Dieldrin promotes proteolytic cleavage of poly(ADP-Ribose) polymerase and apoptosis in dopaminergic cells: Protective effect of mitochondrial anti-apoptotic protein Bcl-2
Dieldrin promotes proteolytic cleavage of poly(ADP-Ribose) polymerase and apoptosis in dopaminergic cells: Protective effect of mitochondrial anti-apoptotic protein Bcl-2
复制标题
DOI：
10.1016/j.neuro.2003.09.014
复制
发表时间：
2004-06-01
期刊：
影响因子：
3.4
通讯作者：
Kanthasamy, AG
中科院分区：
文献类型：
--
作者：
Kitazawa, M;Anantharam, V;Kanthasamy, AG
之前，我们证明了有机氯农药dileldrin可诱导多巴胺能PC12细胞的线粒体去极化、caspase-3激活和凋亡。我们还证明了蛋白激酶Cdelta (PKCdelta)，一个新的PKC蛋白家族的成员，被caspase-3蛋白水解激活，介导凋亡细胞死亡过程。在本研究中，我们进一步表征了主要线粒体抗凋亡蛋白Bcl-2对狄氏剂诱导的多巴胺能细胞凋亡事件的保护作用。暴露于dieldrin (30-100 muM) 3小时内，载体转染的PC12细胞产生显著的细胞毒性和caspase-3激活，而人bcl -2转染的PC12细胞几乎完全抵抗dieldrin诱导的细胞毒性和caspase-3激活。此外，dieldrin （30-300 muM）处理可诱导聚adp -核糖聚合酶（PARP）的蛋白水解裂解，该裂解可通过caspase-3抑制剂Z-DEVD-FMK和Z-VAD-FMK预处理阻断。此外，与载体对照细胞相比，在bcl -2过表达的PC12细胞中，狄氏剂诱导的染色质凝聚和DNA断裂被完全阻断。总之，这些结果清楚地表明，线粒体抗凋亡蛋白的过表达可以保护dieldrin诱导的凋亡细胞死亡，并进一步表明，dieldrin主要改变线粒体功能，从而启动多巴胺能细胞的凋亡细胞死亡。(C) 2003 Elsevier Inc.版权所有。
Previously, we demonstrated that the organochlorine pesticide dieldrin induces mitochondrial depolarization, caspase-3 activation and apoptosis in dopaminergic PC12 cells. We also demonstrated that protein kinase Cdelta (PKCdelta), a member of a novel PKC family of proteins, is proteolytically activated by caspase-3 to mediate apoptotic cell death processes. In the present study, we have further characterized the protective effect of the major mitochondrial anti-apoptotic protein Bcl-2 against dieldrin-induced apoptotic events in dopaminergic cells. Exposure to dieldrin (30-100 muM) produced significant cytotoxicity and caspase-3 activation within 3 h in vector-transfected PC12 cells, whereas human Bcl-2-transfected PC12 cells were almost completely resistant to dieldrin-induced cytotoxicity and caspase-3 activation. Also, dieldrin (30-300 muM) treatment induced proteolytic cleavage of poly(ADP-ribose) polymerase (PARP), which was blocked by pretreatment with caspase-3 inhibitors Z-DEVD-FMK and Z-VAD-FMK. Additionally, dieldrin-induced chromatin condensation and DNA fragmentation were completely blocked in Bcl-2-overexpressed PC12 cells as compared to vector control cells. Together, these results clearly indicate that overexpression of mitochondrial anti-apoptotic protein protects against dieldrin-induced apoptotic cell death and further suggest that dieldrin primarily alters mitochondrial function to initiate apoptotic cell death in dopaminergic cells. (C) 2003 Elsevier Inc. All rights reserved.