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Cancer Cell. 2002 Apr;1(3):237-46.

Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein.

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Department of Adult Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.


Inactivation of the von Hippel-Lindau tumor suppressor gene is linked to the development of hereditary (VHL Disease-associated) and sporadic clear cell carcinoma of the kidney. The VHL gene product, pVHL, targets the heterodimeric transcription factor HIF for polyubiquitination, and restoration of pVHL function in VHL(-/-) renal carcinoma cells suppresses their ability to form tumors in nude mice. Here we show that tumor suppression by pVHL can be overridden by a HIF variant that escapes pVHL control. These studies prove that HIF is a critical downstream target of pVHL and establish that activation of HIF target genes can promote tumorigenesis in vivo.

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