p44/42 MAP kinase and c-Jun N-terminal kinase contribute to the up-regulation of caspase-3 in manganese-induced apoptosis in PC12 cells
p44/42 MAP kinase and c-Jun N-terminal kinase contribute to the up-regulation of caspase-3 in manganese-induced apoptosis in PC12 cells
复制标题
DOI：
10.1016/j.brainres.2006.03.126
复制
发表时间：
2006-07-12
期刊：
影响因子：
2.9
通讯作者：
Hirata, Yoko
中科院分区：
文献类型：
--
作者：
Ito, Yoshimasa;Oh-hashi, Kentaro;Hirata, Yoko
Caspase-3（32 kDa）是细胞凋亡的主要蛋白酶执行者之一，并通过链内蛋白水解切割激活，其产生大亚基（17 kDa）和小亚基（12 kDa）。通常，在凋亡刺激后，裂解的半胱天冬酶-3的水平增加，而半胱天冬酶-3的水平降低。已经显示，在创伤性脑损伤或局灶性缺血后，皮质中半胱天冬酶-3 mRNA水平增加。在本研究中，我们证明，caspase-3的mRNA和蛋白的增加，在凋亡的PC 12细胞暴露于锰强烈诱导caspase-3裂解。caspase-3蛋白的上调在锰处理的PC 12细胞中是明显的，并且在顺铂、鱼藤酮和A23187处理的细胞中是中等的，但在血清剥夺、茴香霉素、喜树碱、放线菌酮或星形孢菌素处理的细胞中没有观察到，其中所有处理均诱导广泛的DNA片段化。用MEK抑制剂U 0126预处理可以部分减弱锰诱导的caspase-3 mRNA上调，但用c-Jun N末端激酶（INK）抑制剂SP 600125预处理则没有减弱。相反，caspase-3蛋白的增加被U 0126和SP 600125抑制。这些结果表明，p44/42 MAPK参与了锰诱导的PC 12细胞凋亡过程中caspase-3 mRNA的上调，JNK途径参与了caspase-3蛋白水平的后调节。(c)2006 Elsevier B. V.保留所有权利。
Caspase-3 (32 kDa) is one of the primary protease executioners of apoptosis and is activated by intra-chain proteolytic cleavage, which generates a large subunit (17 kDa) and a small subunit (12 kDa). Typically, after apoptotic stimuli, the level of cleaved caspase-3 increases while that of caspase-3 decreases. It has been shown that caspase-3 mRNA levels increase in cortex following traumatic brain injury or focal ischemia. In the present study, we demonstrate that both caspase-3 mRNA and protein increase in apoptotic PC12 cells following exposure to manganese which strongly induces caspase-3 cleavage. Up-regulation of caspase-3 protein was evident in manganese-treated PC12 cells and was moderate in cisplatin-, rotenone- and A23187-treated cells but was not observed in serum deprivation-, anisomycin-, camptothecin-, cycloheximide- or staurosporine-treated cells in which all treatments induced extensive DNA fragmentation. Manganese-induced up-regulation of caspase-3 mRNA was partially attenuated by the pretreatment with the MEK inhibitor U0126, but not with the c-Jun N-terminal kinase (INK) inhibitor SP600125. In contrast, the increase in caspase-3 protein was suppressed by both U0126 and SP600125. These results suggest that p44/42 MAPK contributes to the up-regulation of caspase-3 mRNA and the JNK pathway regulates caspase-3 protein levels posttranslationally in manganese-induced apoptosis in PC12 cells. (c) 2006 Elsevier B.V. All rights reserved.