POSTTRANSCRIPTIONAL REGULATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR MESSENGER-RNA BY THE PRODUCT OF THE VHL TUMOR-SUPPRESSOR GENE

The VHL tumor suppressor gene is inactivated in patients with von Hipp el-Lindau disease and in most sporadic clear cell renal carcinomas. Al though VHL protein function remains unclear, VHL does interact with th e elongin BC subunits in vivo and regulates RNA polymerase II elongati on activity in vitro by inhibiting formation of the elongin ABC comple x, Expression of wild-type VHL in renal carcinoma cells with inactivat ed endogenous VHL resulted in unaltered in vitro cell growth and decre ased vascular endothelial growth factor (VEGF) mRNA expression and res ponsiveness to serum deprivation. VEGF is highly expressed in many tum ors, including VHL-associated and sporadic renal carcinomas, and it st imulates neoangiogenesis in growing solid tumors. Despite 5-fold diffe rences in VEGF mRNA levels, VHL overexpression did not affect VEGF tra nscription initiation or elongation as would have been suggested by VH L-elongin association. These results suggest that VHL regulates VEGF e xpression at a post-transcriptional level and that VHL inactivation in target cells causes a loss of VEGF suppression, leading to formation of a vascular stroma.