Mechanism of von Hippel-Lindau Protein-Mediated Suppression of Nuclear Factor kappa B Activity

Abstract

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