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Molecular and Cellular Biology, September 2005, p. 7546-7556, Vol. 25, No. 17
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.17.7546-7556.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Jiabin An1 and Matthew B. Rettig1,2*

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{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.

* Corresponding author. Mailing address: VA Greater Los Angeles Healthcare System—West Los Angeles, 11301 Wilshire Blvd., Building 304, Room E1-113, Los Angeles, CA 90073. Phone: (310) 268-3622. Fax: (310) 268-4567. E-mail: matthew.rettig{at}med.va.gov.

Molecular and Cellular Biology, September 2005, p. 7546-7556, Vol. 25, No. 17
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.17.7546-7556.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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