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Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-1alpha but Not HIF-2alpha.

Hypoxia-inducible factors (HIFs) are transcription factors that mediate adaptive responses to reduced oxygen availability. HIF-alpha subunits are stabilized under conditions of acute hypoxia. However, prolonged hypoxia leads to decay of HIF-1alpha but not HIF-2alpha protein levels by unknown mechanisms. Here, we identify Hsp70 and CHIP (carboxyl terminus of Hsc70-interacting protein) as HIF-1alpha-interacting proteins. Hsp70, through recruiting the ubiquitin ligase CHIP, promotes the ubiquitination and proteasomal degradation of HIF-1alpha but not HIF-2alpha, thereby inhibiting HIF-1-dependent gene expression. Disruption of Hsp70-CHIP interaction blocks HIF-1alpha degradation mediated by Hsp70 and CHIP. Inhibition of Hsp70 or CHIP synthesis by RNA interference increases protein levels of HIF-1alpha but not HIF-2alpha and attenuates the decay of HIF-1alpha levels during prolonged hypoxia. Thus, Hsp70- and CHIP-dependent ubiquitination represents a molecular mechanism by which prolonged hypoxia selectively reduces the levels of HIF-1alpha but not HIF-2alpha protein.

Pubmed ID: 19940151

Authors

  • Luo W
  • Zhong J
  • Chang R
  • Hu H
  • Pandey A
  • Semenza GL

Journal

The Journal of biological chemistry

Publication Data

February 5, 2010

Associated Grants

  • Agency: NHLBI NIH HHS, Id: N01 HV028180
  • Agency: NHLBI NIH HHS, Id: N01-HV28180
  • Agency: NCRR NIH HHS, Id: U54 RR020839

Mesh Terms

  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Hypoxia
  • Cell Line
  • Cell Line, Tumor
  • HSP70 Heat-Shock Proteins
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunoblotting
  • Immunoprecipitation
  • Mutation
  • Proteasome Endopeptidase Complex
  • Protein Binding
  • RNA Interference
  • Transfection
  • Ubiquitin-Protein Ligases
  • Ubiquitination