title: RACK1 vs. HSP90: competition for HIF-1 alpha degradation vs. stabilization.
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.
authors.affiliation: Vascular Biology Program, Institute of Cell Engineering, Department of Pediatrics, and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Ye V
authors.initials: YV
authors.lastname: Liu
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D000075065:Elongin; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C000616396:ELOB protein, human; C000616395:ELOC protein, human; D000075065:Elongin; D018841:HSP90 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; C419368:RACK1 protein, human; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D019204:GTP-Binding Proteins