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Perspectives
RACK1 vs. HSP90: Competition for HIF-1α Degradation vs. Stabilization
Ye V. Liu and Gregg L. Semenza
volume 6 | issue 6
15 March 2007Pages: 656 - 659
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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-1α and HIF-1β subunits. O2-dependent degradation of the HIF-1α 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-1α and induce O2/PHD/VHL-independent degradation of HIF-1α. Recently, we reported the identification of receptor of activated protein C kinase (RACK1) as a novel HIF-1α interacting protein. RACK1 promotes the O2/PHD/VHL-independent and proteasome-dependent degradation of HIF-1α. RACK1 competes with HSP90 for binding to the PAS-A domain of HIF-1α. RACK1 activity is required for the mechanism of action for the HSP90 inhibitor 17-allylaminogeldanamycin to induce HIF-1α degradation. RACK1 binds to Elongin-C and recruits Elongin-B and other components of E3 ubiquitin ligase to HIF-1α. The ubiquitination and degradation of HIF-1α are promoted by RACK1. RACK1 is an essential component of an O2/PHD/VHL-independent system for regulating HIF-1α 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
Ye V. Liu
The Johns Hopkins University School of Medicine
Gregg L. Semenza
The Johns Hopkins University School of Medicine
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.