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 (HIF alpha). 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 HIF alpha is necessary and sufficient for VHL-mediated tumor suppression. The downstream targets of HIF alpha that promote renal carcinogenesis have not been completely elucidated. Recently, VHL loss was shown to activate nuclear factor kappa B (NF-kappa B), a family of transcription factors that promotes tumor growth. Here we show that VHL loss drives NF-kappa B activation by resulting in HIF alpha 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)/I kappa B-kinase alpha/NF-kappa B 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.