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

Division of Hematology/Oncology, Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System— West Los Angeles, Los Angeles, California 90073,¹ Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095²

Received 24 March 2005/ Returned for modification 26 April 2005/ Accepted 17 June 2005

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

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