The VHL tumor suppressor and HIF: insights from genetic studies in mice

Cell Death Differ. 2008 Apr;15(4):650-9. doi: 10.1038/sj.cdd.4402313. Epub 2008 Jan 25.


The von Hippel-Lindau tumor suppressor gene product, pVHL, functions as the substrate recognition component of an E3-ubiquitin ligase, which targets the oxygen-sensitive alpha-subunit of hypoxia-inducible factor (HIF) for rapid proteasomal degradation under normoxic conditions and as such plays a central role in molecular oxygen sensing. Mutations in pVHL can be found in familial and sporadic clear cell carcinomas of the kidney, hemangioblastomas of the retina and central nervous system, and pheochromocytomas, underscoring its gatekeeper function in the pathogenesis of these tumors. Tissue-specific gene targeting of VHL in mice has demonstrated that efficient execution of pVHL-mediated HIF proteolysis under normoxia is fundamentally important for survival, proliferation, differentiation and normal physiology of many cell types, and has provided novel insights into the biological function of individual HIF transcription factors. In this review, we discuss the role of HIF in the development of the VHL phenotype.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism
  • Gene Expression Regulation, Developmental
  • Gene Expression Regulation, Neoplastic
  • Genotype
  • Germ-Line Mutation
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism
  • Mice
  • Mice, Knockout
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Phenotype
  • Ubiquitin-Protein Ligases / metabolism
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism*
  • von Hippel-Lindau Disease / genetics
  • von Hippel-Lindau Disease / metabolism*
  • von Hippel-Lindau Disease / pathology


  • Basic Helix-Loop-Helix Transcription Factors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • endothelial PAS domain-containing protein 1
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, mouse