期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 45, 期 7, 页码 1035-1044出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2008.07.011
关键词
cadmium; apoptosis; reactive oxygen species; protein phosphatase 2A; protein phosphatase 5; c-Jun N-terminal kinase; exctracellular signal-regulated kinase 1/2
Cadmium (Cd), a highly toxic environmental pollutant, induces neurodegenerative diseases. Recently we have demonstrated that Cd may induce neuronal apoptosis in part through activation Of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 1/2 (Erk1/2) pathways. However, the underlying mechanism remains enigmatic. Here we show that Cd induced generation of reactive oxygen species (ROS), leading to apoptosis of PC12 and SH-SY5Y cells. Pretreatment with N-acetyl-L-cysteine (NAC) scavenged Cd-induced ROS, and prevented cell death, suggesting that Cd-induced apaptosis is attributed to its induction of ROS. Furthermore, we found that Cd-induced ROS inhibited serine/threonine protein phosphatases 2A (PP2A) and 5 (PP5), leading to activation of Erk1/2 and JNK, which was abrogated by NAC. Overexpression of PP2A or PP5 partially prevented Cd-induced activation of Erk1/2 and JNK, as well as cell death. Cd-induced ROS was also linked to the activation of caspase-3. Pretreatment with inhibitors of JNK (SP600125) and Erk1/2 (1-10126) partially blocked Cd-induced deavage of caspase-3 and prevented cell death. However, zVAD-fmk, a pail caspase inhibitor, only partially prevented Cd-induced apoptosis. The results indicate that Cd induction of ROS inhibits PP2A and PP5, leading to activation of JNK( and EFk1/2 pathways, and consequently resulting in caspase-dependent and -independent apoptosis of neuronal cells. The findings Strongly suggest that the inhibitors of JNK, Erk1/2, or antioxidants may be exploited for prevention of Cd-induced neurodeggenerative diseases. (C) 2008 Elsevier Inc. All Fights 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