p38 MAP kinase mediates arsenite-induced apoptosis through FOXO3a activation and induction of Bim transcription

Sodium arsenite induces apoptosis in PC12 cells by activating the stress-activated p38 MAP kinase and the pro-apoptotic Bcl-2 family protein BimEL. However, the relationship between p38 and BimEL in this apoptosis has not been fully defined. Here, we report that sodium arsenite stimulates the protein expression and promoter activity of BimEL in a p38-dependent manner. Sodium arsenite also caused nuclear translocation of FOXO3a, indicative of FOXO3a activation. Addition of a p38 inhibitor prevented FOXO3a nuclear translocation. RNAi knock down of FOXO3a inhibited Bim promoter activity, BimEL protein expression, and arsenite-induced apoptosis. Our data identify p38 activation of FOXO3a and subsequent induction of BimEL expression as a novel apoptotic mechanism. Together with our previous finding that BimEL is phosphorylated and activated by p38, these results demonstrate that p38 induces apoptosis by regulating BimEL at both the transcriptional and post-translational levels.