RACK1 competes with HSP90 for binding to HIF-1alpha and is required for O(2)-independent and HSP90 inhibitor-induced degradation of HIF-1alpha.

Hypoxia-inducible factor 1 (HIF-1) regulates transcription in response to changes in O(2) concentration. O(2)-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 complex, and the proteasome. Inhibition of heat-shock protein 90 (HSP90) leads to O(2)/PHD/VHL-independent degradation of HIF-1alpha. We have ...
identified the receptor of activated protein kinase C (RACK1) as a HIF-1alpha-interacting protein that promotes PHD/VHL-independent proteasomal degradation of HIF-1alpha. RACK1 competes with HSP90 for binding to the PAS-A domain of HIF-1alpha in vitro and in human cells. HIF-1alpha 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-1alpha. Elongin-C-binding sites in RACK1 and VHL show significant sequence similarity. Thus, RACK1 is an essential component of an O(2)/PHD/VHL-independent mechanism for regulating HIF-1alpha stability through competition with HSP90 and recruitment of the Elongin-C/B ubiquitin ligase complex.
Mesh Terms:
Amino Acid Sequence, Benzoquinones, Binding, Competitive, Cell Line, GTP-Binding Proteins, HSP90 Heat-Shock Proteins, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Lactams, Macrocyclic, Molecular Sequence Data, Neoplasm Proteins, Oxygen, Protein Binding, Proteomics, RNA Interference, Receptors, Cell Surface, Sequence Homology, Amino Acid, Transcription Factors, Transcriptional Activation, Von Hippel-Lindau Tumor Suppressor Protein
Mol. Cell
Date: Jan. 26, 2007
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