FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor
- David Lando1,4,
- Daniel J. Peet1,4,
- Jeffrey J. Gorman2,
- Dean A. Whelan2,
- Murray L. Whitelaw1,5, and
- Richard K. Bruick3,5
- 1Department of Molecular BioSciences (Biochemistry) and the Centre for the Molecular Genetics of Development, Adelaide University SA 5005, Australia; 2CSIRO Health Sciences and Nutrition, Parkville VIC 3052, Australia; 3Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9152, USA
Abstract
Mammalian cells adapt to hypoxic conditions through a transcriptional response pathway mediated by the hypoxia-inducible factor, HIF. HIF transcriptional activity is suppressed under normoxic conditions by hydroxylation of an asparagine residue within its C-terminal transactivation domain, blocking association with coactivators. Here we show that the protein FIH-1, previously shown to interact with HIF, is an asparaginyl hydroxylase. Like known hydroxylase enzymes, FIH-1 is an Fe(II)-dependent enzyme that uses molecular O2 to modify its substrate. Together with the recently discovered prolyl hydroxylases that regulate HIF stability, this class of oxygen-dependent enzymes comprises critical regulatory components of the hypoxic response pathway.
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Footnotes
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↵4 These authors contributed equally to this work.
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↵5 Corresponding authors.
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E-MAIL murray.whitelaw{at}adelaide.edu.au; FAX 0011-1-214-648-3346.
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E-MAIL bruick{at}biochem.swmed.edu; FAX (214) 648-3346.
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.991402.
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- Received March 14, 2002.
- Accepted April 30, 2002.
- Cold Spring Harbor Laboratory Press
