The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity.

摘要: The von Hippel-Lindau tumor suppressor gene (VHL) has a critical role in the pathogenesis of clear-cell renal cell carcinoma (RCC), as VHL mutations have been found both disease-associated and sporadic RCCs. Recent studies suggest that vascular endothelial growth factor (VEGF) mRNA is upregulated RCC- tumors. We therefore assessed effect product on VEGF expression. promoter-luciferase constructs were transiently cotransfected with wild-type (wt-VHL) vector several lines, including 293 embryonic kidney RCC lines. wt-VHL protein inhibited promoter activity dose-dependent manner up to 5- 10-fold. Deletion analysis defined 144-bp region necessary for repression. This VHL-responsive element GC rich specifically binds transcription Sp1 crude nuclear extracts. In Drosophila cells, represses Sp1-mediated activation but not basal promoter. next demonstrated coimmunoprecipitates part same complex and, by using glutathione-S-transferase-VHL fusion purified Sp1, directly interact. Furthermore, endogenous levels suppressed permanent lines expressing wt-VHL, run-on indicated regulation occurs at least partly transcriptional level. These observations support new mechanism VHL-mediated repression via direct inhibitory action loss inhibition may be important disease RCC.