WWOX (WW domain containing oxidoreductase)

2007-04-01   Teresa Druck , Hoda Hagrass , Kay Huebner 

BRT Rm. 940, 460 W. 12th Ave, Columbus, OH 43210





WWOX is comprised of 9 coding exons in a region of approximately one million base pairs that includes the common fragile site FRA16D.


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.


None reported.


Atlas Image
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.


WWOX is a 414 amino acid protein that contains two WW domains and a short-chain dehydrogenase/reductase (SDR) domain.


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.


Cytoplasm, mitochondria.


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.



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 name
Breast cancer, esophageal and non-small cell lung cancer.
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.
In a sampling of 132 breast cancer tissues, high level WWOX expression was associated with better disease free survival.


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


Pubmed IDLast YearTitleAuthors
160911502005Characterization of the linkage disequilibrium structure and identification of tagging-SNPs in five DNA repair genes.Allen-Brady K et al
173604582007Targeted deletion of Wwox reveals a tumor suppressor function.Aqeilan RI et al
117194292001WWOX, the FRA16D gene, behaves as a suppressor of tumor growth.Bednarek AK et al
162238822005WWOX gene restoration prevents lung cancer growth in vitro and in vivo.Fabbri M et al
171788502006Physical association with WWOX suppresses c-Jun transcriptional activity.Gaudio E et al
159983742005Concordant loss of fragile gene expression early in breast cancer development.Guler G et al
162259882006Roles of FHIT and WWOX fragile genes in cancer.Iliopoulos D et al
164389312006PKA-mediated protein phosphorylation regulates ezrin-WWOX interaction.Jin C et al
119560802002Genetic alterations of the tumor suppressor gene WWOX in esophageal squamous cell carcinoma.Kuroki T et al
150731252004The tumor suppressor gene WWOX at FRA16D is involved in pancreatic carcinogenesis.Kuroki T et al
150647222004WWOX binds the specific proline-rich ligand PPXY: identification of candidate interacting proteins.Ludes-Meyers JH et al
162880442005Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox.Mahajan NP et al
169412252006WWOX protein expression in normal human tissues.Nunez MI et al
115729892001WWOX: a candidate tumor suppressor gene involved in multiple tumor types.Paige AJ et al
152663102004Frequent downregulation and loss of WWOX gene expression in human hepatocellular carcinoma.Park SW et al
161526102006Characterization of the tumor suppressor gene WWOX in primary human oral squamous cell carcinomas.Pimenta FJ et al
163602962006WWOX--the FRA16D cancer gene: expression correlation with breast cancer progression and prognosis.Płuciennik E et al
168186162006A role for the WWOX gene in prostate cancer.Qin HR et al
108612922000Common chromosomal fragile site FRA16D sequence: identification of the FOR gene spanning FRA16D and homozygous deletions and translocation breakpoints in cancer cells.Ried K et al
125917412003WW domain containing oxidoreductase gene expression is altered in non-small cell lung cancer.Yendamuri S et al
161169622005Deletion and mutation of WWOX exons 6-8 in human non-small cell lung cancer.Zhou Y et al

Other Information

Locus ID:

NCBI: 51741
MIM: 605131
HGNC: 12799
Ensembl: ENSG00000186153


dbSNP: 51741
ClinVar: 51741
TCGA: ENSG00000186153


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Signal TransductionREACTOMER-HSA-162582
Signaling by ERBB4REACTOMER-HSA-1236394
Nuclear signaling by ERBB4REACTOMER-HSA-1251985
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factorsREACTOMER-HSA-8864260
Activation of the TFAP2 (AP-2) family of transcription factorsREACTOMER-HSA-8866907
Negative regulation of activity of TFAP2 (AP-2) family transcription factorsREACTOMER-HSA-8866904

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
195843462009Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data.93
150707302004Functional association between Wwox tumor suppressor protein and p73, a p53 homolog.92
162880442005Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox.89
160616582005WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function.84
117194292001WWOX, the FRA16D gene, behaves as a suppressor of tumor growth.80
155486922004Physical and functional interactions between the Wwox tumor suppressor protein and the AP-2gamma transcription factor.65
156743282005Fragile genes as biomarkers: epigenetic control of WWOX and FHIT in lung, breast and bladder cancer.62
162197682005WOX1 is essential for tumor necrosis factor-, UV light-, staurosporine-, and p53-mediated cell death, and its tyrosine 33-phosphorylated form binds and stabilizes serine 46-phosphorylated p53.62
184876092008The WWOX tumor suppressor is essential for postnatal survival and normal bone metabolism.62
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62


Teresa Druck ; Hoda Hagrass ; Kay Huebner

WWOX (WW domain containing oxidoreductase)

Atlas Genet Cytogenet Oncol Haematol. 2007-04-01

Online version: http://atlasgeneticsoncology.org/gene/508/wwox-(ww-domain-containing-oxidoreductase)