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oai:docta.ucm.es:20.500.14352/935222024-05-20T13:50:47Zcom_20.500.14352_14col_20.500.14352_15

p38α Mediates Cell Survival in Response to Oxidative Stress via Induction of Antioxidant Genes Gutiérrez Uzquiza, Álvaro Arechederra, María Bragado Domingo, Paloma Aguirre-Ghiso, Julio A. Porras Gallo, María Almudena Biología molecular (Química) 23 Química 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. National Institutes of Health Ministerio de Ciencia, Innovación y Universidades (España) Comunidad de Madrid Universidad Complutense de Madrid Samuel Waxman Cancer Research Foundation Tumor Dormancy New York Stem Cell Science Depto. de Bioquímica y Biología Molecular Fac. de Farmacia TRUE pub 2024-01-17T08:47:35Z 2024-01-17T08:47:35Z 2012-01 journal article VoR https://hdl.handle.net/20.500.14352/93522 0021-9258 10.1074/jbc.m111.323709 1083-351X eng info:eu-repo/grantAgreement/CA109182 info:eu-repo/grantAgreement/ES017146 info:eu-repo/grantAgreement/FIS-PI070071 info:eu-repo/grantAgreement/SAF-2010-20198-C02-01 Gutiérrez-Uzquiza Á, Arechederra M, Bragado P, Aguirre-Ghiso JA, Porras A. p38α Mediates Cell Survival in Response to Oxidative Stress via Induction of Antioxidant Genes. Journal of Biological Chemistry 2012;287:2632–42. https://doi.org/10.1074/jbc.M111.323709. Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ open access application/pdf