THE VON-HIPPEL-LINDAU GENE-PRODUCT INHIBITS VASCULAR-PERMEABILITY FACTOR VASCULAR ENDOTHELIAL GROWTH-FACTOR EXPRESSION IN RENAL-CELL CARCINOMA BY BLOCKING PROTEIN-KINASE-C PATHWAYS

Mutation or loss of function of the von Hippel-Lindau (VHL) tumor supp ressor gene is regularly found in sporadic renal cell carcinomas (RCC) , well vascularized malignant tumors that characteristically overexpre ss vascular permeability factor/vascular endothelial growth factor (VP F/VEGF). The wild-type VHL (wt VHL) gene product acts to suppress VPF/ VEGF expression, which is overexpressed when wt-VHL is inactive. The p resent study investigated the pathways by which VHL regulates VPF/VEGF expression, We found that inhibition of protein kinase C (PKC) repres ses VPF/VEGF expression in RCC cells that regularly overexpress VPF/VE GF. The wt-VHL expressed by stably transfected RCC cells forms cytopla smic complexes with two specific PKC isoforms, xi and delta, and preve nts their translocation to the cell membrane where they otherwise woul d engage in signaling steps that lead to VPF/VEGF overexpression. Othe r experiments implicated mitogen-activated protein kinase (MAPK) phosp horylation as a downstream step in PKC regulation of VPF/VEGF expressi on. Taken together, these data demonstrate that wt-VHL, by neutralizin g PKC isoforms xi and delta and thereby inhibiting MAPK activation, pl ays an important role in preventing aberrant VPF/VEGF overexpression a nd the angiogenesis that results from such overexpression.