p38α mediates cell survival in response to oxidative stress via induction of antioxidant genes: effect on the p70S6K pathway

• Published in: The Journal of biological chemistry 2012-01, Vol.287 (4), p.2632-2642
• Main Authors: Gutiérrez-Uzquiza, Álvaro, Arechederra, María, Bragado, Paloma, Aguirre-Ghiso, Julio A, Porras, Almudena
• Format: Article
• Language: English
• Subjects: Acetylcysteine - pharmacology; Activating Transcription Factor 2 - genetics; Activating Transcription Factor 2 - metabolism; Animals; Catalase - biosynthesis; Catalase - genetics; Cell Line; Cell Survival - drug effects; Cell Survival - physiology; Free Radical Scavengers - pharmacology; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - physiology; Hydrogen Peroxide - pharmacology; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 14 - genetics; Mitogen-Activated Protein Kinase 14 - metabolism; Oxidants - pharmacology; Oxidative Stress - drug effects; Oxidative Stress - physiology; Ribosomal Protein S6 Kinases, 70-kDa - genetics; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Signal Transduction; Signal Transduction - drug effects; Signal Transduction - physiology; Superoxide Dismutase - biosynthesis; Superoxide Dismutase - genetics; Superoxide Dismutase-1; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.323709

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.