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Description

UV radiation resistance-associated gene protein (UniProt: Q9P2Y5, also known as p63) is encoded by UVRAG gene (Gene ID: 7405) in human. UVRAG is a key autophagic tumor suppressor that is shown to be mutated in several common human cancers. UVRAG as a critical regulator of intracellular membrane trafficking, autophagy, and chromosomal stability. It contains four functional domains, a proline-rich domain, a lipid-binding C2 domain, a Beclin1-binding coiled-coil domain (CCD) and a C-terminal domain. UVRAG is truncated by a frameshift (FS) mutation in colorectal cancer cells. UVRAG-FS is shown to abolish the normal functions of UVRAG, including autophagy, in a dominant-negative manner. Ectopic expression of UVRAG-FS in both embryonic stem cells and cancer cells results in extensive centrosome amplification and concomitant aneuploidy. UVRAG-FS can also enhance the sensitivity to anticancer agents, such as 5-fluorouracil (5-FU), oxaliplatin, and irinotecan. Expression of UVRAG-FS is reported to trigger colorectal cancer metastatic spread through Rac1 activation and epithelial-to-mesenchymal transition, independently of autophagy. UVRAG-FS metastatic tumors display higher levels of p62 than primary tumors, which indicates suppressed autophagy. (Ref.: He, S., et al. (2015). Nat Commun. 6: 7839).