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

• Published in: Cancer cell 2002-04, Vol.1 (3), p.237-246
• Main Authors: Kondo, Keiichi, Klco, Jeff, Nakamura, Eijiro, Lechpammer, Mirna, Kaelin, William G
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cycloheximide - pharmacology; Down-Regulation; Genes, Tumor Suppressor - physiology; Glucose Transporter Type 1; Humans; Immunoenzyme Techniques; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Ligases - physiology; Mice; Mice, Nude; Monosaccharide Transport Proteins - metabolism; Mutation; Plasmids; Protein Synthesis Inhibitors - pharmacology; Retroviridae - genetics; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transfection; Tumor Cells, Cultured; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; Von Hippel-Lindau Tumor Suppressor Protein
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/S1535-6108(02)00043-0

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.