Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein.
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.
Kondo
Keiichi
K
Department of Adult Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Klco
Jeff
J
Nakamura
Eijiro
E
Lechpammer
Mirna
M
Kaelin
William G
WG
D000818:Animals; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003513:Cycloheximide / Q000494:pharmacology; D015536:Down-Regulation; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D051272:Glucose Transporter Type 1; D006801:Humans; D007124:Immunoenzyme Techniques; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008025:Ligases / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009154:Mutation; D010957:Plasmids; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012190:Retroviridae / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; D011500:Protein Synthesis Inhibitors; C495677:SLC2A1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D003513:Cycloheximide; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008025:Ligases; C497446:VHL protein, human