RACK1 Competes with HSP90 for Binding to HIF-1 alpha and Is Required for O sub(2)- Independent and HSP90 Inhibitor-Induced Degradation of HIF-1 alpha

Hypoxia-inducible factor 1 (HIF-1) regulates transcription in response to changes in O sub(2) concentration. O sub(2)-dependent degradation of the HIF-1 alpha subunit is mediated by prolyl hydroxylase (PHD), the von Hippel-Lindau (VHL)/Elongin-C/Elongin-B E3 ubiquitin ligase complex, and the proteas...

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Published in:Molecular cell 2007-01, Vol.25 (2), p.207-217
Main Authors: Liu, Ye V, Baek, Jin H, Zhang, Huafeng, Diez, Roberto, Cole, Robert N, Semenza, Gregg L
Format: Article
Language:English
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Summary:Hypoxia-inducible factor 1 (HIF-1) regulates transcription in response to changes in O sub(2) concentration. O sub(2)-dependent degradation of the HIF-1 alpha 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 sub(2)/PHD/VHL-independent degradation of HIF-1 alpha . We have identified the receptor of activated protein kinase C (RACK1) as a HIF-1 alpha -interacting protein that promotes PHD/VHL- independent proteasomal degradation of HIF-1 alpha . RACK1 competes with HSP90 for binding to the PAS-A domain of HIF-1 alpha in vitro and in human cells. HIF-1 alpha 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-1 alpha . Elongin-C-binding sites in RACK1 and VHL show significant sequence similarity. Thus, RACK1 is an essential component of an O sub(2)/PHD/VHL-independent mechanism for regulating HIF-1 alpha stability through competition with HSP90 and recruitment of the Elongin-C/B ubiquitin ligase complex.
ISSN:1097-2765
DOI:10.1016/j.molcel.2007.01.001