Inhibition of insulin-like growth factor-I-mediated cell signaling by the von Hippel-Lindau gene product in renal cancer

Insulin-like growth factor-I (IGF-I)-mediated signaling is thought to be in volved in the regulation of multiple cellular functions in different tumors including renal cell carcinoma (RCC). Blocking IGF-I signaling by any of t he several strategies abolishes or delays the progression of a variety of t umors in animal models. Herein, me demonstrate that in RCC cell lines, IGF- I-mediated signaling is found to be inhibited in the presence of wild type von Hippel-Lindau (VHL) tumor suppresser gene. Moreover, molecular modeling and biochemical approaches have revealed that beta-domain of the VHL gene product by interacting directly with protein kinase C delta inhibits its as sociation with IGF-IR for downstream signaling. We also demonstrated that R CC has IGF-I-mediated invasive activity where protein kinase C delta is an important downstream molecule, and this invasiveness can be blocked by wild type VHL. These experiments thus elucidate a novel tumor suppresser functi on of VHL with its unique kinase inhibitory domain.