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Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.

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Affiliations

  • 1. The Henry Wellcome Building of Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
      Authors
    • Jaakkola P 1
    (1 author)

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Science, 05 Apr 2001, 292(5516):468-472
https://doi.org/10.1126/science.1059796 PMID: 11292861 

A comment on this article appears in "Signal transduction. How do cells sense oxygen?" Science. 2001 Apr 20;292(5516):449-51.

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-1alpha subunit is regulated through hydroxylation of a proline residue (HIF-1alpha 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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Read article at publisher's site: https://doi.org/10.1126/science.1059796

Read article for free, from open access legal sources, via Unpaywall: https://www.science.org/cms/asset/1cf7b4d3-79d4-424c-a64b-b18f3c4973d4/pap.pdfUnpaywall

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