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

Álvaro Gutiérrez-Uzquiza, María Arechederra, Paloma Bragado, Julio A. Aguirre-Ghiso, Almudena Porras

Research output: Contribution to journalArticlepeer-review

104 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2632-2642
Number of pages11
JournalJournal of Biological Chemistry
Volume287
Issue number4
DOIs
StatePublished - Jan 20 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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