[PDF][PDF] RACK1 competes with HSP90 for binding to HIF-1α and is required for O2-independent and HSP90 inhibitor-induced degradation of HIF-1α
YV Liu, JH Baek, H Zhang, R Diez, RN Cole… - Molecular cell, 2007 - cell.com
YV Liu, JH Baek, H Zhang, R Diez, RN Cole, GL Semenza
Molecular cell, 2007•cell.comSummary Hypoxia-inducible factor 1 (HIF-1) regulates transcription in response to changes
in O 2 concentration. O 2-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
complex, and the proteasome. Inhibition of heat-shock protein 90 (HSP90) leads to O
2/PHD/VHL-independent degradation of HIF-1α. We have identified the receptor of activated
protein kinase C (RACK1) as a HIF-1α-interacting protein that promotes PHD/VHL …
in O 2 concentration. O 2-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
complex, and the proteasome. Inhibition of heat-shock protein 90 (HSP90) leads to O
2/PHD/VHL-independent degradation of HIF-1α. We have identified the receptor of activated
protein kinase C (RACK1) as a HIF-1α-interacting protein that promotes PHD/VHL …
Summary
Hypoxia-inducible factor 1 (HIF-1) regulates transcription in response to changes in O2 concentration. 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 complex, and the proteasome. Inhibition of heat-shock protein 90 (HSP90) leads to O2/PHD/VHL-independent degradation of HIF-1α. We have identified the receptor of activated protein kinase C (RACK1) as a HIF-1α-interacting protein that promotes PHD/VHL-independent proteasomal degradation of HIF-1α. RACK1 competes with HSP90 for binding to the PAS-A domain of HIF-1α in vitro and in human cells. HIF-1α 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-1α. Elongin-C-binding sites in RACK1 and VHL show significant sequence similarity. Thus, RACK1 is an essential component of an O2/PHD/VHL-independent mechanism for regulating HIF-1α stability through competition with HSP90 and recruitment of the Elongin-C/B ubiquitin ligase complex.
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