Oxidative stress-induced apoptosis is mediated by ERK1/2 phosphorylation
Oxidative stress-induced apoptosis is mediated by ERK1/2 phosphorylation
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DOI：
10.1016/s0014-4827(03)00391-4
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发表时间：
2003-11-15
影响因子：
3.7
通讯作者：
Lee, YS
中科院分区：
文献类型：
--
作者：
Lee, YJ;Cho, HN;Lee, YS
已知氧化应激在多种细胞类型中诱导凋亡，显然是通过调节细胞内信号传导途径。高浓度H2 O2可诱导L929小鼠成纤维细胞凋亡。为了阐明H2 O2介导的细胞凋亡的机制，检测了ERK 1/2、p38-MAPK和JNK 1/2磷酸化，发现ERK 1/2和JNK 1/2被H2 O2激活。用PD 98059或显性负性ERK 2转染处理L929细胞抑制ERK 1/2活化可阻断H2 O2诱导的细胞凋亡，而显性负性JNK 1或JNK 2或MKK 4或MKK 7转染抑制JNK 1/2则不影响H2 O2介导的细胞凋亡。H2 O2介导的ERK 1/2激活不仅依赖于Ras-Raf，而且还依赖于酪氨酸激酶（PDGF β受体和Src）和PKC δ。H2 O2介导的PKC δ依赖性和酪氨酸激酶依赖性ERK 1/2激活相互独立。基于上述结果，我们首次提出氧化损伤诱导的细胞凋亡是由ERK 1/2磷酸化介导的，这种磷酸化不仅依赖于Ras-Raf，而且还依赖于酪氨酸激酶和PKC δ。(C)2003年爱思唯尔公司All rights reserved.
Oxidative stress is known to induce apoptosis in a wide variety of cell types, apparently by modulating intracellular signaling pathways. High concentrations of H2O2 have been found to induce apoptosis in L929 mouse fibroblast cells. To elucidate the mechanisms of H2O2-mediated apoptosis, ERK1/2, p38-MAPK, and JNK1/2 phosphorylation was examined, and ERK1/2 and JNK1/2 were found to be activated by H2O2. Inhibition of ERK1/2 activation by treatment of L929 cells with PD98059 or dominant-negative ERK2 transfection blocked H2O2-induced apoptosis, while inhibition of JNK1/2 by dominant-negative JNK1 or JNK2 or MKK4 or MKK7 transfection did not affect H2O2-mediated apoptosis. H2O2-mediated ERK1/2 activation was not only Ras-Raf dependent, but also both tyrosine kinase (PDGFbeta receptor and Src) and PKCdelta dependent. H2O2-mediated PKCdelta-dependent and tyrosine kinase-dependent ERK1/2 activations were independent from each other. Based on the above results, we suggest for the first time that oxidative damage-induced apoptosis is mediated by ERK1/2 phosphorylation which is not only Ras-Raf dependent, but also both tyrosine kinase and PKCdelta dependent. (C) 2003 Elsevier Inc. All rights reserved.