HIF-1-dependent transcriptional activity is required for oxygen-mediated HIF-1alpha degradation

FEBS Lett. 2001 Feb 23;491(1-2):85-90. doi: 10.1016/s0014-5793(01)02159-7.

Abstract

Hypoxia-inducible factor-1alpha (HIF-1alpha) plays a central role in oxygen homeostasis. In normoxia, HIF-1alpha is a short lived protein, whereas hypoxia rapidly increases HIF-1alpha protein levels by relaxing its ubiquitin-proteasome-dependent degradation. In this study, we show that the p42/p44 MAP kinase cascade, known to phosphorylate HIF-1alpha, does not modulate the degradation/stabilization profile of HIF-1alpha. However, we present evidence that the rate of HIF-1alpha degradation depends on the duration of hypoxic stress. We demonstrate that degradation of HIF-1alpha is suppressed by: (i) inhibiting general transcription with actinomycin D or (ii) specifically blocking HIF-1-dependent transcriptional activity. In keeping with these findings, we postulate that HIF-1alpha is targetted to the proteasome via a HIF-1alpha proteasome targetting factor (HPTF) which expression is directly under the control of HIF-1-mediated transcriptional activity. Although HPTF is not yet molecularly identified, it is clearly distinct from the von Hippel-Lindau protein (pVHL).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Hypoxia
  • Cysteine Endopeptidases / metabolism
  • DNA-Binding Proteins / metabolism*
  • Dactinomycin / pharmacology
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunoblotting
  • Ligases*
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism*
  • Multienzyme Complexes / metabolism
  • Nuclear Proteins / metabolism*
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Oxygen / metabolism*
  • Phosphorylation
  • Precipitin Tests
  • Proteasome Endopeptidase Complex
  • Proteins / metabolism
  • RNA, Messenger / biosynthesis
  • Transcription Factors / metabolism*
  • Tumor Suppressor Proteins*
  • Ubiquitin-Protein Ligases*
  • Von Hippel-Lindau Tumor Suppressor Protein

Substances

  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Multienzyme Complexes
  • Nuclear Proteins
  • Nucleic Acid Synthesis Inhibitors
  • Proteins
  • RNA, Messenger
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Dactinomycin
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Ligases
  • VHL protein, human
  • Oxygen