期刊
BIOCHEMICAL PHARMACOLOGY
卷 69, 期 1, 页码 133-146出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2004.08.035
关键词
mitochondria; oxidative stress; PKC; gene delivery; manganese; Parkinson's disease
资金
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES010586] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS045133] Funding Source: NIH RePORTER
- NIEHS NIH HHS [ES10586, R01 ES010586] Funding Source: Medline
- NINDS NIH HHS [NS45133] Funding Source: Medline
Chronic inorganic manganese exposure causes selective toxicity to the nigrostriatal dopaminergic system, resulting in a Parkinsonian-like neurological condition known as Manganism. Apoptosis has been shown to occur in manganese-induced neurotoxicity; however, the down-stream cellular target of caspase-3 that contributes to DNA fragmentation is not established. Herein, we demonstrate that proteolytic activation of protein kinase Cdelta (PKCdelta) by caspase-3 plays a critical role in manganese-induced apoptotic cell death. Treatment of PC12 cells with manganese caused a sequential activation of mitochondrial-dependent pro-apoptotic events, including mitochondrial membrane depolarization, cytochrome c release, caspase-3 activation, and DNA fragmentation. Overexpression of Bcl-2 in PC12 cells remarkably attenuated each of these events, indicating that the mitochondrial-dependent apoptotic cascade contributes to manganese-induced apoptosis. Furthermore, PKCdelta was proteolytically cleaved by caspase-3, causing a persistent activation of the kinase. The manganese-induced proteolytic cleavage of PKCdelta was significantly blocked by Bcl-2-overexpression. Administration of active recombinant PKCdelta induced DNA fragmentation in PC12 cells, suggesting a pro-apoptotic role of PKCdelta. Furthermore, expression of catalytically inactive mutant PKCdelta(K376R) via a lentiviral gene delivery system effectively attenuated manganese-induced apoptosis. Together, these results suggest that the mitochondrial-dependent caspase cascade mediates apoptosis via proteolytic activation of PKCdelta in manganese-induced neurotoxicity. (C) 2004 Elsevier Inc. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据