Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O 2 -Regulated Prolyl Hydroxylation-Reference-Cited by-同舟云学术

Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O 2 -Regulated Prolyl Hydroxylation

Published:2001-04-20 Issue:5516 Volume:292 Page:468-472
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Jaakkola Panu¹,Mole David R.¹,Tian Ya-Min¹,Wilson Michael I.¹,Gielbert Janine²,Gaskell Simon J.²,Kriegsheim Alexander von³,Hebestreit Holger F.³,Mukherji Mridul⁴,Schofield Christopher J.⁴,Maxwell Patrick H.¹,Pugh ‡ Christopher W.¹,Ratcliffe ‡ Peter J.¹

Affiliation:

1. The Henry Wellcome Building of Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.

2. Michael Barber Centre for Mass Spectrometry, Department of Chemistry, University of Manchester Institute of Science and Technology, Manchester M60 1QD, UK.

3. Glycobiology Institute, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.

4. The Oxford Centre for Molecular Sciences and The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK.

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-α 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-1α subunit is regulated through hydroxylation of a proline residue (HIF-1α P564) by an enzyme we have termed HIF-α 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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference49 articles.

1. Semenza G. L., Genes Dev. 14, 1983 (2000).

2. N. V. Iyer et al. Genes Dev. 12 149 (1997).

3. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.

4. Regulation of hypoxia-inducible factor 1 is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway

5. Hypoxia-inducible Factor 1α (HIF-1α) Protein Is Rapidly Degraded by the Ubiquitin-Proteasome System under Normoxic Conditions

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