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doi: 10.1242/10.1242/jcs.00655
Commentary |
The Henry Wellcome Building of Genomic Medicine, Roosevelt Drive, Oxford OX3 7BN, UK
* Author for correspondence (e-mail: pjr{at}well.ox.ac.uk)
Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor that
plays a crucial role in mediating cellular responses to oxygen. Oxygen
availability influences multiple steps in HIF activation and recent studies
have indicated that at least two steps in this process are governed by a novel
mode of signal transduction involving enzymatic hydroxylation of specific
amino acid residues in HIF-
subunits by a series of 2-oxoglutarate
(2-OG)-dependent oxygenases. These enzymes are non-haem iron enzymes that use
dioxygen in the hydroxylation reaction and therefore provide a direct link
between the availability of molecular oxygen and regulation of HIF. Prolyl
hydroxylation regulates proteolytic destruction of HIF- by the von
Hippel-Lindau ubiquitin ligase complex, whereas HIF- asparaginyl
hydroxylation regulates recruitment of transcriptional coactivators. The
involvement of at least two distinct types of 2-OG-dependent oxygenase in
oxygen-regulated transcription suggests that these enzymes may be well suited
to a role in cellular oxygen sensing.
Key words: Hypoxia inducible factor-, Prolyl hydroxylation, Asparaginyl hydroxylation, von Hippel-Lindau protein, Ubiquitylation
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