Mechanism of von Hippel-Lindau protein-mediated suppression of nuclear factor kappa B activity.

Biallelic inactivating mutations of the von Hippel-Lindau tumor suppressor gene (VHL) are a hallmark of clear cell renal cell carcinoma (CCRCC), the most common histologic subtype of RCC. Biallelic VHL loss results in accumulation of hypoxia-inducible factor alpha (HIFalpha). Restoring expression of the wild-type protein encoded by VHL (pVHL) in tumors with biallelic VHL inactivation (VHL(-)(/)(-)) suppresses tumorigenesis, and pVHL-mediated degradation of HIFalpha is necessary and sufficient for VHL-mediated tumor suppression. The downstream targets of HIFalpha that promote renal carcinogenesis have not been completely elucidated. Recently, VHL loss was shown to activate nuclear factor kappa B (NF-kappaB), a family of transcription factors that promotes tumor growth. Here we show that VHL loss drives NF-kappaB activation by resulting in HIFalpha accumulation, which induces expression of transforming growth factor alpha, with consequent activation of an epidermal growth factor receptor/phosphatidylinositol-3-OH kinase/protein kinase B (AKT)/IkappaB-kinase alpha/NF-kappaB signaling cascade. We also show that components of this signaling pathway promote the growth of VHL(-)(/)(-) tumor cells. Members of this pathway represent viable drug targets in VHL(-)(/)(-) tumors, such as those associated with CCRCC.