HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing

Science. 2001 Apr 20;292(5516):464-8. doi: 10.1126/science.1059817. Epub 2001 Apr 5.

Abstract

HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). We found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and Fe(2+), this protein modification may play a key role in mammalian oxygen sensing.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Hypoxia
  • Cell Line
  • Cobalt / pharmacology
  • Deferoxamine / pharmacology
  • Humans
  • Hydroxylation
  • Hydroxyproline / metabolism*
  • Ligases*
  • Mass Spectrometry
  • Mice
  • Molecular Sequence Data
  • Oxygen / physiology*
  • Protein Structure, Tertiary
  • Proteins / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Trans-Activators / chemistry
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins*
  • Ubiquitin-Protein Ligases*
  • Ubiquitins / metabolism
  • Von Hippel-Lindau Tumor Suppressor Protein

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Proteins
  • Recombinant Fusion Proteins
  • Trans-Activators
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Ubiquitins
  • endothelial PAS domain-containing protein 1
  • Cobalt
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Ligases
  • VHL protein, human
  • cobaltous chloride
  • Deferoxamine
  • Hydroxyproline
  • Oxygen