Hypoxia-induced Activation of HIF-1: Role of HIF-1alpha-Hsp90 Interaction

FEBS Lett. 1999 Oct 29;460(2):251-6. doi: 10.1016/s0014-5793(99)01359-9.

Abstract

The protein chaperone heat shock protein 90 (Hsp90) is a major regulator of different transcription factors such as MyoD, a basic helix loop helix (bHLH) protein, and the bHLH-Per-aryl hydrocarbon nuclear translocator (ARNT)-Sim (PAS) factors Sim and aryl hydrocarbon receptor (Ahr). The transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), involved in the response to hypoxia, also belongs to the bHLH-PAS family. This work was aimed to investigate the putative role of Hsp90 in HIF-1 activation by hypoxia. Using a EGFP-HIF-1alpha fusion protein, co-immunoprecipitation experiments evidenced that the chimeric protein expressed in COS-7 cells interacts with Hsp90 in normoxia but not in hypoxia. We also demonstrated that Hsp90 interacts with the bHLH-PAS domain of HIF-1alpha. Moreover, Hsp90 is not co-translocated with HIF-1alpha into the nucleus. At last, we showed that Hsp90 activity is essential for HIF-1 activation in hypoxia since it is inhibited in the presence of geldanamycin. These results indicate that Hsp90 is a major regulator in HIF-1alpha activation.

MeSH terms

  • Animals
  • COS Cells
  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • Endothelium, Vascular
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Hypoxia / metabolism*
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Microscopy, Fluorescence
  • Molecular Chaperones
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Time Factors
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transfection

Substances

  • DNA-Binding Proteins
  • HIF1A protein, human
  • HSP90 Heat-Shock Proteins
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Molecular Chaperones
  • Nuclear Proteins
  • Transcription Factors