FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor

David Lando; Daniel J Peet; Jeffrey J Gorman; Dean A Whelan; Murray L Whitelaw; Richard K Bruick

doi:10.1101/gad.991402

FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor

Genes Dev. 2002 Jun 15;16(12):1466-71. doi: 10.1101/gad.991402.

Authors

David Lando¹, Daniel J Peet, Jeffrey J Gorman, Dean A Whelan, Murray L Whitelaw, Richard K Bruick

Affiliation

¹ Department of Molecular BioSciences (Biochemistry) and the Centre for the Molecular Genetics of Development, Adelaide University SA 5005, Australia.

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 O(2) 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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Amino Acid Sequence
Animals
Asparagine / chemistry*
Basic Helix-Loop-Helix Transcription Factors
Cell Line
Glutathione Transferase / metabolism
Humans
Hydroxylation
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit
Iron / metabolism
Ketoglutaric Acids / metabolism
Mass Spectrometry
Mice
Mixed Function Oxygenases / metabolism*
Molecular Sequence Data
Oxygen / metabolism
Plasmids / metabolism
Protein Binding
Protein Structure, Tertiary
Recombinant Fusion Proteins / metabolism
Recombinant Proteins / metabolism
Repressor Proteins / metabolism*
Repressor Proteins / physiology*
Sequence Homology, Amino Acid
Trans-Activators / metabolism
Transcription Factors / metabolism
Transcription, Genetic*
Transcriptional Activation
Transfection

Substances

Basic Helix-Loop-Helix Transcription Factors
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Ketoglutaric Acids
Recombinant Fusion Proteins
Recombinant Proteins
Repressor Proteins
Trans-Activators
Transcription Factors
endothelial PAS domain-containing protein 1
Asparagine
Iron
Mixed Function Oxygenases
HIF1AN protein, human
aspartic acid 2-oxoglutarate-dependent dioxygenase
Glutathione Transferase
Oxygen