TY - JOUR
T1 - p38α mediates cell survival in response to oxidative stress via induction of antioxidant genes
T2 - Effect on the p70S6K pathway
AU - Gutiérrez-Uzquiza, Álvaro
AU - Arechederra, María
AU - Bragado, Paloma
AU - Aguirre-Ghiso, Julio A.
AU - Porras, Almudena
PY - 2012/1/20
Y1 - 2012/1/20
N2 - We reveal a novel pro-survival role for mammalian p38α in response to H 2O 2, which involves an up-regulation of antioxidant defenses. The presence of p38α increases basal and H 2O 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 2O 2-induced SOD-2 expression through a direct regulation of transcription mediated by activating transcription factor 2 (ATF-2) and (ii) H 2O 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 2O 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.
AB - We reveal a novel pro-survival role for mammalian p38α in response to H 2O 2, which involves an up-regulation of antioxidant defenses. The presence of p38α increases basal and H 2O 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 2O 2-induced SOD-2 expression through a direct regulation of transcription mediated by activating transcription factor 2 (ATF-2) and (ii) H 2O 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 2O 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.
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U2 - 10.1074/jbc.M111.323709
DO - 10.1074/jbc.M111.323709
M3 - Article
C2 - 22139847
AN - SCOPUS:84856070960
SN - 0021-9258
VL - 287
SP - 2632
EP - 2642
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 4
ER -