Kim Sun Don, Moon Chang Kyu, Eun Su-Yong, Ryu Pan Dong, Jo Sangmee Ahn
Department of Biomedical Sciences, National Institute of Health, Seoul 122-701, Republic of Korea.
Biochem Biophys Res Commun. 2005 Mar 4;328(1):326-34. doi: 10.1016/j.bbrc.2004.11.173.
Cd induces oxidative stress and apoptosis in various cells by activating mitogen-activated protein kinases (MAPKs), but the precise signaling components of the MAPK cascade and their role in neuronal apoptosis are still unclear. Here, we report that Cd treatment of SH-SY5Y cells caused apoptosis through sequential phosphorylation of the apoptosis signal regulating kinase 1, MAPK kinase 4, c-Jun N-terminal kinase (JNK), and c-Jun as determined by overexpression of dominant negative (DN) constructs of these genes or using a specific JNK inhibitor SP600125. Both Cd-induced JNK and c-Jun phosphorylation and apoptosis were inhibited dramatically by N-acetyl-L-cysteine, a free radical scavenger. In addition, caspase inhibitors, zDEVD and zVAD, reduced apoptosis but not JNK and c-Jun phosphorylation induced by Cd, while overexpression of DN JNK1 inhibited caspase-3 activity. Taken together, our data suggested that the JNK/c-Jun signaling cascade plays a crucial role in Cd-induced neuronal cell apoptosis and provides a molecular linkage between oxidative stress and neuronal apoptosis.
镉通过激活丝裂原活化蛋白激酶（MAPK）在各种细胞中诱导氧化应激和凋亡，但MAPK级联反应的确切信号成分及其在神经元凋亡中的作用仍不清楚。在此，我们报告，通过过表达这些基因的显性负性（DN）构建体或使用特异性JNK抑制剂SP600125确定，镉处理SH-SY5Y细胞通过凋亡信号调节激酶1、MAPK激酶4、c-Jun氨基末端激酶（JNK）和c-Jun的顺序磷酸化导致凋亡。自由基清除剂N-乙酰-L-半胱氨酸显著抑制镉诱导的JNK和c-Jun磷酸化以及凋亡。此外，半胱天冬酶抑制剂zDEVD和zVAD减少了凋亡，但未抑制镉诱导的JNK和c-Jun磷酸化，而DN JNK1的过表达抑制了半胱天冬酶-3活性。综上所述，我们的数据表明JNK/c-Jun信号级联在镉诱导的神经元细胞凋亡中起关键作用，并在氧化应激和神经元凋亡之间提供了分子联系。
