Department of Molecular Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
Cell. 2011 Apr 1;145(1):92-103. doi: 10.1016/j.cell.2011.02.023.
Upon DNA damage, ataxia telangiectasia mutated (ATM) kinase triggers multiple events to promote cell survival and facilitate repair. If damage is excessive, ATM stimulates cytokine secretion to alert neighboring cells and apoptosis to eliminate the afflicted cell. ATM augments cell survival by activating nuclear factor (NF)-κB; however, how ATM induces cytokine production and apoptosis remains elusive. Here we uncover a p53-independent mechanism that transmits ATM-driven cytokine and caspase signals upon strong genotoxic damage. Extensive DNA lesions stimulated two sequential NF-κB activation phases, requiring ATM and NEMO/IKK-γ: The first phase induced TNF-α-TNFR1 feedforward signaling, promoting the second phase and driving RIP1 phosphorylation. In turn, RIP1 kinase triggered JNK3/MAPK10-dependent interleukin-8 secretion and FADD-mediated proapoptotic caspase-8 activation. Thus, in the context of excessive DNA damage, ATM employs NEMO and RIP1 kinase through autocrine TNF-α signaling to switch on cytokine production and caspase activation. These results shed light on cell-fate regulation by ATM.
在 DNA 损伤后，共济失调毛细血管扩张突变蛋白激酶（ATM）激酶触发多种事件以促进细胞存活并促进修复。如果损伤过大，ATM 会刺激细胞因子分泌以提醒邻近细胞，并通过细胞凋亡来消除受影响的细胞。ATM 通过激活核因子（NF）-κB 来增加细胞存活；然而，ATM 如何诱导细胞因子产生和细胞凋亡仍然难以捉摸。在这里，我们揭示了一种不依赖于 p53 的机制，该机制在强烈的遗传毒性损伤下传递 ATM 驱动的细胞因子和半胱天冬酶信号。广泛的 DNA 损伤刺激了两个连续的 NF-κB 激活阶段，需要 ATM 和 NEMO/IKK-γ：第一阶段诱导 TNF-α-TNFR1 正反馈信号，促进第二阶段并驱动 RIP1 磷酸化。反过来，RIP1 激酶触发 JNK3/MAPK10 依赖性白细胞介素-8 分泌和 FADD 介导的促凋亡半胱天冬酶-8 激活。因此，在过量的 DNA 损伤情况下，ATM 通过自分泌 TNF-α 信号利用 NEMO 和 RIP1 激酶来开启细胞因子产生和半胱天冬酶激活。这些结果阐明了 ATM 对细胞命运的调节作用。
