title: Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1alpha.
abstract: Hypoxia-inducible factor 1alpha (HIF-1alpha) functions as a transcription factor that is activated by decreased cellular oxygen concentrations to induce expression of a network of genes involved in angiogenesis, erythropoiesis, and glucose homeostasis. Here we demonstrate that two members of the SRC-1/p160 family of transcriptional coactivators harboring histone acetyltransferase activity, SRC-1 and transcription intermediary factor 2 (TIF2), are able to interact with HIF-1alpha and enhance its transactivation potential in a hypoxia-dependent manner. HIF-1alpha contains within its C terminus two transactivation domains. The hypoxia-inducible activity of both these domains was enhanced by either SRC-1 or the CREB-binding protein (CBP)/p300 coactivator. Moreover, at limiting concentrations, SRC-1 produced this effect in synergy with CBP. Interestingly, this effect was strongly potentiated by the redox regulatory protein Ref-1, a dual-function protein harboring DNA repair endonuclease and cysteine reducing activities. These data indicate that all three proteins, CBP, SRC-1, and Ref-1, are important components of the hypoxia signaling pathway and have a common function in regulation of HIF-1alpha function in hypoxic cells. Given the absence of cysteine residues in one of the Ref-1-regulated transactivation domains of HIF-1alpha, it is thus possible that Ref-1 functions in hypoxic cells by targeting critical steps in the recruitment of the CBP-SRC-1 coactivator complex.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Carrero
authors.forename: K
authors.initials: K
authors.lastname: Okamoto
authors.forename: P
authors.initials: P
authors.lastname: Coumailleau
authors.forename: S
authors.initials: S
authors.lastname: O'Brien
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: L
authors.initials: L
authors.lastname: Poellinger
mesh_terms: D000818:Animals; D019556:COS Cells; D050882:CREB-Binding Protein; D015687:Cell Hypoxia / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D051548:Histone Acetyltransferases; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D050882:CREB-Binding Protein; D051548:Histone Acetyltransferases; D056920:Nuclear Receptor Coactivator 1; D010100:Oxygen