RACK1 competes with HSP90 for binding to HIF-1alpha and is required for O(2)-independent and HSP90 inhibitor-induced degradation of HIF-1alpha

Mol Cell. 2007 Jan 26;25(2):207-17. doi: 10.1016/j.molcel.2007.01.001.


Hypoxia-inducible factor 1 (HIF-1) regulates transcription in response to changes in O(2) concentration. O(2)-dependent degradation of the HIF-1alpha subunit is mediated by prolyl hydroxylase (PHD), the von Hippel-Lindau (VHL)/Elongin-C/Elongin-B E3 ubiquitin ligase complex, and the proteasome. Inhibition of heat-shock protein 90 (HSP90) leads to O(2)/PHD/VHL-independent degradation of HIF-1alpha. We have identified the receptor of activated protein kinase C (RACK1) as a HIF-1alpha-interacting protein that promotes PHD/VHL-independent proteasomal degradation of HIF-1alpha. RACK1 competes with HSP90 for binding to the PAS-A domain of HIF-1alpha in vitro and in human cells. HIF-1alpha degradation induced by the HSP90 inhibitor 17-allylaminogeldanamycin is abolished by RACK1 loss of function. RACK1 binds to Elongin-C and promotes ubiquitination of HIF-1alpha. Elongin-C-binding sites in RACK1 and VHL show significant sequence similarity. Thus, RACK1 is an essential component of an O(2)/PHD/VHL-independent mechanism for regulating HIF-1alpha stability through competition with HSP90 and recruitment of the Elongin-C/B ubiquitin ligase complex.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Benzoquinones / pharmacology
  • Binding, Competitive
  • Cell Line
  • Elongin
  • GTP-Binding Proteins / antagonists & inhibitors
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • In Vitro Techniques
  • Lactams, Macrocyclic / pharmacology
  • Molecular Sequence Data
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Oxygen / metabolism
  • Protein Binding
  • Proteomics
  • RNA Interference
  • Receptors for Activated C Kinase
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Sequence Homology, Amino Acid
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism


  • Benzoquinones
  • ELOB protein, human
  • ELOC protein, human
  • Elongin
  • HIF1A protein, human
  • HSP90 Heat-Shock Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lactams, Macrocyclic
  • Neoplasm Proteins
  • RACK1 protein, human
  • Receptors for Activated C Kinase
  • Receptors, Cell Surface
  • Transcription Factors
  • tanespimycin
  • Von Hippel-Lindau Tumor Suppressor Protein
  • GTP-Binding Proteins
  • VHL protein, human
  • Oxygen