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

Abstract

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

ID4 regulates mammary gland development by suppressing p38MAPK activity

“…pBimEL was not activated following Id4 knockdown-mediated p38MAPK activation in ZD2855 mammary tumor cells (data not shown). Furthermore, ConsiRNA-and Id4siRNA-treated ZD2855 mammary tumor cells did not exhibit differences in the levels of p53 and FOXO3 (data not shown), which have also been reported to mediate p38MAPK-induced apoptosis (Cai et al, 2006;Cai and Xia, 2008). Therefore, it is not yet clear how Id4 loss and the associated p38MAPK activation cause apoptosis in these mammary cancer cells.…”

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

“…Roscovitine was purchased from LC Laboratories. Antibodies against Cdk5 (C-8), actin (C-2), Lamin A (H-102), Foxo3 (N-15), MAP2 (H300) and PSD95 (7E3) were purchased from Santa Cruz Biotechnology (Cai and Xia, 2008;Chang et al, 2011Chang et al, , 2012. All antibodies were used at 1:1000 dilution.…”

BH3-only proteins and their roles in programmed cell death

“…Although BH3-only proteins are often considered as the first step in the apoptosis signaling cascade, mainly because their overexpression or BH3 peptides are sufficient to trigger cell death in vitro, they are activated in vivo by a signaling cascade that is unlikely to have, as sole target, a particular BH3 protein. Let's take an example: Sodium arsenite kills PC12 cells by activating p38 MAP kinase, which in turn causes the translocation of FoxO3A into the nucleus, which induces the expression of BimEL (Cai and Xia, 2008). How many targets other than FoxO3A may have p38 activated, how many genes other than Bim may have FoxO3A turned on, or off ?…”