p38 MAP kinase mediates bax translocation in nitric oxide-induced apoptosis in neurons.
p38 MAP kinase mediates bax translocation in nitric oxide-induced apoptosis in neurons.
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DOI：
10.1083/jcb.150.2.335
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发表时间：
2000-07-24
影响因子：
7.8
通讯作者：
Morrison, R S
中科院分区：
文献类型：
--
作者：
Ghatan, S;Larner, S;Kinoshita, Y;Hetman, M;Patel, L;Xia, Z;Youle, R J;Morrison, R S
一氧化氮是一种化学信使，与缺血、神经退行性疾病和兴奋性毒性相关的神经元损伤有关。兴奋性毒性损伤导致NO形成增加，以及刺激神经元中的p38促分裂原活化蛋白（MAP）激酶。在本研究中，我们确定了一氧化氮诱导的神经元细胞死亡是否依赖于p38 MAP激酶活性。硝普钠（SNP），一氧化氮供体，提高半胱天冬酶的活性，并诱导死亡的人SH-SY 5 Y神经母细胞瘤细胞和原代培养的皮层神经元。伴随治疗SB 203580，p38 MAP激酶抑制剂，减少半胱天冬酶的诱导和保护SH-SY 5 Y细胞和原代培养的皮质神经元从NO诱导的细胞死亡，而半胱天冬酶抑制剂zVAD-fastin没有提供显着的保护。p38 MAP激酶的作用通过观察进一步证实，SB 203580阻断了SNP处理后细胞死亡激活剂Bax从细胞质到线粒体的易位。此外，表达组成型活性形式的MKK 3，p38 MAP激酶的直接激活剂促进Bax易位和细胞死亡的SNP的情况下。Bax缺陷的皮质神经元对SNP具有抗性，进一步证明Bax在这种细胞死亡模式中的必要性。这些结果表明，p38 MAP激酶活性在NO介导的神经元细胞死亡中起着关键作用，通过刺激Bax易位到线粒体，从而激活细胞死亡途径。
Nitric oxide is a chemical messenger implicated in neuronal damage associated with ischemia, neurodegenerative disease, and excitotoxicity. Excitotoxic injury leads to increased NO formation, as well as stimulation of the p38 mitogen-activated protein (MAP) kinase in neurons. In the present study, we determined if NO-induced cell death in neurons was dependent on p38 MAP kinase activity. Sodium nitroprusside (SNP), an NO donor, elevated caspase activity and induced death in human SH-SY5Y neuroblastoma cells and primary cultures of cortical neurons. Concomitant treatment with SB203580, a p38 MAP kinase inhibitor, diminished caspase induction and protected SH-SY5Y cells and primary cultures of cortical neurons from NO-induced cell death, whereas the caspase inhibitor zVAD-fmk did not provide significant protection. A role for p38 MAP kinase was further substantiated by the observation that SB203580 blocked translocation of the cell death activator, Bax, from the cytosol to the mitochondria after treatment with SNP. Moreover, expressing a constitutively active form of MKK3, a direct activator of p38 MAP kinase promoted Bax translocation and cell death in the absence of SNP. Bax-deficient cortical neurons were resistant to SNP, further demonstrating the necessity of Bax in this mode of cell death. These results demonstrate that p38 MAP kinase activity plays a critical role in NO-mediated cell death in neurons by stimulating Bax translocation to the mitochondria, thereby activating the cell death pathway.