RT Journal Article
T1 p38α Mediates Cell Survival in Response to Oxidative Stress via Induction of Antioxidant Genes
A1 Gutiérrez Uzquiza, Álvaro
A1 Arechederra, María
A1 Bragado Domingo, Paloma
A1 Aguirre-Ghiso, Julio A.
A1 Porras Gallo, María Almudena
AB 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.
SN 0021-9258
YR 2012
FD 2012-01
LK https://hdl.handle.net/20.500.14352/93522
UL https://hdl.handle.net/20.500.14352/93522
LA eng
NO 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.
NO National Institutes of Health
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO Comunidad de Madrid
NO Universidad Complutense de Madrid
NO Samuel Waxman Cancer Research Foundation Tumor Dormancy
NO New York Stem Cell Science
DS Docta Complutense
RD 1 jul 2024