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

Cancer Cell. 2002 Apr;1(3):237-46. doi: 10.1016/s1535-6108(02)00043-0.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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

Substances

  • Glucose Transporter Type 1
  • Monosaccharide Transport Proteins
  • Protein Synthesis Inhibitors
  • SLC2A1 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Cycloheximide
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Ligases
  • VHL protein, human