p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65.
The stress-activated c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein (MAP) kinase (p38) regulate apoptosis induced by several forms of cellular insults. Potential targets for these kinases include members of the Bcl-2 family proteins, which mediate apoptosis generated through the mitochondria-initiated, intrinsic cell death pathway. Indeed, the activities of several Bcl-2 family proteins, both pro- and anti-apoptotic, are controlled by JNK phosphorylation. For example, the pro-apoptotic activity of Bim(EL), a member of the Bcl-2 family, is stimulated by JNK phosphorylation at Ser-65. In contrast, there is no reported evidence that p38-induced apoptosis is due to direct phosphorylation of Bcl-2 family proteins. Here we report evidence that sodium arsenite-induced apoptosis in PC12 cells may be due to direct phosphorylation of Bim(EL) at Ser-65 by p38. This conclusion is supported by data showing that ectopic expression of a wild type, but not a non-phosphorylatable S65A mutant of Bim(EL), potentiates sodium arsenite-induced apoptosis and by experiments showing direct phosphorylation of Bim(EL) at Ser-65 by p38 in vitro. Furthermore, sodium arsenite induced Bim(EL) phosphorylation at Ser-65, which was blocked by p38 inhibition. This study provides the first example whereby p38 induces apoptosis by phosphorylating a member of the Bcl-2 family and illustrates that phosphorylation of Bim(EL) on Ser-65 may be a common regulatory point for cell death induced by both JNK and p38 pathways.
Cai
Beibei
B
Toxicology Program, Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195-7234, USA.
Chang
Sandra H
SH
Becker
Esther B E
EB
Bonni
Azad
A
Xia
Zhengui
Z
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000378:metabolism; D018053:Arsenites / Q000494:pharmacology; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D018384:Oxidative Stress; D016716:PC12 Cells; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000737:chemistry; D017670:Sodium Compounds / Q000494:pharmacology; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D018053:Arsenites; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D017670:Sodium Compounds; D012694:Serine; C017947:sodium arsenite; D048051:p38 Mitogen-Activated Protein Kinases