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Signaling hypoxia by hypoxia-inducible factor protein hydroxylases: a historical overview and future perspectives

Authors Bishop T, Ratcliffe P

Received 17 September 2014

Accepted for publication 2 October 2014

Published 5 December 2014 Volume 2014:2 Pages 197—213

DOI https://doi.org/10.2147/HP.S47598

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 6

Editor who approved publication: Prof. Dr. Dörthe Katschinski


Tammie Bishop, Peter J Ratcliffe

Nuffield Department of Medicine, University of Oxford, Oxford, UK

Abstract: By the early 1900s, the close matching of oxygen supply with demand was recognized to be a fundamental requirement for physiological function, and multiple adaptive responses to environment hypoxia had been described. Nevertheless, the widespread operation of mechanisms that directly sense and respond to levels of oxygen in animal cells was not appreciated for most of the twentieth century with investigators generally stressing the regulatory importance of metabolic products. Work over the last 25 years has overturned that paradigm. It has revealed the existence of a set of “oxygen-sensing” 2-oxoglutarate dependent dioxygenases that catalyze the hydroxylation of specific amino acid residues and thereby control the stability and activity of hypoxia-inducible factor. The hypoxia-inducible factor hydroxylase pathway regulates a massive transcriptional cascade that is operative in essentially all animal cells. It transduces a wide range of responses to hypoxia, extending well beyond the classical boundaries of hypoxia physiology. Here we review the discovery and elucidation of these pathways, and consider the opportunities and challenges that have been brought into focus by the findings, including new implications for the integrated physiology of hypoxia and therapeutic approaches to ischemic/hypoxic disease.

Keywords: hypoxia, oxygen-sensing, HIF, 2-oxoglutarate oxygenase, hydroxylase, cell signaling

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