title: HIF-1α restricts NF-κB-dependent gene expression to control innate immunity signals.
abstract: Hypoxia and inflammation are intimately linked. It is known that nuclear factor κB (NF-κB) regulates the hypoxia-inducible factor (HIF) system, but little is known about how HIF regulates NF-κB. Here, we show that HIF-1α represses NF-κB-dependent gene expression. HIF-1α depletion results in increased NF-κB transcriptional activity both in mammalian cells and in the model organism Drosophila melanogaster. HIF-1α depletion enhances the NF-κB response, and this required not only the TAK-IKK complex, but also CDK6. Loss of HIF-1α results in an increased angiogenic response in mammalian cancer cells and increased mortality in Drosophila following infection. These results indicate that HIF-1α is required to restrain the NF-κB response, and thus prevents excessive and damaging pro-inflammatory responses.
authors.affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dow Street, DD1 5EH, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bandarra
authors.affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dow Street, DD1 5EH, UK.
authors.forename: John
authors.initials: J
authors.lastname: Biddlestone
authors.affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dow Street, DD1 5EH, UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: Mudie
authors.affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dow Street, DD1 5EH, UK.
authors.forename: H-Arno J
authors.initials: HA
authors.lastname: Müller
authors.affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dow Street, DD1 5EH, UK. s.rocha@dundee.ac.uk.
authors.forename: Sonia
authors.initials: S
authors.lastname: Rocha
mesh_terms: D000818:Animals; D002460:Cell Line; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology; D004927:Escherichia coli Infections / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000378:metabolism; D007113:Immunity, Innate / Q000235:genetics*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008322:Mammals / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D015398:Signal Transduction / Q000235:genetics*; D016019:Survival Analysis; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D051361:Cyclin-Dependent Kinase 6; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051550:I-kappa B Kinase; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D000099151:MAP Kinase Kinase Kinase 7; C100429:Sima protein, Drosophila
keywords: Drosophila; HIF-1; Hypoxia; IKK; Inflammation; NF-κB