期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 281, 期 35, 页码 25215-25222出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M512627200
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资金
- NIEHS NIH HHS [ES 012215, T32 ES007032] Funding Source: Medline
- NINDS NIH HHS [NS44069, NS421021] Funding Source: Medline
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 antiapoptotic, 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 BimEL 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 BimEL, potentiates sodium arsenite-induced apoptosis and by experiments showing direct phosphorylation of BimEL at Ser-65 by p38 in vitro. Furthermore, sodium arsenite induced BimEL 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 BimEL on Ser-65 may be a common regulatory point for cell death induced by both JNK and p38 pathways.
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