title: A conserved family of prolyl-4-hydroxylases that modify HIF.
abstract: Mammalian cells respond to changes in oxygen availability through a conserved pathway that is regulated by the hypoxia-inducible factor (HIF). The alpha subunit of HIF is targeted for degradation under normoxic conditions by a ubiquitin-ligase complex that recognizes a hydroxylated proline residue in HIF. We identified a conserved family of HIF prolyl hydoxylase (HPH) enzymes that appear to be responsible for this posttranslational modification. In cultured mammalian cells, inappropriate accumulation of HIF caused by forced expression of the HIF-1alpha subunit under normoxic conditions was attenuated by coexpression of HPH. Suppression of HPH in cultured Drosophila melanogaster cells by RNA interference resulted in elevated expression of a hypoxia-inducible gene (LDH, encoding lactate dehydrogenase) under normoxic conditions. These findings indicate that HPH is an essential component of the pathway through which cells sense oxygen.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard L3.124, Dallas, TX 75390-9152, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Bruick
authors.forename: S L
authors.initials: SL
authors.lastname: McKnight
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D003001:Cloning, Molecular; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D017344:Genes, Insect; D017930:Genes, Reporter; D006801:Humans; D006900:Hydroxylation; D006909:Hydroxyproline / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012330:RNA, Double-Stranded / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D013379:Substrate Specificity; D014157:Transcription Factors; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D012330:RNA, Double-Stranded; D011994:Recombinant Proteins; D014157:Transcription Factors; D007770:L-Lactate Dehydrogenase; D011393:Procollagen-Proline Dioxygenase; D006909:Hydroxyproline; D010100:Oxygen