Hypoxia-inducible factor-1 alpha (HIF-1 alpha) escapes O(2)-driven proteasomal degradation irrespective of its subcellular localization: nucleus or cytoplasm

EMBO Rep. 2001 Jul;2(7):615-20. doi: 10.1093/embo-reports/kve130. Epub 2001 Jul 3.


Eukaryotic cells sense oxygen and adapt to hypoxia by regulating a number of genes. Hypoxia-inducible factor 1 (HIF-1) is the 'master' in this pleiotypic response. HIF-1 comprises two members of the basic helix--loop--helix transcription factor family, HIF-1 alpha and HIF-1 beta. The HIF-1 alpha protein is subject to drastic O(2)-dependent proteasomal control. However, the signalling components regulating the 'switch' for 'escaping' proteasomal degradation under hypoxia are still largely unknown. The rapid nuclear translocation of HIF-1 alpha could represent an efficient way to escape from this degradation. We therefore asked, where in the cell is HIF-1 alpha degraded? To address this question, we trapped HIF-1 alpha either in the cytoplasm, by fusing HIF-1 alpha to the cytoplasmic domain of the Na(+)-H(+) exchanger (NHE-1), or in the nucleus, by treatment with leptomycin B. Surprisingly, we found that HIF-1 alpha is stabilized by hypoxia and undergoes O(2)-dependent proteasomal degradation with an identical half-life (5--8 min) in both cellular compartments. Therefore, HIF-1 alpha entry into the nucleus is not, as proposed, a key event that controls its stability. This result markedly contrasts with the mechanism that controls p53 degradation via MDM2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / analogs & derivatives*
  • Acetylcysteine / pharmacology
  • Active Transport, Cell Nucleus / drug effects
  • Active Transport, Cell Nucleus / physiology
  • Antibiotics, Antineoplastic / pharmacology
  • Cell Fractionation
  • Cell Hypoxia / physiology
  • Cell Line
  • Cell Nucleus / metabolism*
  • Cysteine Endopeptidases / drug effects
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Cytoplasm / metabolism*
  • Fatty Acids, Unsaturated / pharmacology
  • Humans
  • Immunoblotting
  • Multienzyme Complexes / drug effects
  • Multienzyme Complexes / metabolism*
  • Oxygen / metabolism
  • Proteasome Endopeptidase Complex
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sodium-Hydrogen Exchangers / genetics
  • Transcription Factors / metabolism*
  • Transfection


  • Antibiotics, Antineoplastic
  • Cysteine Proteinase Inhibitors
  • Fatty Acids, Unsaturated
  • Multienzyme Complexes
  • Recombinant Fusion Proteins
  • Sodium-Hydrogen Exchangers
  • Transcription Factors
  • growth factor-activatable Na-H exchanger NHE-1
  • lactacystin
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Oxygen
  • Acetylcysteine
  • leptomycin B