title: p38α mediates cell survival in response to oxidative stress via induction of antioxidant genes: effect on the p70S6K pathway.
abstract: We reveal a novel pro-survival role for mammalian p38α in response to H(2)O(2), which involves an up-regulation of antioxidant defenses. The presence of p38α increases basal and H(2)O(2)-induced expression of the antioxidant enzymes: superoxide-dismutase 1 (SOD-1), SOD-2, and catalase through different mechanisms, which protects from reactive oxygen species (ROS) accumulation and prevents cell death. p38α was found to regulate (i) H(2)O(2)-induced SOD-2 expression through a direct regulation of transcription mediated by activating transcription factor 2 (ATF-2) and (ii) H(2)O(2)-induced catalase expression through regulation of protein stability and mRNA expression and/or stabilization. As a consequence, SOD and catalase activities are higher in WT MEFs. We also found that this p38α-dependent antioxidant response allows WT cells to maintain an efficient activation of the mTOR/p70S6K pathway. Accordingly, the loss of p38α leads to ROS accumulation in response to H(2)O(2), which causes cell death and inactivation of mTOR/p70S6K signaling. This can be rescued by either p38α re-expression or treatment with the antioxidants, N-acetyl cysteine, or exogenously added catalase. Therefore, our results reveal a novel homeostatic role for p38α in response to oxidative stress, where ROS removal is favored by antioxidant enzymes up-regulation, allowing cell survival and mTOR/p70S6K activation.
authors.affiliation: Departamento de Bioquímica y Biología Molecular II Facultad de Farmacia, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Ciudad Universitaria, 28040 Madrid, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Gutiérrez-Uzquiza
authors.forename: María
authors.initials: M
authors.lastname: Arechederra
authors.forename: Paloma
authors.initials: P
authors.lastname: Bragado
authors.forename: Julio A
authors.initials: JA
authors.lastname: Aguirre-Ghiso
authors.forename: Almudena
authors.initials: A
authors.lastname: Porras
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002374:Catalase / Q000096:biosynthesis* / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D016166:Free Radical Scavengers / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D000072105:Superoxide Dismutase-1; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D000111:Acetylcysteine; D051698:Activating Transcription Factor 2; D002374:Catalase; D016166:Free Radical Scavengers; D006861:Hydrogen Peroxide; D048308:Mitogen-Activated Protein Kinase 14; D016877:Oxidants; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D058570:TOR Serine-Threonine Kinases; D000099156:Superoxide Dismutase 2; C497106:Atf2 protein, mouse; C000606291:Sod1 protein, mouse; C546843:mTOR protein, mouse