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The von Hippel-Lindau tumor suppressor gene protects cells from UV-mediated apoptosis
A R Schoenfeld1, T Parris, A Eisenberger
1Department of Microbiology and Immunology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Abstract:
The familial cancer syndrome, von Hippel-Lindau (VHL) disease, characterized by a predisposition to renal cell carcinoma and certain other tumor types, is caused by mutational inactivation of the VHL tumor suppressor gene. Loss of VHL gene function is detected also in the vast majority of sporadic renal cell carcinomas. Previous reports have determined a protective role for VHL in response to serum withdrawal and glucose deprivation. In this study, the effect of UV irradiation on VHL-negative and VHL-positive renal carcinoma cells was examined. VHL-negative 786-O renal carcinoma cells underwent 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 proteasome-dependent degradation in VHL-negative 786-O cells following UV treatment. However, p21 and p27 protein levels were stable in VHL-positive cells. Also, levels of the anti-apoptotic proteins, Bcl-2 and Bcl-xL were elevated in VHL-positive cells, consistent with the protection from apoptotic stimuli. UV treatment led to increased S phase in VHL-negative, but not VHL-positive cells. Thus, following UV irradiation, diminution of p21 and p27 levels resulted in a hyperproliferative state in VHL-negative cells, leading to apoptosis. These results suggest that loss of VHL function promotes apoptosis and may provide selective pressure toward cells that are able to escape apoptosis, leading to tumorigenesis.
Insights
Loss of the von Hippel-Lindau (VHL) gene in renal cells causes UV-induced apoptosis by degrading cell cycle inhibitors. Restoring VHL function protects cells from UV damage and promotes survival.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Von Hippel-Lindau (VHL) disease is a familial cancer syndrome linked to VHL tumor suppressor gene inactivation.
- VHL gene loss is common in sporadic renal cell carcinoma (RCC).
- VHL protein is known to protect cells against serum withdrawal and glucose deprivation.
Purpose of the Study:
- To investigate the effect of UV irradiation on renal carcinoma cells with and without VHL gene function.
- To elucidate the molecular mechanisms underlying VHL's role in cellular response to UV damage.
Main Methods:
- Comparison of UV irradiation effects on VHL-negative (786-O) and VHL-positive (reconstituted) renal carcinoma cells.
- Analysis of apoptosis markers, cell cycle regulators (p53, Bax, p21, p27), and anti-apoptotic proteins (Bcl-2, Bcl-xL).
- Assessment of cell cycle progression (S phase) and protein degradation pathways (proteasome).
Main Results:
- VHL-negative cells underwent apoptosis after UV irradiation, while VHL-positive cells were protected.
- UV treatment caused proteasome-dependent degradation of p21 and p27 in VHL-negative cells, but not in VHL-positive cells.
- VHL-positive cells showed elevated anti-apoptotic proteins (Bcl-2, Bcl-xL) and stable p21/p27 levels, preventing UV-induced apoptosis and hyperproliferation.
Conclusions:
- Loss of VHL function promotes UV-induced apoptosis in renal carcinoma cells.
- The degradation of p21 and p27 in VHL-deficient cells leads to a hyperproliferative state, ultimately resulting in apoptosis.
- These findings suggest that VHL loss creates selective pressure favoring the survival of cells that can evade apoptosis, contributing to tumorigenesis.