Sensing of ambient dioxygen levels and appropriate feedback mechanisms are essential processes for all multicellular organisms. In animals, moderate hypoxia causes an increase in the transcription levels of specific genes, including those encoding vascular endothelial growth factor and erythropoietin. The hypoxic response is mediated by hypoxia-inducible factor (HIF), an αβ heterodimeric transcription factor in which both the HIF subunits are members of the basic helix–loop–helix PAS (PER-ARNT-SIM) domain family. Under hypoxic conditions, levels of HIFα rise, allowing dimerization with HIFβ and initiating transcriptional activation. Two types of dioxygen-dependent modification to HIFα have been identified, both of which inhibit the transcriptional response. Firstly, HIFα undergoes trans-4-hydroxylation at two conserved proline residues that enable its recognition by the von Hippel-Lindau tumour-suppressor protein. Subsequent ubiquitinylation, mediated by an ubiquitin ligase complex, targets HIFα for degradation. Secondly, hydroxylation of an asparagine residue in the C-terminal transactivation domain of HIFα directly prevents its interaction with the co-activator p300. Hydroxylation of HIFα is catalysed by enzymes of the iron(II)- and 2-oxoglutarate-dependent dioxygenase family. In humans, three prolyl hydroxylase isoenzymes (PHD1–3) and an asparagine hydroxylase [factor inhibiting HIF (FIH)] have been identified. The role of 2-oxoglutarate oxygenases in the hypoxic and other signalling pathways is discussed.
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Conference Article|
June 01 2003
The role of iron and 2-oxoglutarate oxygenases in signalling
K.S. Hewitson;
K.S. Hewitson
1
Oxford Centre for Molecular Sciences and the Department of Chemistry, Dyson Perrins Laboratory, South Parks Road, Oxford OX1 3QY, U.K.
1To whom correspondence should be addressed (e-mail either kirsty.hewitson@chem.ox.ac.uk or christopher.schofield@chem.ox.ac.uk).
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L.A. McNeill;
L.A. McNeill
Oxford Centre for Molecular Sciences and the Department of Chemistry, Dyson Perrins Laboratory, South Parks Road, Oxford OX1 3QY, U.K.
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J.M. Elkins;
J.M. Elkins
Oxford Centre for Molecular Sciences and the Department of Chemistry, Dyson Perrins Laboratory, South Parks Road, Oxford OX1 3QY, U.K.
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C.J. Schofield
C.J. Schofield
1
Oxford Centre for Molecular Sciences and the Department of Chemistry, Dyson Perrins Laboratory, South Parks Road, Oxford OX1 3QY, U.K.
1To whom correspondence should be addressed (e-mail either kirsty.hewitson@chem.ox.ac.uk or christopher.schofield@chem.ox.ac.uk).
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Publisher: Portland Press Ltd
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2003 Biochemical Society
2003
Biochem Soc Trans (2003) 31 (3): 510–515.
Citation
K.S. Hewitson, L.A. McNeill, J.M. Elkins, C.J. Schofield; The role of iron and 2-oxoglutarate oxygenases in signalling. Biochem Soc Trans 1 June 2003; 31 (3): 510–515. doi: https://doi.org/10.1042/bst0310510
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