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Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O-2-regulated prolyl hydroxylation

Jaakkola, P; Mole, DR; Tian, YM; Wilson, MI; Gielbert, J; Gaskell, SJ; ... Ratcliffe, PJ; + view all (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O-2-regulated prolyl hydroxylation. SCIENCE , 292 (5516) 468 - 472.

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Abstract

Hypoxia-inducible factor (HIF) is a transcriptional complex that plays a central role in the regulation of gene expression by oxygen. In oxygenated and iron replete cells, HIF-alpha subunits are rapidly destroyed by a mechanism that involves ubiquitylation by the von Hippel-Lindau tumor suppressor (pVHL) E3 Ligase complex. This process is suppressed by hypoxia and iron chelation, allowing transcriptional activation. Here we show that the interaction between human pVHL and a specific domain of the HIF-1 alpha subunit is regulated through hydroxylation of a proline residue (HIF-1 alpha P564) by an enzyme we have termed HIF-alpha prolyl-hydroxylase (HIF-PH). An absolute requirement for dioxygen as a cosubstrate and iron as cofactor suggests that HIF-PH functions directly as a cellular oxygen sensor.

Type:Article
Title:Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O-2-regulated prolyl hydroxylation
Keywords:TUMOR-SUPPRESSOR PROTEIN, INDUCIBLE FACTOR 1-ALPHA, UBIQUITIN-LIGASE COMPLEX, DEPENDENT PROTEOLYSIS, ERYTHROPOIETIN GENE, FACTOR-I, HYPOXIA, HIF-1-ALPHA, ACTIVATION, BINDING
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)

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