New horizons in hypoxia signaling pathways.
Investigation into the regulation of the erythropoietin gene by oxygen led to the discovery of a process of direct oxygen sensing that transduces many cellular and systemic responses to hypoxia. The oxygen-sensitive signal is generated through the catalytic action of a series of 2-oxoglutarate-dependent oxygenases that regulate the transcription factor hypoxia-inducible factor (HIF) by the post-translational hydroxylation of specific amino acid residues. Here we review the implications of the unforeseen complexity of the HIF transcriptional cascade for the physiology and pathophysiology of hypoxia, and consider the origins of post-translational hydroxylation as a signaling process.
Target Discovery Institute, University of Oxford, OX3 7FZ, UK. Electronic address: chris.pugh@ndm.ox.ac.uk.
Christopher W
CW
Pugh
Target Discovery Institute, University of Oxford, OX3 7FZ, UK; Francis Crick Institute, Midland Road, London NW1 1AT, UK. Electronic address: peter.ratcliffe@ndm.ox.ac.uk.
Peter J
PJ
Ratcliffe
D000818:Animals; D006801:Humans; D006900:Hydroxylation / Q000502:physiology; D000860:Hypoxia / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
D014157:Transcription Factors; D010100:Oxygen
Cancer; Hypoxia; Hypoxia-inducible factor; Prolyl hydroxylase; Protein hydroxylation; Transcription