THE VON-HIPPEL-LINDAU TUMOR-SUPPRESSOR GENE IS REQUIRED FOR CELL-CYCLE EXIT UPON SERUM WITHDRAWAL

The inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene predisposes affected individuals to the human VHL cancer syndrome and is associated with sporadic renal cell carcinomas (RCC) and brain hema ngioblastomas, VHL-negative 786-0 RCC cells are tumorigenic in nude mi ce which is suppressed by the reintroduction of VHL. Remarkably, this occurs without affecting the growth rate and cell cycle profile of the se cells in culture, The 786-0 cell line, like many cancer cells, fail s to exit the cell cycle upon serum withdrawal, Here, it is shown that reintroduction of the wild-type VHL gene restores the ability of VHL- negative RCC cancer cells to exit the cell cycle and enter G(0)/quiesc ence in low serum, Both VHL-positive and VHL-negative RCC cells exit t he cell cycle by contact inhibition, The cyclin-dependent kinase inhib itor, p27, accumulates upon serum withdrawal, only in the presence of VHL, as a result of the stabilization of the protein, We propose that the loss of wild-type VHL gene results in a specific cellular defect i n serum-dependent growth control, which may initiate tumor formation, This is corrected by the reintroduction of wild-type VHL, implicating VHL as the first tumor suppressor involved in the regulation of cell c ycle exit, which is consistent with its gatekeeper function in the kid ney.