p38 MAPK regulates phosphorylation of Bad via MA-dependent suppression of the MEK1/2-ERK1/2 survival pathway in TNF-α induced endothelial apoptosis
p38 MAPK regulates phosphorylation of Bad via MA-dependent suppression of the MEK1/2-ERK1/2 survival pathway in TNF-α induced endothelial apoptosis
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DOI：
10.1016/j.cellsig.2005.05.023
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发表时间：
2006-04-01
影响因子：
4.8
通讯作者：
Pörn-Ares, MI
中科院分区：
文献类型：
--
作者：
Grethe, S;Pörn-Ares, MI
我们最近报道，p38 MAPK通过磷酸化和下调Bcl-xL来调节TNF诱导的内皮细胞凋亡。在这里，我们描述了这样的细胞凋亡包括p38 NIAPK介导的，蛋白磷酸酶2A（PP 2A）依赖的，MEK-ERK通路的下调。用fostriecin或calyculin A抑制PP 2A显著增加MEK磷酸化，暴露于p38 MAPK抑制剂SB 203580也是如此。MEK的抑制增强了TNF诱导的caspase-3活性和细胞死亡，并且这两种事件都被fostriecin或calyculin A抑制。免疫沉淀实验表明，p38 MAPK，PP 2A和MEK之间的关联，和磷酸酶测定的结果表明，PP 2A是p38 MAPK的下游目标。重要的是，发现Bad在Ser-112的磷酸化受p38 MAPK和PP 2A调节。总之，本研究结果表明一种新的p38 MAPK介导的凋亡途径，涉及通过PP 2A依赖性抑制MEK-ERK途径激活Bad。(c)2005年爱思唯尔公司All rights reserved.
We recently reported that p38 MAPK regulates TNF-induced endothelial apoptosis via phosphorylation and downregulation of Bcl-xL. Here, we describe that such apoptosis includes p38 NIAPK-mediated, protein phosphatase 2A (PP2A)-dependent, downregulation of the MEK-ERK pathway. Inhibition of PP2A with fostriecin or calyculin A significantly increased MEK phosphorylation, as did exposure to the p38 MAPK inhibitor SB203580. Inhibition of MEK potentiated TNF-induced caspase-3 activity and cell death, and both those events were suppressed by treatment with fostriecin or calyculin A. Immunoprecipitation experiments revealed an association between p38 MAPK, PP2A and MEK, and the results of a phosphatase assay suggested that PP2A is a downstream target of p38 MAPK. Importantly, phosphorylation of Bad at Ser-112 was found to be regulated by p38 MAPK and PP2A. In summary, the present findings indicate a novel p38 MAPK-mediated apoptosis pathway, involving activation of Bad via PP2A-dependent inhibition of the MEK-ERK pathway. (c) 2005 Elsevier Inc. All rights reserved.