A1 Refereed original research article in a scientific journal
Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O-2-regulated prolyl hydroxylation
Authors: Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Publication year: 2001
Journal:: Science
Journal name in source: SCIENCE
Journal acronym: SCIENCE
Volume: 292
Issue: 5516
First page : 468
Last page: 472
Number of pages: 5
ISSN: 0036-8075
DOI: https://doi.org/10.1126/science.1059796
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.
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