Differential role of caspase-8 and BID activation during radiation- and CD95-induced apoptosis
Differential role of caspase-8 and BID activation during radiation- and CD95-induced apoptosis
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DOI：
10.1038/sj.onc.1203401
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发表时间：
2000-02-24
期刊：
影响因子：
8
通讯作者：
Schulze-Osthoff, K
中科院分区：
文献类型：
--
作者：
Belka, C;Rudner, J;Schulze-Osthoff, K
CD 95死亡受体的激活以及电离辐射诱导人淋巴瘤细胞的凋亡性细胞死亡。半胱天冬酶的激活是细胞凋亡诱导的标志，与细胞凋亡触发无关。与死亡受体信号传导相反，辐射诱导的半胱天冬酶激活的确切机制还不清楚。我们提供的证据表明，辐射和CD 95刺激都诱导Jurkat T细胞中caspase-8和BID的快速活化，随后是凋亡。为了分析caspase-8在凋亡级联中的相对位置，我们研究了过表达Bcl-2或Bcl-x（L）的Jurkat细胞中的caspase活化和凋亡。Caspase-8激活，促凋亡BID裂解和细胞凋亡在这些细胞中的辐射响应被废除，而对CD 95刺激的反应仅部分衰减过表达的Bcl-2家族成员。与此同时，Bcl-2/Bcl-x（L）的过表达抑制了辐射引起的线粒体跨膜电位（Δ Psi（m））的降低。发现caspase-8基因缺陷的Jurkat细胞对CD 95完全耐受，然而，caspase-8阴性细胞中辐射诱导的凋亡反应仅显示出适度的降低。我们的结论是，电离辐射激活caspase-8和BID下游的线粒体损伤表明，与CD 95相反，这两个事件的功能作为刽子手，而不是启动程序的凋亡过程。
Activation of the CD95 death receptor as well as ionizing radiation induces apoptotic cell death in human lymphoma cells. The activation of caspases is a hallmark of apoptosis induction irrespective of the apoptotic trigger. In contrast to death receptor signaling, the exact mechanisms of radiation-induced caspase activation are not well understood. We provide evidence that both, radiation and CD95 stimulation, induce the rapid activation of caspase-8 and BID followed by apoptosis in Jurkat T-cells, To analyse the relative position of caspase-8 within the apoptotic cascade we studied caspase activation and apoptosis in Jurkat cells overexpressing Bcl-2 or Bcl-x(L). Caspase-8 activation, proapoptotic BID cleavage and apoptosis in response to radiation were abrogated in these cells, while the responses to CD95 stimulation were only partially attenuated by overexpression of Bcl-2 family members. In parallel, the breakdown of the mitochondrial transmembrane potential (Delta Psi(m),) in response to radiation was inhibited by overexpression of Bcl-2/Bcl-x(L) Jurkat cells genetically deficient for caspase-8 were found to be completely resistant towards CD95, However, radiation-induced apoptotic responses in caspase-8-negative cells displayed only a modest reduction. We conclude that ionizing radiation activates caspase-8 and BID downstream of mitochondrial damage suggesting that, in contrast to CD95, both events function as executioners rather than initiators of the apoptotic process.