Overexpression of manganese superoxide dismutase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-KB and activated protein-1
Overexpression of manganese superoxide dismutase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-KB and activated protein-1
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DOI：
10.1074/jbc.273.21.13245
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发表时间：
1998-05-22
影响因子：
4.8
通讯作者：
Aggarwal, BB
中科院分区：
文献类型：
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作者：
Manna, SK;Zhang, HJ;Aggarwal, BB
最近发现的几种细胞内蛋白与肿瘤坏死因子 (TNF) 受体相关，并激活核转录因子 (NF)-kappa B、c-Jun 激酶和细胞凋亡。然而，其机制尚不清楚。在本报告中，我们研究了活性氧中间体在 TNF 诱导的信号传导中的作用。人乳腺癌MCF-7细胞中锰超氧化物歧化酶（Mn-SOD）的过度表达完全消除了TNF介导的NF-κB激活、IκBα降解、p65核易位和NF-κB依赖性报告基因表达。除 TNF 外，佛波酯、大田酸、神经酰胺和脂多糖诱导的 NF-κ B 诱导的激活也被 Mn-SOD 阻断，表明存在共同的激活途径。然而，H2O2 诱导的 NF-κ B 激活被增强。此外，Mn-SOD 还可阻断 TNF 介导的激活蛋白 1、应激激活的 c-Jun 蛋白激酶和丝裂原激活的蛋白激酶激酶的激活。 Mn-SOD 转染细胞也完全抑制了 TNF 诱导的抗增殖作用和 caspase-3 激活（细胞凋亡指标）。 Mn-SOD 也能抑制大田酸、H2O2 和紫杉醇诱导的细胞凋亡，但不会抑制长春新碱、长春花碱或道诺霉素诱导的细胞凋亡。总的来说，这些结果表明，除了最近发现的几种信号分子外，活性氧中间体在 NF-κ B 的激活、活化的 Protein-1、c-Jun 激酶以及 TNF 和其他药物诱导的细胞凋亡中发挥着关键作用。
Several recently identified intracellular proteins associate with the tumor necrosis factor (TNF) receptor and activate nuclear transcription factor (NF)-kappa B, c-Jun kinase, and apoptosis. However, the mechanism is not understood. In the present report, we investigated the role of reactive oxygen intermediates in TNF-induced signaling. Overexpression of manganese superoxide dismutase (Mn-SOD) in human breast cancer MCF-7 cells completely abolished TNF-mediated NF-kappa B activation, I kappa B alpha degradation, p65 nuclear translocation, and NF-kappa B-dependent reporter gene expression. Besides TNF, phorbol ester-, okadaic acid-, ceramide-, and lipopolysaccharide-induced activation of NF-kappa B was blocked by Mn-SOD, indicating a common pathway of activation. H2O2-induced NF-kappa B activation, however, was potentiated. In addition, Mn-SOD blocked the TNF-mediated activation of activated protein-1, stress-activated c-Jun protein kinase, and mitogen-activated protein kinase kinase. TNF-induced antiproliferative effects and caspase-3 activation, indicators of apoptosis, were also completely suppressed by transfection of cells with Mn-SOD. Suppression of apoptosis induced by okadaic acid, H2O2, and taxol was also inhibited by Mn-SOD but not that induced by vincristine, vinblastine, or daunomycin. Overall, these results demonstrate that, in addition to several recently identified signaling molecules, reactive oxygen intermediates play a critical role in activation of NF-kappa B, activated protein-1, c-Jun kinase, and apoptosis induced by TNF and other agents.