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Molecular and Cellular Biology, August 2007, p. 5381-5392, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.00282-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Hypoxia-Inducible Factor Linked to Differential Kidney Cancer Risk Seen with Type 2A and Type 2B VHL Mutations ^,

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115,¹ Howard Hughes Medical Institute, Chevy Chase, Maryland 20815,² Department of Urology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115,³ Rosetta Inpharmatics LLC, Seattle, Washington 98109⁴

Received 15 February 2007/ Returned for modification 1 April 2007/ Accepted 17 May 2007

Clear cell carcinoma of the kidney is a major cause of mortality in patients with von Hippel-Lindau (VHL) disease, which is caused by germ line mutations that inactivate the VHL tumor suppressor gene. Biallelic VHL inactivation, due to mutations or hypermethylation, is also common in sporadic clear cell renal carcinomas. The VHL gene product, pVHL, is part of a ubiquitin ligase complex that targets the alpha subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF) for destruction under well-oxygenated conditions. All VHL mutations linked to classical VHL disease compromise this pVHL function although some missense mutations result in a low risk of kidney cancer (type 2A VHL disease) while others result in a high risk (type 2B VHL disease). We found that type 2A mutants were less defective than type 2B mutants when reintroduced into VHL^–/– renal carcinoma cells with respect to HIF regulation. A stabilized version of HIF2 promoted tumor growth by VHL^–/– cells engineered to produce type 2A mutants, while knock-down of HIF2 in cells producing type 2B mutants had the opposite effect. Therefore, quantitative differences with respect to HIF deregulation are sufficient to account for the differential risks of kidney cancer linked to VHL mutations.

Published ahead of print on 25 May 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

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