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 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.
Cai
Beibei
B
Toxicology Program, Department of Environmental and Occupational Health Sciences, University of Washington, Box 357234, Seattle, Washington 98195-7234, USA.
Xia
Zhengui
Z
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D018053:Arsenites / Q000494:pharmacology*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000502:physiology; D004789:Enzyme Activation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis*; D008954:Models, Biological; D016716:PC12 Cells; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D017670:Sodium Compounds / Q000494:pharmacology*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D018053:Arsenites; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007093:Imidazoles; D011725:Pyridines; D017670:Sodium Compounds; C017947:sodium arsenite; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D048031:JNK Mitogen-Activated Protein Kinases; C498884:c-jun N-terminal kinase Bim(EL), rat; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole