Role of ERK activation in cisplatin-induced apoptosis in OK renal epithelial cells
Role of ERK activation in cisplatin-induced apoptosis in OK renal epithelial cells
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DOI：
10.1002/jat.1081
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发表时间：
2005-09-01
影响因子：
3.3
通讯作者：
Kim, JM
中科院分区：
文献类型：
--
作者：
Kim, YK;Kim, HJ;Kim, JM
顺铂可诱导多种细胞类型的凋亡。然而，顺铂诱导肾上皮细胞凋亡的信号通路尚不清楚。本研究旨在利用负鼠肾细胞确定细胞外信号调节激酶（ERK）在顺铂诱导的肾上皮细胞凋亡中的作用。50gm顺铂诱导细胞凋亡呈时间依赖性。顺铂治疗引起ERK1/2的持续活化，而ERK1/2上游激酶MEK1/2的抑制剂PD98059和U0126可以阻止ERK1/2的持续活化。瞬时转染具有组成性活性MEK1的细胞增加了顺铂诱导的细胞凋亡，而具有MEK1显性阴性突变体的细胞则减少了细胞凋亡。顺铂诱导Bax表达、线粒体膜去极化、线粒体细胞色素c释放和caspase-3激活增加，而MEK抑制剂可阻止这些变化。这些结果表明：(1)ERK1/2激活是顺铂诱导肾上皮细胞凋亡的必要条件；(2) ERK1/2通过作用于Bax表达上游介导线粒体依赖性凋亡信号。版权所有(C) 2005 John Wiley & Sons, Ltd。
Cisplatin induces apoptosis in a variety of cell types. However, the signaling pathway of cisplatin-induced lapoptosis in renal epithelial cells,is poorly understood. The present study was undertaken to determine the role of the extracellular signal-regulated kinase (ERK) in cisplatin-induced apoptosis of renal epithelial cells using opossum kidney cells. Cisplatin at 50 gm induced apoptosis in a time-dependent manner. Cisplatin treatment caused sustained activation of ERK1/2, which was prevented by PD98059 and U0126, inhibitors of ERK1/2 upstream kinase MEK1/2. Transient transfection of cells with constitutive active MEK1 increased the cisplatin-induced apoptosis, whereas that with a dominant-negative mutant of MEK1 decreased it. Cisplatin induced an increase in Bax expression, mitochondrial membrane depolarization, mitochondrial cytochrome c release and caspase-3 activation, and these changes were prevented by the MEK inhibitor. These results suggested that (1) the ERK1/2 activation is required for the cisplatin-induced apoptosis of renal epithelial cells; and (2) ERK1/2 mediates the mitochondria-dependent apoptotic signaling by acting upstream of Bax expression. Copyright (C) 2005 John Wiley & Sons, Ltd.