The FIH hydroxylase is a cellular peroxide sensor that modulates HIF transcriptional activity.
Hypoxic and oxidant stresses can coexist in biological systems, and oxidant stress has been proposed to activate hypoxia pathways through the inactivation of the 'oxygen-sensing' hypoxia-inducible factor (HIF) prolyl and asparaginyl hydroxylases. Here, we show that despite reduced sensitivity to cellular hypoxia, the HIF asparaginyl hydroxylase--known as FIH, factor inhibiting HIF--is strikingly more sensitive to peroxide than the HIF prolyl hydroxylases. These contrasting sensitivities indicate that oxidant stress is unlikely to signal hypoxia directly to the HIF system, but that hypoxia and oxidant stress can interact functionally as distinct regulators of HIF transcriptional output.
Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK. nmasson@well.ox.ac.uk
Norma
N
Masson
Rachelle S
RS
Singleton
Rok
R
Sekirnik
David C
DC
Trudgian
Lucy J
LJ
Ambrose
Melroy X
MX
Miranda
Ya-Min
YM
Tian
Benedikt M
BM
Kessler
Christopher J
CJ
Schofield
Peter J
PJ
Ratcliffe
D015687:Cell Hypoxia / Q000235:genetics; D002460:Cell Line; D003545:Cysteine / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010545:Peroxides / Q000378:metabolism* / Q000494:pharmacology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014158:Transcription, Genetic
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010545:Peroxides; D012097:Repressor Proteins; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; D003545:Cysteine