A role for the p38 mitogen-activated protein kinase pathway in the transcriptional activation of p53 on genotoxic stress by chemotherapeutic agents

The tumor suppressor p53 plays a central role in sensing damaged DNA and or chestrating the consequent cellular responses. However, how DNA damage lead s to the activation of p53 is still poorly understood. In this study, we ha ve found that the p38 mitogen-activated protein kinase (MAPK) plays a key r ole in the activation of p53 by genotoxic stress when provoked by chemother apeutic agents. Indeed, we found that blockade of p38 prevents stimulation of the transcriptional activity of p53 and that activation of the p38 pathw ay is sufficient to stimulate p53 function. Furthermore, we observed that p 38 does not affect the accumulation of p53 in response to DNA damage or its nuclear localization. In contrast, we observed that p38 associates physica lly with p53, and we provide evidence that this MAPK phosphorylates the NH2 -terminal transactivation domain of p5.7 in serine 33, thereby stimulating its functional activity. Moreover, inhibition of the p38 MAPK diminished th e apoptotic fraction of cells exposed to chemotherapeutic agents and increa sed cell survival, thus suggesting a role for p38 activation in the apoptot ic response to genotoxic stress when elicited by drugs used in cancer thera py.