p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65
p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65
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DOI：
10.1074/jbc.m512627200
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发表时间：
2006-09-01
影响因子：
4.8
通讯作者：
Xia, Zhengui
中科院分区：
文献类型：
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作者：
Cai, Beibei;Chang, Sandra H.;Xia, Zhengui
应激激活的c-jun氨基末端蛋白激酶(JNK)和p38丝裂原活化蛋白(MAP)激酶(P38)调节多种形式的细胞损伤诱导的细胞凋亡。这些激酶的潜在靶点包括Bcl-2家族蛋白的成员，这些蛋白通过线粒体启动的内在细胞死亡途径介导细胞凋亡。事实上，几个Bcl-2家族蛋白的活性，无论是促凋亡还是抗凋亡，都是由JNK磷酸化控制的。例如，Bim(EL)是Bcl-2家族的成员之一，它的促凋亡活性是由Ser-65处的JNK磷酸化刺激的。相反，目前还没有证据表明p38诱导的细胞凋亡是由于bcl2家族蛋白的直接磷酸化。在这里，我们报告了亚砷酸钠诱导PC12细胞凋亡的证据，可能是由于p38直接磷酸化了Ser-65处的BimEL。支持这一结论的数据表明，BimEL的野生型而不是非磷酸化的S65A突变体的异位表达增强了亚砷酸钠诱导的细胞凋亡，并且体外实验表明p38直接磷酸化了BimEL的Ser-65位。此外，亚砷酸钠诱导Ser-65处BimEL的磷酸化，并被p38抑制。这项研究提供了第一个例子，p38通过磷酸化Bcl-2家族的一个成员来诱导细胞凋亡，并说明BimEL在Ser-65上的磷酸化可能是JNK和p38途径诱导细胞死亡的共同调控点。
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.