AP-1-independent sensitization to oxidative stress-induced apoptosis by proteasome inhibitors.
AP-1-independent sensitization to oxidative stress-induced apoptosis by proteasome inhibitors.
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DOI：
10.1016/j.bbrc.2004.02.081
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发表时间：
2004-04
影响因子：
3.1
通讯作者：
N. Hiramatsu;A. Kasai;Jian Yao;Yiman Meng;M. Takeda;S. Maeda;M. Kitamura
中科院分区：
文献类型：
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作者：
N. Hiramatsu;A. Kasai;Jian Yao;Yiman Meng;M. Takeda;S. Maeda;M. Kitamura
过氧化氢（H2O2）通过c-Jun n-末端激酶(JNK)-激活蛋白-1 （AP-1）和细胞外信号调节激酶(ERK)-AP-1途径诱导系膜细胞凋亡。我们最近发现，亚毒性剂量的蛋白酶体抑制剂MG132和lactacystin可显著增强h2o2诱导的系膜细胞凋亡。在本报告中，我们研究了参与这一现象的分子机制，特别是关注AP-1途径。报告细胞实验显示，MG132诱导AP-1活化。然而，AP-1、维甲酸和姜黄素的药物抑制剂并没有抑制MG132的促凋亡作用。转染JNK的显性阴性突变体或c-Jun的显性阴性突变体对JNK - ap -1的抑制均未减弱MG132对细胞凋亡的促进作用。同样，PD98059或ERK的显性阴性突变体对ERK - ap -1的抑制也不影响MG132的促凋亡作用。有趣的是，MG132预处理并没有增强H2O2对AP-1的激活。这些数据表明，蛋白酶体抑制剂具有一种新的、不依赖ap -1的促进细胞凋亡的作用。
Hydrogen peroxide (H2O2) induces apoptosis of mesangial cells via c-Jun N-terminal kinase (JNK)-activator protein-1 (AP-1) and extracellular signal-regulated kinase (ERK)-AP-1 pathways. We recently found that subtoxic doses of proteasome inhibitors, MG132 and lactacystin, dramatically enhanced H2O2-induced apoptosis in mesangial cells. In this report, we examined molecular mechanisms involved in this phenomenon, especially focusing on AP-1 pathways. Reporter assays showed that MG132 induced activation of AP-1. However, pharmacological inhibitors of AP-1, retinoic acid, and curcumin, did not suppress the proapoptotic effect of MG132. Suppression of JNK–AP-1 by transfection with either a dominant-negative mutant of JNK or a dominant-negative mutant of c-Jun did not attenuate the apoptosis enhancement by MG132. Similarly, suppression of ERK–AP-1 by PD98059 or dominant-negative mutants of ERK did not affect the apoptosis-promoting effect of MG132. Interestingly, pretreatment with MG132 did not enhance activation of AP-1 by H2O2. These data suggested a novel, AP-1-independent promotion of apoptosis by proteasome inhibitors.