title: Mitochondrial reactive oxygen species activation of p38 mitogen-activated protein kinase is required for hypoxia signaling.
abstract: Mammalian cells have the ability to sense low oxygen levels (hypoxia). An adaptive response to hypoxia involves the induction of the transcription factor hypoxia-inducible factor 1 (HIF-1). The intracellular signaling pathways that regulate HIF-1 activation during hypoxia remain unknown. Here, we demonstrate that p38alpha-/- cells fail to activate HIF-1 under hypoxic conditions. Cells deficient in Mkk3 and Mkk6, the upstream regulators of p38alpha, also fail to activate HIF-1 under hypoxic conditions. The p38alpha-/- cells are able to activate HIF-1 in response to anoxia or iron chelators during normoxia. Furthermore, the hypoxic activation of p38alpha and HIF-1 was abolished by myxothiazol, a mitochondrial complex III inhibitor, and glutathione peroxidase 1 (GPX1), a scavenger of hydrogen peroxide. Thus, the activation of p38alpha and HIF-1 is dependent on the generation of mitochondrial reactive oxygen species. These results provide genetic evidence that p38 mitogen-activated protein kinase signaling is essential for HIF-1 activation.
authors.affiliation: Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA.
authors.forename: Brooke M
authors.initials: BM
authors.lastname: Emerling
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
authors.forename: Emma
authors.initials: E
authors.lastname: Black
authors.forename: Angel R
authors.initials: AR
authors.lastname: Nebreda
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.forename: Navdeep S
authors.initials: NS
authors.lastname: Chandel
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000378:metabolism; D008689:Methacrylates; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013844:Thiazoles / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000094765:Glutathione Peroxidase GPX1
chemical_list: D004268:DNA-Binding Proteins; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008689:Methacrylates; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D013844:Thiazoles; D014157:Transcription Factors; C030517:myxothiazol; D005979:Glutathione Peroxidase; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482531:Map2k3 protein, mouse; C482567:Map2k6 protein, mouse; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse