Tumor suppressor protein VHL is induced at high cell density and mediates contact inhibition of cell growth

In spite of the general recognition of von Hippel-Lindau (VHL) as a tumor s uppressor gene, the physiological and pathological importance of VHL protei n in cell growth regulation and tumorigenesis remains unclear, Here we show that in normal human renal proximal tubule epithelial cells (RPTEC), the s teady-state amount of VHL protein is strictly regulated by cell density. Th e cellular VHL content is more than 100-fold higher in dense cultures than in sparse cultures, The increase in VHL protein at high cell density was al so observed for NIH3T3 fibroblasts, suggesting the generality of the phenom enon. The growth rates of renal cell carcinoma cells lacking an intact VHL gene and their derivatives with wild-type or mutant VHL expression vector d o not differ significantly when they are growing in log-phase. Importantly, however, there is a difference when they reach confluency: cells lacking w ild-type VHL grew continuously, while cells expressing exogenous VHL protei n showed relatively limited cell growth. Using an ecdysone-inducible VHL ex pressing cell line, we also show that the growth inhibition at high cell de nsity can be released by attenuating the VHL expression, Taken together, we propose that VHL protein functions as a growth suppressor at high cell den sity, and this might be the basis of the tumor suppressor function of VHL.