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首页> 外文期刊>Molecular pharmacology. >Phorbol 12-myristate 13-acetate protects against tumor necrosis factor (TNF)-induced necrotic cell death by modulating the recruitment of TNF receptor 1-associated death domain and receptor-interacting protein into the TNF receptor 1 signaling comple
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Phorbol 12-myristate 13-acetate protects against tumor necrosis factor (TNF)-induced necrotic cell death by modulating the recruitment of TNF receptor 1-associated death domain and receptor-interacting protein into the TNF receptor 1 signaling comple

机译：Phorbol 12-肉豆蔻酸酯13-乙酸酯通过调节TNF受体1相关死亡域的募集和与受体相互作用的蛋白进入TNF受体1信号传导复合物，来防御肿瘤坏死因子（TNF）诱导的坏死细胞死亡。

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摘要

Protein kinase C (PKC) triggers cellular signals that regulate proliferation or death in a cell- and stimulus-specific manner. Although previous studies have demonstrated that activation of PKC with phorbol 12-myristate 13-acetate (PMA) protects cells from apoptosis induced by a number of mechanisms, including death receptor ligation, little is known about the effect or mechanism of PMA in the necrotic cell death. Here, we demonstrate that PMA-mediated activation of PKC protects against tumor necrosis factor (TNF)-induced necrosis by disrupting formation of the TNF receptor (TNFR)1 signaling complex. Pretreatment with PMA protected L929 cells from TNF-induced necrotic cell death in a PKC-dependent manner, but it did not protect against DNA-damaging agents, including doxorubicin (Adriamycin) and camptothecin. Analysis of the upstream signaling events affected by PMA revealed that it markedly inhibited the TNF-induced recruitment of TNFR1-associated death domain protein (TRADD) and receptor-interacting protein (RIP) to TNFR1, subsequently inhibiting TNF-induced activation of nuclear factor-kappaB and c-Jun NH2-terminal kinase (JNK). However, JNK inhibitors do not significantly affect TNF-induced necrosis, suggesting that the inhibition of JNK activation by PMA is not part of the antinecrotic mechanism. In addition, PMA acted as an antagonist of TNF-induced reactive oxygen species (ROS) production, thereby suppressing activation of ROS-mediated poly(ADP-ribose)polymerase (PARP), and thus inhibiting necrotic cell death. Furthermore, during TNF-induced necrosis, PARP was significantly activated in wild-type mouse embryonic fibroblast (MEF) cells but not in RIP-/- or TNFR-associated factor 2-/-MEF cells. Taken together, these results suggest that PKC activation ensures effective shutdown of the death receptor-mediated necrotic cell death pathway by modulating formation of the death receptor signaling complex.
机译：蛋白激酶C（PKC）触发以细胞和刺激特异性方式调节增殖或死亡的细胞信号。尽管以前的研究表明，用佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）激活PKC可以保护细胞免受多种机制（包括死亡受体连接）诱导的凋亡，但对于PMA在坏死细胞中的作用或机制知之甚少死亡。在这里，我们证明PMA介导的PKC激活可通过破坏TNF受体（TNFR）1信号复合物的形成来防御肿瘤坏死因子（TNF）诱导的坏死。用PMA预处理以PKC依赖的方式保护L929细胞免受TNF诱导的坏死细胞死亡的侵害，但它不能抵抗DNA破坏剂，包括阿霉素（阿霉素）和喜树碱。对受PMA影响的上游信号事件的分析表明，它显着抑制了TNF诱导的TNFR1相关死亡域蛋白（TRADD）和受体相互作用蛋白（RIP）募集到TNFR1，随后抑制了TNF诱导的核因子-活化。 kappaB和c-Jun NH2末端激酶（JNK）。但是，JNK抑制剂不会显着影响TNF诱导的坏死，这表明PMA对JNK激活的抑制作用不是抗肿瘤作用机制的一部分。此外，PMA可以作为TNF诱导的活性氧（ROS）产生的拮抗剂，从而抑制ROS介导的聚（ADP-核糖）聚合酶（PARP）的活化，从而抑制坏死细胞的死亡。此外，在TNF诱导的坏死过程中，PARP在野生型小鼠胚胎成纤维细胞（MEF）细胞中被显着激活，而在RIP-/-或TNFR相关因子2-/-MEF细胞中则未被激活。两者合计，这些结果表明PKC激活通过调节死亡受体信号转导复合物的形成，确保了死亡受体介导的坏死细胞死亡途径的有效关闭。

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