL, Daniel RL, Laflin KJ, Bergsagel PL, Kiguchi K, Brenner AJ, Aldaz CM
Cancer research. 2001 ; 61 (22) : 8068-8073.
PMID 11719429
 
WWOX: a candidate tumor suppressor gene involved in multiple tumor types.
Paige AJ, Taylor KJ, Taylor C, Hillier SG, Farrington S, Scott D, Porteous DJ, Smyth JF, Gabra H, Watson JE
Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (20) : 11417-11422.
PMID 11572989
 
Genetic alterations of the tumor suppressor gene WWOX in esophageal squamous cell carcinoma.
Kuroki T, Trapasso F, Shiraishi T, Alder H, Mimori K, Mori M, Croce CM
Cancer research. 2002 ; 62 (8) : 2258-2260.
PMID 11956080
 
WWOX, the common chromosomal fragile site, FRA16D, cancer gene.
Ludes-Meyers JH, Bednarek AK, Popescu NC, Bedford M, Aldaz CM
Cytogenetic and genome research. 2003 ; 100 (1-4) : 101-110.
PMID 14526170
 
WW domain containing oxidoreductase gene expression is altered in non-small cell lung cancer.
Yendamuri S, Kuroki T, Trapasso F, Henry AC, Dumon KR, Huebner K, Williams NN, Kaiser LR, Croce CM
Cancer research. 2003 ; 63 (4) : 878-881.
PMID 12591741
 
Loss of WWOX expression in gastric carcinoma.
Aqeilan RI, Kuroki T, Pekarsky Y, Albagha O, Trapasso F, Baffa R, Huebner K, Edmonds P, Croce CM
Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 ; 10 (9) : 3053-3058.
PMID 15131042
 
Physical and functional interactions between the Wwox tumor suppressor protein and the AP-2gamma transcription factor.
Aqeilan RI, Palamarchuk A, Weigel RJ, Herrero JJ, Pekarsky Y, Croce CM
Cancer research. 2004 ; 64 (22) : 8256-8261.
PMID 15548692
 
Functional association between Wwox tumor suppressor protein and p73, a p53 homolog.
Aqeilan RI, Pekarsky Y, Herrero JJ, Palamarchuk A, Letofsky J, Druck T, Trapasso F, Han SY, Melino G, Huebner K, Croce CM
Proceedings of the National Academy of Sciences of the United States of America. 2004 ; 101 (13) : 4401-4406.
PMID 15070730
 
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 (8) : 1605-1614.
PMID 15073846
 
The tumor suppressor gene WWOX at FRA16D is involved in pancreatic carcinogenesis.
Kuroki T, Yendamuri S, Trapasso F, Matsuyama A, Aqeilan RI, Alder H, Rattan S, Cesari R, Nolli ML, Williams NN, Mori M, Kanematsu T, Croce CM
Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 ; 10 (7) : 2459-2465.
PMID 15073125
 
WWOX binds the specific proline-rich ligand PPXY: identification of candidate interacting proteins.
Ludes-Meyers JH, Kil H, Bednarek AK, Drake J, Bedford MT, Aldaz CM
Oncogene. 2004 ; 23 (29) : 5049-5055.
PMID 15064722
 
Frequent downregulation and loss of WWOX gene expression in human hepatocellular carcinoma.
Park SW, Ludes-Meyers J, Zimonjic DB, Durkin ME, Popescu NC, Aldaz CM
British journal of cancer. 2004 ; 91 (4) : 753-759.
PMID 15266310
 
WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function.
Aqeilan RI, Donati V, Palamarchuk A, Trapasso F, Kaou M, Pekarsky Y, Sudol M, Croce CM
Cancer research. 2005 ; 65 (15) : 6764-6772.
PMID 16061658
 
WWOX gene restoration prevents lung cancer growth in vitro and in vivo.
Fabbri M, Iliopoulos D, Trapasso F, Aqeilan RI, Cimmino A, Zanesi N, Yendamuri S, Han SY, Amadori D, Huebner K, Croce CM
Proceedings of the National Academy of Sciences of the United States of America. 2005 ; 102 (43) : 15611-15616.
PMID 16223882
 
