title: Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein.
abstract: 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.
authors.affiliation: Department of Adult Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kondo
authors.forename: Jeff
authors.initials: J
authors.lastname: Klco
authors.forename: Eijiro
authors.initials: E
authors.lastname: Nakamura
authors.forename: Mirna
authors.initials: M
authors.lastname: Lechpammer
authors.forename: William G
authors.initials: WG
authors.lastname: Kaelin
mesh_terms: 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
chemical_list: 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