SEPARATION OF OXIDANT-INITIATED AND REDOX-REGULATED STEPS IN THE NF-KAPPA-B SIGNAL-TRANSDUCTION PATHWAY
SEPARATION OF OXIDANT-INITIATED AND REDOX-REGULATED STEPS IN THE NF-KAPPA-B SIGNAL-TRANSDUCTION PATHWAY
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DOI：
10.1073/pnas.91.24.11527
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发表时间：
1994-11-22
影响因子：
11.1
通讯作者：
HERZENBERG, LA
中科院分区：
文献类型：
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作者：
ANDERSON, MT;STAAL, FJT;HERZENBERG, LA
研究表明，总体NF-κ B信号转导开始于一系列平行的刺激特异性途径，通过这些途径，细胞因子（肿瘤坏死因子α）、氧化剂（过氧化氢和丝裂霉素C）和佛波酯（佛波醇12肉豆蔻酸酯13-乙酸酯）分别启动信号传导。这些初始途径最终形成一个共同途径，所有的刺激剂最终通过该共同途径发出NF-κ B激活的信号。我们区分的刺激特异性途径显示，氧化刺激触发NF-κ B B激活只有一个两个人的T细胞系（维尔茨堡，但不是Jurkat），而肿瘤坏死因子欧盟和佛波醇12-肉豆蔻酸酯13-乙酸酯容易刺激两个线。我们提出的共同途径作为会计的共同要求和信号通路的属性的最简单的方式。我们在该共同途径中包括氧化还原调节机制，以解释先前证明的Jurkat细胞中NF-κ B活化的氧化还原调节（其中氧化剂不活化NF-κ B）;我们通过显示激酶活性（可由除莠霉素A和酪氨酸磷酸化蛋白47证实）是两种细胞系中测试的所有刺激物活化NF-κ B所需的，将酪氨酸磷酸化置于共同途径中。由于氧化剂产生的内部位点已被证明在烟碱刺激的NF-κ B活化中起关键作用，并且由于酪氨酸激酶和磷酸酶活性已知被氧化剂改变，这些发现表明细胞内氧化还原状态通过调节NF-κ B信号转导途径的共同步骤内的酪氨酸磷酸化事件来控制NF-κ B活化。
Studies presented here show that overall NF-kappa B signal transduction begins with a parallel series of stimuli-specific pathways through which cytokines (tumor necrosis factor alpha), oxidants (hydrogen peroxide and mitomycin C), and phorbol ester (phorbol 12 myristate 13-acetate) individually initiate signaling. These initial pathways culminate in a common pathway through which all of the stimulating agents ultimately signal NF-kappa B activation. We distinguish the stimuli-specific pathways by showing that the oxidative stimuli trigger NF-kappa B activation in only one of two human T-cell lines (Wurzburg but not Jurkat), whereas tumor necrosis factor eu and phorbol 12-myristate 13-acetate readily stimulate in both lines. We propose the common pathway as the simplest way of accounting for the common requirements and properties of the signaling pathway. We include a redox-regulatory mechanism(s) in this common pathway to account for the previously demonstrated redox regulation of NF-kappa B activation in Jurkat cells (in which oxidants don't activate NF-kappa B); we put tyrosine phosphorylation in the common pathway by showing that kinase activity (inhibitable by herbimycin A and tyrphostin 47) is required for NF-kappa B activation by all stimuli tested in both cell lines. Since internal sites of oxidant production have been shown to play a key role in the cytokine-stimulated activation of NF-kappa B, and since tyrosine kinase and phosphatase activities are known to be altered by oxidants, these findings suggest that intracellular redox status controls NF-kappa B activation by regulating tyrosine phosphorylation event(s) within the common step of the NF-kappa B signal transduction pathway.