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RACK1 vs HSP90: competition for HIF-1 alpha degradation vs stabilization Liu YV; Semenza GLCell Cycle 2007[Mar]; 6 (6): 656-9Oxygen 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.|Animals[MESH]|Binding, Competitive[MESH]|Elongin[MESH]|GTP-Binding Proteins/genetics/*metabolism/physiology[MESH]|HSP90 Heat-Shock Proteins/genetics/*metabolism/physiology[MESH]|Humans[MESH]|Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism/physiology[MESH]|Neoplasm Proteins/genetics/*metabolism/physiology[MESH]|Protein Binding[MESH]|Receptors for Activated C Kinase[MESH]|Receptors, Cell Surface/genetics/*metabolism/physiology[MESH]|Transcription Factors/metabolism[MESH]|Ubiquitin-Protein Ligases/metabolism[MESH] |
