Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

WWOX (WW domain containing oxidoreductase)

Identity

Other namesFOR
murine name WOX1
HGNC (Hugo) WWOX
LocusID (NCBI) 51741
Location 16q23.1
Location_base_pair Starts at 78133310 and ends at 79246564 bp from pter ( according to hg19-Feb_2009)  [Mapping]

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
HGNC (Hugo)WWOX   12799
Cards
AtlasWWOXID508ch16q23
Entrez_Gene (NCBI)WWOX  51741  WW domain containing oxidoreductase
GeneCards (Weizmann)WWOX
Ensembl (Hinxton)ENSG00000186153 [Gene_View]  chr16:78133310-79246564 [Contig_View]  WWOX [Vega]
ICGC DataPortalENSG00000186153
cBioPortalWWOX
AceView (NCBI)WWOX
Genatlas (Paris)WWOX
WikiGenes51741
SOURCE (Princeton)NM_001291997 NM_016373 NM_018560 NM_130788 NM_130790 NM_130791 NM_130792 NM_130844
Genomic and cartography
GoldenPath (UCSC)WWOX  -  16q23.1   chr16:78133310-79246564 +  16q23.3-q24.1   [Description]    (hg19-Feb_2009)
EnsemblWWOX - 16q23.3-q24.1 [CytoView]
Mapping of homologs : NCBIWWOX [Mapview]
OMIM605131   
Gene and transcription
Genbank (Entrez)AF187015 AF211943 AF227526 AF227527 AF227528
RefSeq transcript (Entrez)NM_001291997 NM_016373 NM_018560 NM_130788 NM_130790 NM_130791 NM_130792 NM_130844
RefSeq genomic (Entrez)AC_000148 NC_000016 NC_018927 NG_011698 NT_010498 NW_001838328 NW_004929402
Consensus coding sequences : CCDS (NCBI)WWOX
Cluster EST : UnigeneHs.461453 [ NCBI ]
CGAP (NCI)Hs.461453
Alternative Splicing : Fast-db (Paris)GSHG0011372
Alternative Splicing GalleryENSG00000186153
Gene ExpressionWWOX [ NCBI-GEO ]     WWOX [ SEEK ]   WWOX [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9NZC7 (Uniprot)
NextProtQ9NZC7  [Medical]
With graphics : InterProQ9NZC7
Splice isoforms : SwissVarQ9NZC7 (Swissvar)
Catalytic activity : Enzyme1.1.1.- [ Enzyme-Expasy ]   1.1.1.-1.1.1.- [ IntEnz-EBI ]   1.1.1.- [ BRENDA ]   1.1.1.- [ KEGG ]   
Domaine pattern : Prosite (Expaxy)WW_DOMAIN_1 (PS01159)    WW_DOMAIN_2 (PS50020)   
Domains : Interpro (EBI)DH_sc/Rdtase_SDR [organisation]   Glc/ribitol_DH [organisation]   NAD(P)-bd_dom [organisation]   WW_dom [organisation]  
Related proteins : CluSTrQ9NZC7
Domain families : Pfam (Sanger)adh_short (PF00106)    WW (PF00397)   
Domain families : Pfam (NCBI)pfam00106    pfam00397   
Domain families : Smart (EMBL)WW (SM00456)  
DMDM Disease mutations51741
Blocks (Seattle)Q9NZC7
PDB (SRS)1WMV   
PDB (PDBSum)1WMV   
PDB (IMB)1WMV   
PDB (RSDB)1WMV   
Human Protein AtlasENSG00000186153 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ9NZC7
HPRD05501
IPIIPI00299802   IPI00107869   IPI00099822   IPI00107757   IPI00030484   IPI00045224   IPI00550494   IPI01018931   IPI00382752   IPI01009530   
Protein Interaction databases
DIP (DOE-UCLA)Q9NZC7
IntAct (EBI)Q9NZC7
FunCoupENSG00000186153
BioGRIDWWOX
InParanoidQ9NZC7
Interologous Interaction database Q9NZC7
IntegromeDBWWOX
STRING (EMBL)WWOX
Ontologies - Pathways
Ontology : AmiGOosteoblast differentiation  protein binding  nucleus  cytoplasm  cytoplasm  mitochondrion  Golgi apparatus  cytosol  cytosol  plasma membrane  microvillus  steroid metabolic process  Wnt signaling pathway  oxidoreductase activity  oxidoreductase activity  enzyme binding  negative regulation of Wnt signaling pathway  positive regulation of transcription from RNA polymerase II promoter  protein dimerization activity  cofactor binding  skeletal system morphogenesis  coenzyme binding  oxidation-reduction process  cellular response to transforming growth factor beta stimulus  intrinsic apoptotic signaling pathway by p53 class mediator  extrinsic apoptotic signaling pathway  positive regulation of extrinsic apoptotic signaling pathway  positive regulation of extrinsic apoptotic signaling pathway in absence of ligand  
Ontology : EGO-EBIosteoblast differentiation  protein binding  nucleus  cytoplasm  cytoplasm  mitochondrion  Golgi apparatus  cytosol  cytosol  plasma membrane  microvillus  steroid metabolic process  Wnt signaling pathway  oxidoreductase activity  oxidoreductase activity  enzyme binding  negative regulation of Wnt signaling pathway  positive regulation of transcription from RNA polymerase II promoter  protein dimerization activity  cofactor binding  skeletal system morphogenesis  coenzyme binding  oxidation-reduction process  cellular response to transforming growth factor beta stimulus  intrinsic apoptotic signaling pathway by p53 class mediator  extrinsic apoptotic signaling pathway  positive regulation of extrinsic apoptotic signaling pathway  positive regulation of extrinsic apoptotic signaling pathway in absence of ligand  
Protein Interaction DatabaseWWOX
Wikipedia pathwaysWWOX
Gene fusion - rearrangments
Rearrangement : TICdb- [-]  -  WWOX [15q15.1]
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)WWOX
snp3D : Map Gene to Disease51741
SNP (GeneSNP Utah)WWOX
SNP : HGBaseWWOX
Genetic variants : HAPMAPWWOX
Exome VariantWWOX
1000_GenomesWWOX 
ICGC programENSG00000186153 
Somatic Mutations in Cancer : COSMICWWOX 
CONAN: Copy Number AnalysisWWOX 
Mutations and Diseases : HGMDWWOX
Mutations and Diseases : intOGenWWOX
Genomic VariantsWWOX  WWOX [DGVbeta]
dbVarWWOX
ClinVarWWOX
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM605131   
MedgenWWOX
GENETestsWWOX
Disease Genetic AssociationWWOX
Huge Navigator WWOX [HugePedia]  WWOX [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneWWOX
Homology/Alignments : Family Browser (UCSC)WWOX
Phylogenetic Trees/Animal Genes : TreeFamWWOX
Chemical/Protein Interactions : CTD51741
Chemical/Pharm GKB GenePA37398
Clinical trialWWOX
Cancer Resource (Charite)ENSG00000186153
Other databases
Probes
Litterature
PubMed163 Pubmed reference(s) in Entrez
CoreMineWWOX
iHOPWWOX
OncoSearchWWOX

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

Search in all EBI   NCBI

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
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/WWOXID508ch16q23.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Tue Sep 23 18:59:21 CEST 2014

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.