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|Title:||Asparagine hydroxylation of the HIF transactivation domain: A hypoxic switch|
|Citation:||Science, 2002; 295(5556):858-861|
|Publisher:||Amer Assoc Advancement Science|
|Organisation:||Centre for the Molecular Genetics of Development|
|David Lando, Daniel J. Peet, Dean A. Whelan, Jeffrey J. Gorman and Murray L. Whitelaw|
|Abstract:||The hypoxia-inducible factors (HIFs) 1α and 2α are key mammalian transcription factors that exhibit dramatic increases in both protein stability and intrinsic transcriptional potency during low-oxygen stress. This increased stability is due to the absence of proline hydroxylation, which in normoxia promotes binding of HIF to the von Hippel-Lindau (VHL tumor suppressor) ubiquitin ligase. We now show that hypoxic induction of the COOH-terminal transactivation domain (CAD) of HIF occurs through abrogation of hydroxylation of a conserved asparagine in the CAD. Inhibitors of Fe(II)- and 2-oxoglutarate-dependent dioxygenases prevented hydroxylation of the Asn, thus allowing the CAD to interact with the p300 transcription coactivator. Replacement of the conserved Asn by Ala resulted in constitutive p300 interaction and strong transcriptional activity. Full induction of HIF-1α and -2α, therefore, relies on the abrogation of both Pro and Asn hydroxylation, which during normoxia occur at the degradation and COOH-terminal transactivation domains, respectively.|
|Keywords:||Cell Line; Animals; Humans; Mice; Oxygen; Mixed Function Oxygenases; Asparagine; Proline; Trans-Activators; Recombinant Fusion Proteins; Transcription Factors; Amino Acid Substitution; Cell Hypoxia; Amino Acid Sequence; Protein Structure, Tertiary; Hydroxylation; Mutation; Molecular Sequence Data; Basic Helix-Loop-Helix Transcription Factors; Hypoxia-Inducible Factor 1, alpha Subunit; Mass Spectrometry; Transcriptional Activation|
|Appears in Collections:||Molecular and Biomedical Science publications|
Centre for the Molecular Genetics of Development publications
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