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首页> 外文期刊>Oncogene >DISC-mediated activation of caspase-2 in DNA damage-induced apoptosis
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DISC-mediated activation of caspase-2 in DNA damage-induced apoptosis

机译：DISC介导的caspase-2在DNA损伤诱导的凋亡中的激活

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The tumor suppressor p53 protein supports growth arrest and is able to induce apoptosis, a signaling cascade regulated by sequential activation of caspases. Mechanisms that lead from p53 to activation of individual initiator caspases are still unclear. The present model for caspase-2 activation includes PIDDosome complex formation. However, in certain experimental models, elimination of complex constituents PIDD or RAIDD did not significantly influence caspase-2 activation, suggesting the existence of an alternative activation platform for caspase-2. Here we have investigated the link between p53 and caspase-2 in further detail and report that the latter is able to utilize the CD95 DISC as an activation platform. The recruitment of caspase-8 to this complex is required for activation of caspase-2. In the experimental system used, the DISC is formed through a distinct, p53-dependent upregulation of CD95. Moreover, we show that caspase-2 and -8 cleave Bid, and that both act simultaneously upstream of mitochondrial cytochrome c release. Finally, a direct interaction between the two caspases and the ability of caspase-8 to cleave caspase-2 are demonstrated. Thus, the observed functional link between caspase-8 and -2 within the DISC represents an alternative mechanism to the PIDDosome for caspase-2 activation in response to DNA damage.
机译：肿瘤抑制因子p53蛋白支持生长停滞并能够诱导凋亡，这是由胱天蛋白酶顺序激活调节的信号传导级联。从p53导致单个启动子半胱天冬酶激活的机制仍不清楚。 caspase-2激活的当前模型包括PIDDosome复合物的形成。但是，在某些实验模型中，消除复杂成分PIDD或RAIDD不会显着影响caspase-2的激活，这表明存在caspase-2的替代激活平台。在这里，我们进一步研究了p53和caspase-2之间的联系，并报告了后者能够利用CD95 DISC作为激活平台。将caspase-8募集到该复合物中是激活caspase-2所必需的。在所使用的实验系统中，DISC是通过CD95独特的，依赖p53的上调形成的。此外，我们显示caspase-2和-8会切割Bid，并且两者都同时作用于线粒体细胞色素c释放的上游。最后，证明了两个胱天蛋白酶之间的直接相互作用以及胱天蛋白酶8切割胱天蛋白酶2的能力。因此，在DISC中观察到的caspase-8和-2之间的功能性连接代表PIDDosome的另一种机制，可响应DNA损伤激活caspase-2。

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