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Hypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing

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Abstract

This article outlines the need for a homeostatic response to alterations in cellular oxygenation. It describes work on erythropoietin control that led to the discovery of the hypoxia-inducible transcription factor (HIF-1) and the parallel recognition that this system was responsive to a widespread oxygen-sensing mechanism. Subsequently, multiple HIF isoforms have been shown to have overlapping but non-redundant functions, controlling expression of genes involved in diverse processes such as angiogenesis, vascular tone, metal transport, glycolysis, mitochondrial function, cell growth and survival. The major role of prolyl and asparaginyl hydroxylation in regulating HIFs is described, as well as the identification of PHD1-3 and FIH as the oxygen-sensing enzymes responsible for these hydroxylations. Current understanding of other processes that modulate overall HIF activity, including influences from other signalling mechanisms such as kinases and nitric oxide levels, and the existence of a variety of feedback loops are outlined. The effects of some mutations in this pathway are documented as is knowledge of other substrates for these enzymes. The importance of PHD1-3 and FIH, and the large family of 2-oxoglutarate and iron(II)-dependent dioxygenases of which they are a part, in biology and medicine are discussed (part of a multi-author review).

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Acknowledgments

The authors acknowledge many uncited contributions from co-workers in the field and helpful discussions with those involved now, and in the past, with oxygen-sensing research in Oxford. Work in the authors’ laboratory has been funded by the Wellcome Trust, MRC, CRUK, BHF, European Commission and a Fellowship to MC from Jesus College, Oxford. CWP is a scientific co-founder of ReOx Ltd.

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  1. Henry Wellcome Building for Molecular Physiology, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK

    James D. Webb, Mathew L. Coleman & Christopher W. Pugh

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  1. James D. Webb
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  2. Mathew L. Coleman
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Correspondence to Christopher W. Pugh.

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Webb, J.D., Coleman, M.L. & Pugh, C.W. Hypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing. Cell. Mol. Life Sci. 66, 3539–3554 (2009). https://doi.org/10.1007/s00018-009-0147-7

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