Targeting of HIF- alpha to the von Hippel-Lindau ubiquitilation complex by O sub(2)-regulated prolyl hydroxylation

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, HIV- alpha subunits are rapidly destroyed by a mechanism that involves ubiquitylation by the von Hippel-Lindau tumor suppressor...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2001-04, Vol.292 (5516), p.468-472
Main Authors: Jaakkola, P, Mole, DR, Tian, Ya-Min, Wilson, MI, Gielbert, J, Gaskell, S J, von Kriegsheim, A, Hebestreit, H F, Mukherji, M, Schofield, C J, Maxwell, PH, Pugh, C W, Ratcliffe, P J
Format: Article
Language:English
Subjects:
hypoxia-inducible factor
von Hippel-Lindau protein
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Summary: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, HIV- alpha subunits are rapidly destroyed by a mechanism that involves ubiquitylation by the von Hippel-Lindau tumor suppressor (pHVL) 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.
ISSN:0036-8075