The von Hippel-Lindau tumor suppressor gene protects cells from UV-mediated apoptosis

The familial cancer syndrome, von Hlippel-Lindau (VHL) disease, characteriz ed by a predisposition to renal cell carcinoma and certain other tumor type s, is caused by mutational inactivation of the VHL tumor suppressor gene. L oss of VHL gene function is detected also in the vast majority of sporadic renal cell carcinomas. Previous reports have determined a protective role f or VHL in response to serum withdrawal and glucose deprivation, In this stu dy, the effect of UV irradiation on VHL-negative and VHL-positive renal car cinoma cells was examined, VHL-negative 786-O renal carcinoma cells underwe nt apoptosis following UV irradiation, In contrast, reintroduction of wild- type VHL expression protected 786-O cells from UV-mediated cell death, p53 and Bax levels were equivalent in VHL-negative and VHL-positive 786-O cells . Strikingly, cyclin-dependent kinase? inhibitors p21 and p27 underwent pro teasome-dependent degradation in VHL-negative 786-O cells following UV trea tment. However, p21 and p27 protein levels were stable in VHL-positive cell s. Also, levels of the anti-apoptotic proteins, Bcl-2 and Bcl-xL were eleva ted in VH L-positive cells, consistent with the protection from apoptotic s timuli, UV treatment led to increased S phase in VHL-negative, but not VHL- positive cells, Thus, following UV irradiation, diminution of p21 and p27 l evels resulted in a hyperproliferative state in VHL-negative cells, leading to apoptosis, These results suggest that loss of VHL function promotes apo ptosis and may provide selective pressure toward cells that are able to esc ape apoptosis, leading to tumorigenesis.