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Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.

Hypoxia-inducible factor (HIF) is a transcriptional complex that plays a central role in the regulation of gene expression by oxygen. In oxygenated and iron replete cells, HIF-alpha subunits are rapidly destroyed by a mechanism that involves ubiquitylation by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. This process is suppressed by hypoxia and iron chelation, allowing transcriptional activation. Here we show that the interaction between human pVHL and a specific domain of the HIF-1alpha subunit is regulated through hydroxylation of a proline residue (HIF-1alpha P564) by an enzyme we have termed HIF-alpha prolyl-hydroxylase (HIF-PH). An absolute requirement for dioxygen as a cosubstrate and iron as cofactor suggests that HIF-PH functions directly as a cellular oxygen sensor.

Pubmed ID: 11292861

Authors

  • Jaakkola P
  • Mole DR
  • Tian YM
  • Wilson MI
  • Gielbert J
  • Gaskell SJ
  • von Kriegsheim A
  • Hebestreit HF
  • Mukherji M
  • Schofield CJ
  • Maxwell PH
  • Pugh CW
  • Ratcliffe PJ

Journal

Science (New York, N.Y.)

Publication Data

April 20, 2001

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Ascorbic Acid
  • Cell Hypoxia
  • DNA-Binding Proteins
  • Deferoxamine
  • Ferrous Compounds
  • Humans
  • Hydroxylation
  • Hydroxyproline
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ligases
  • Molecular Sequence Data
  • Nuclear Proteins
  • Oxygen
  • Point Mutation
  • Procollagen-Proline Dioxygenase
  • Protein Structure, Tertiary
  • Proteins
  • Recombinant Fusion Proteins
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Transcription Factors
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases
  • Ubiquitins
  • Von Hippel-Lindau Tumor Suppressor Protein