WWOX (WW domain containing oxidoreductase)
2007-04-01 Teresa Druck , Hoda Hagrass , Kay Huebner AffiliationBRT Rm. 940, 460 W. 12th Ave, Columbus, OH 43210
Identity
HGNC
LOCATION
16q23.1
LOCUSID
ALIAS
D16S432E,DEE28,EIEE28,FOR,FRA16D,HHCMA56,PRO0128,SCAR12,SDR41C1,WOX1
FUSION GENES
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.
Proteins
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 name
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.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 16091150 | 2005 | Characterization of the linkage disequilibrium structure and identification of tagging-SNPs in five DNA repair genes. | Allen-Brady K et al |
| 17360458 | 2007 | Targeted deletion of Wwox reveals a tumor suppressor function. | Aqeilan RI et al |
| 11719429 | 2001 | WWOX, the FRA16D gene, behaves as a suppressor of tumor growth. | Bednarek AK et al |
| 16223882 | 2005 | WWOX gene restoration prevents lung cancer growth in vitro and in vivo. | Fabbri M et al |
| 17178850 | 2006 | Physical association with WWOX suppresses c-Jun transcriptional activity. | Gaudio E et al |
| 15998374 | 2005 | Concordant loss of fragile gene expression early in breast cancer development. | Guler G et al |
| 16225988 | 2006 | Roles of FHIT and WWOX fragile genes in cancer. | Iliopoulos D et al |
| 16438931 | 2006 | PKA-mediated protein phosphorylation regulates ezrin-WWOX interaction. | Jin C et al |
| 11956080 | 2002 | Genetic alterations of the tumor suppressor gene WWOX in esophageal squamous cell carcinoma. | Kuroki T et al |
| 15073125 | 2004 | The tumor suppressor gene WWOX at FRA16D is involved in pancreatic carcinogenesis. | Kuroki T et al |
| 15064722 | 2004 | WWOX binds the specific proline-rich ligand PPXY: identification of candidate interacting proteins. | Ludes-Meyers JH et al |
| 16288044 | 2005 | Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox. | Mahajan NP et al |
| 16941225 | 2006 | WWOX protein expression in normal human tissues. | Nunez MI et al |
| 11572989 | 2001 | WWOX: a candidate tumor suppressor gene involved in multiple tumor types. | Paige AJ et al |
| 15266310 | 2004 | Frequent downregulation and loss of WWOX gene expression in human hepatocellular carcinoma. | Park SW et al |
| 16152610 | 2006 | Characterization of the tumor suppressor gene WWOX in primary human oral squamous cell carcinomas. | Pimenta FJ et al |
| 16360296 | 2006 | WWOX--the FRA16D cancer gene: expression correlation with breast cancer progression and prognosis. | Płuciennik E et al |
| 16818616 | 2006 | A role for the WWOX gene in prostate cancer. | Qin HR et al |
| 10861292 | 2000 | Common 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 |
| 12591741 | 2003 | WW domain containing oxidoreductase gene expression is altered in non-small cell lung cancer. | Yendamuri S et al |
| 16116962 | 2005 | Deletion 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
Variants:
dbSNP: 51741
ClinVar: 51741
TCGA: ENSG00000186153
COSMIC: WWOX
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37615513 | 2024 | Remote modulation of WWOX by an intronic variant associated with survival of Chinese gastric cancer patients. | 0 |
| 37615513 | 2024 | Remote modulation of WWOX by an intronic variant associated with survival of Chinese gastric cancer patients. | 0 |
| 37248434 | 2023 | WWOX binds MERIT40 and modulates its function in homologous recombination, implications in breast cancer. | 1 |
| 37324196 | 2023 | WWOX Polymorphisms as Predictors of the Biochemical Recurrence of Localized Prostate Cancer after Radical Prostatectomy. | 0 |
| 37897534 | 2023 | Loss of fragile WWOX gene leads to senescence escape and genome instability. | 1 |
| 37974179 | 2023 | Identification of compound heterozygous deletion of the WWOX gene in WOREE syndrome. | 0 |
| 38203337 | 2023 | Mechanistic Investigation of WWOX Function in NF-kB-Induced Skin Inflammation in Psoriasis. | 1 |
| 37248434 | 2023 | WWOX binds MERIT40 and modulates its function in homologous recombination, implications in breast cancer. | 1 |
| 37324196 | 2023 | WWOX Polymorphisms as Predictors of the Biochemical Recurrence of Localized Prostate Cancer after Radical Prostatectomy. | 0 |
| 37897534 | 2023 | Loss of fragile WWOX gene leads to senescence escape and genome instability. | 1 |
| 37974179 | 2023 | Identification of compound heterozygous deletion of the WWOX gene in WOREE syndrome. | 0 |
| 38203337 | 2023 | Mechanistic Investigation of WWOX Function in NF-kB-Induced Skin Inflammation in Psoriasis. | 1 |
| 33629514 | 2022 | Expression of WW domain-containing oxidoreductase and its clinical implication in endometrial adenocarcinoma patients with metabolic syndrome. | 0 |
| 34852950 | 2022 | Association between WWOX/MAF variants and dementia-related neuropathologic endophenotypes. | 5 |
| 35290621 | 2022 | TGFα-EGFR pathway in breast carcinogenesis, association with WWOX expression and estrogen activation. | 1 |
Citation
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
