WWOX
Domain
The WW 1 domain mediates interaction with TP53, and probably TP73, TFAP2C, LITAF and WBP1.
Function
Putative oxidoreductase. Acts as a tumor suppressor and plays a role in apoptosis. Required for normal bone development (By similarity). May function synergistically with p53/TP53 to control genotoxic stress-induced cell death. Plays a role in TGFB1 signaling and TGFB1-mediated cell death. May also play a role in tumor necrosis factor (TNF)-mediated cell death. Inhibits Wnt signaling, probably by sequestering DVL2 in the cytoplasm.
Involvement in disease
Defects in WWOX may be involved in several cancer types. The gene spans the second most common chromosomal fragile site (FRA16D) which is frequently altered in cancers (PubMed:10861292). Alteration of the expression and expression of some isoforms is associated with cancers. However, it is still unclear if alteration of WWOX is directly implicated in cancerogenesis or if it corresponds to a secondary effect (PubMed:10861292, PubMed:11572989, PubMed:15073125, PubMed:15131042, PubMed:15266310).
Esophageal cancer
ESCR
A malignancy of the esophagus. The most common types are esophageal squamous cell carcinoma and adenocarcinoma. Cancer of the esophagus remains a devastating disease because it is usually not detected until it has progressed to an advanced incurable stage.
None
The disease may be caused by variants affecting the gene represented in this entry.
Spinocerebellar ataxia, autosomal recessive, 12
SCAR12
A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR12 is additionally characterized by onset of generalized seizures in infancy, and delayed psychomotor development with intellectual disability. Some patients may also show spasticity.
None
The disease is caused by variants affecting the gene represented in this entry.
Developmental and epileptic encephalopathy 28
DEE28
A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Phosphorylated upon genotoxic stress. Phosphorylation of Tyr-33 regulates interaction with TP53, TP73 and MAPK8. May also regulate proapoptotic activity. Phosphorylation by TNK2 is associated with polyubiquitination and degradation.
Ubiquitinated when phosphorylated by TNK2, leading to its degradation.
Sequence Similarities
Belongs to the short-chain dehydrogenases/reductases (SDR) family.
Tissue Specificity
Widely expressed. Strongly expressed in testis, prostate, and ovary. Overexpressed in cancer cell lines. Isoform 5 and isoform 6 may only be expressed in tumor cell lines.
Cellular localization
- Cytoplasm
- Nucleus
- Mitochondrion
- Golgi apparatus
- Lysosome
- Partially localizes to the mitochondria (PubMed:14695174). Translocates to the nucleus upon genotoxic stress or TNF stimulation (By similarity). Translocates to the nucleus in response to TGFB1 (PubMed:19366691). Isoform 5 and isoform 6 may localize in the nucleus. Localized to the lysosome probably upon binding to VOPP1 (PubMed:30285739).
Alternative names
FOR, SDR41C1, WOX1, WWOX, WW domain-containing oxidoreductase, Fragile site FRA16D oxidoreductase, Short chain dehydrogenase/reductase family 41C member 1