RACK1 vs. HSP90: competition for HIF-1 alpha degradation vs. stabilization

Cell Cycle. 2007 Mar 15;6(6):656-9. doi: 10.4161/cc.6.6.3981. Epub 2007 Mar 7.

Abstract

Oxygen homeostasis represents an essential organizing principle of metazoan evolution and biology. Hypoxia-inducible factor 1 (HIF-1) regulates transcription in response to changes in O2 concentration. HIF-1 is a heterodimeric transcription factor that consists of HIF-1alpha and HIF-1beta subunits. O2 -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, and the proteasome. Inhibitors of heat shock protein 90 (HSP90) dissociate HSP90 from HIF-1alpha and induce O2/PHD/VHL-independent degradation of HIF-1alpha. Recently, we reported the identification of receptor of activated protein C kinase (RACK1) as a novel HIF-1alpha interacting protein. RACK1 promotes the O2/PHD/VHL-independent and proteasome-dependent degradation of HIF-1alpha. RACK1 competes with HSP90 for binding to the PAS-A domain of HIF-1alpha. RACK1 activity is required for the mechanism of action for the HSP90 inhibitor 17-allylaminogeldanamycin to induce HIF-1alpha degradation. RACK1 binds to Elongin-C and recruits Elongin-B and other components of E3 ubiquitin ligase to HIF-1alpha. The ubiquitination and degradation of HIF-1alpha are promoted by RACK1. RACK1 is an essential component of an O2/PHD/VHL-independent system for regulating HIF-1alpha stability through competition with HSP90 and recruitment of the Elongin-C/B ubiquitin ligase complex. Here we discuss how this system may be regulated.

Publication types

  • Comparative Study
  • Review

MeSH terms

  • Animals
  • Binding, Competitive
  • Elongin
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • GTP-Binding Proteins / physiology
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism*
  • HSP90 Heat-Shock Proteins / physiology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasm Proteins / physiology
  • Protein Binding
  • Receptors for Activated C Kinase
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Receptors, Cell Surface / physiology
  • Transcription Factors / metabolism
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • ELOB protein, human
  • ELOC protein, human
  • Elongin
  • HSP90 Heat-Shock Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Neoplasm Proteins
  • RACK1 protein, human
  • Receptors for Activated C Kinase
  • Receptors, Cell Surface
  • Transcription Factors
  • Ubiquitin-Protein Ligases
  • GTP-Binding Proteins