Els artistes i la guerra

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Identification of p38^MAPK-dependent genes with changed transcript abundance in H₂O₂-induced premature senescence of IMR-90 hTERT human fibroblasts

AbstractPremature senescence of IMR-90 human diploid fibroblasts expressing telomerase (hTERT) establishes after exposure to an acute sublethal concentration of H2O2. We showed herein that p38MAPK was phosphorylated after exposure of IMR-90 hTERT cells to H2O2. Selective inhibition of p38MAPK activity attenuated the increase in the proportion of cells positive for senescence associated β-galactosidase activity. We generated a low density DNA array to study gene expression profiles of 240 senescence-related genes. Using this array, p38MAPK inhibitor and p38MAPK small interferent RNA, we identified several p38MAPK-target genes differentially expressed in H2O2-stressed IMR-90 hTERT fibroblasts

Oxidant-induced apoptosis is mediated by oxidation of the actin-regulatory protein cofilin.

Physiological oxidants that are generated by activated phagocytes comprise the main source of oxidative stress during inflammation. Oxidants such as taurine chloramine (TnCl) and hydrogen peroxide (H(2)O(2)) can damage proteins and induce apoptosis, but the role of specific protein oxidation in this process has not been defined. We found that the actin-binding protein cofilin is a key target of oxidation. When oxidation of this single regulatory protein is prevented, oxidant-induced apoptosis is inhibited. Oxidation of cofilin causes it to lose its affinity for actin and to translocate to the mitochondria, where it induces swelling and cytochrome c release by mediating opening of the permeability transition pore (PTP). This occurs independently of Bax activation and requires both oxidation of cofilin Cys residues and dephosphorylation at Ser 3. Knockdown of endogenous cofilin using targeted siRNA inhibits oxidant-induced apoptosis, which is restored by re-expression of wild-type cofilin but not by cofilin containing Cys to Ala mutations. Exposure of cofilin to TnCl results in intramolecular disulphide bonding and oxidation of Met residues to Met sulphoxide, but only Cys oxidation causes cofilin to induce mitochondrial damage