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
Pathology international. 2005 ; 55 (8) : 471-478.
PMID 15998374
 
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 (9) : 1625-1633.
PMID 15674328
 
Frequent loss of WWOX expression in breast cancer: correlation with estrogen receptor status.
Nunez MI, Ludes-Meyers J, Abba MC, Kil H, Abbey NW, Page RE, Sahin A, Klein-Szanto AJ, Aldaz CM
Breast cancer research and treatment. 2005 ; 89 (2) : 99-105.
PMID 15692750
 
Characterization of the linkage disequilibrium structure and identification of tagging-SNPs in five DNA repair genes.
Allen-Brady K, Camp NJ
BMC cancer. 2005 ; 5 : page 99.
PMID 16091150
 
Deletion and mutation of WWOX exons 6-8 in human non-small cell lung cancer.
Zhou Y, Xu Y, Zhang Z
Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban. 2005 ; 25 (2) : 162-165.
PMID 16116962
 
Physical association with WWOX suppresses c-Jun transcriptional activity.
Gaudio E, Palamarchuk A, Palumbo T, Trapasso F, Pekarsky Y, Croce CM, Aqeilan RI
Cancer research. 2006 ; 66 (24) : 11585-11589.
PMID 17178850
 
Roles of FHIT and WWOX fragile genes in cancer.
Iliopoulos D, Guler G, Han SY, Druck T, Ottey M, McCorkell KA, Huebner K
Cancer letters. 2006 ; 232 (1) : 27-36.
PMID 16225988
 
PKA-mediated protein phosphorylation regulates ezrin-WWOX interaction.
Jin C, Ge L, Ding X, Chen Y, Zhu H, Ward T, Wu F, Cao X, Wang Q, Yao X
Biochemical and biophysical research communications. 2006 ; 341 (3) : 784-791.
PMID 16438931
 
Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox.
Mahajan NP, Whang YE, Mohler JL, Earp HS
Cancer research. 2005 ; 65 (22) : 10514-10523.
PMID 16288044
 
WWOX protein expression in normal human tissues.
Nunez MI, Ludes-Meyers J, Aldaz CM
Journal of molecular histology. 2006 ; 37 (3-4) : 115-125.
PMID 16941225
 
Characterization of the tumor suppressor gene WWOX in primary human oral squamous cell carcinomas.
Pimenta FJ, Gomes DA, Perdigˆ£o PF, Barbosa AA, Romano-Silva MA, Gomez MV, Aldaz CM, De Marco L, Gomez RS
International journal of cancer. Journal international du cancer. 2006 ; 118 (5) : 1154-1158.
PMID 16152610
 
WWOX--the FRA16D cancer gene: expression correlation with breast cancer progression and prognosis.
P‰Çuciennik E, Kusi‰Ñska R, Potemski P, Kubiak R, Kordek R, Bednarek AK
European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2006 ; 32 (2) : 153-157.
PMID 16360296
 
A role for the WWOX gene in prostate cancer.
Qin HR, Iliopoulos D, Semba S, Fabbri M, Druck T, Volinia S, Croce CM, Morrison CD, Klein RD, Huebner K
Cancer research. 2006 ; 66 (13) : 6477-6481.
PMID 16818616
 
Targeted deletion of Wwox reveals a tumor suppressor function.
Aqeilan RI, Trapasso F, Hussain S, Costinean S, Marshall D, Pekarsky Y, Hagan JP, Zanesi N, Kaou M, Stein GS, Lian JB, Croce CM
Proceedings of the National Academy of Sciences of the United States of America. 2007 ; 104 (10) : 3949-3954.
PMID 17360458
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written04-2007Teresa Druck, Hoda Hagrass, Kay Huebner
BRT Rm. 940, 460 W. 12th Ave, Columbus, OH 43210.

Citation

This paper should be referenced as such :
Druck T, Hagrass H, Huebner K . WWOX (WW domain containing oxidoreductase). Atlas Genet Cytogenet Oncol Haematol. April 2007 .
URL : http://AtlasGeneticsOncology.org/Genes/WWOXID508ch16q23.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Mon Jul 14 17:51:53 2008


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