Common regulation of apoptosis signaling induced by CD95 and the DNA-damaging stimuli etoposide and γ-radiation downstream from caspase-8 activation
Common regulation of apoptosis signaling induced by CD95 and the DNA-damaging stimuli etoposide and γ-radiation downstream from caspase-8 activation
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DOI：
10.1074/jbc.274.20.14255
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发表时间：
1999-05-14
影响因子：
4.8
通讯作者：
Borst, J
中科院分区：
文献类型：
--
作者：
Boesen-de Cock, JGR;Tepper, AD;Borst, J
死亡受体CD95(APO-1/Fas)、抗癌药物依托泊苷和伽玛射线可诱导人T细胞系Jurkat的凋亡。筛选出的抗CD95诱导细胞凋亡的变异克隆对依托泊苷和辐射诱导的细胞凋亡具有交叉抗性，这表明这些不同刺激诱导的细胞凋亡途径具有共同的关键成分(S)。这些通路不会在CD95连接或caspase-8信号水平上汇聚。而caspase-8功能是CD95介导的细胞色素c释放、效应caspase激活和细胞凋亡所必需的，但当caspase-8被Flipl抑制时，这些反应在依托泊苷处理和照射的细胞中不受影响。CD95、依托泊苷和伽玛射线辐射激活的Jurkat细胞中，Caspase效应蛋白的处理和细胞色素c的释放均受到抑制，提示在Jurkat细胞中，CD95、依托泊苷和伽玛射线激活的凋亡信号通路受到共同的线粒体调控。这三种刺激都能诱导野生型细胞产生神经酰胺，但不能诱导抗性变异细胞产生神经酰胺。外源性神经酰胺在突变细胞中绕过了凋亡抵抗，但在转Bcl2基因的细胞中不能，这表明CD95、依托泊苷和伽玛射线诱导的凋亡信号在不同于Bcl2靶向的水平上受到共同的调控。
The death receptor CD95 (APO-1/Fas), the anticancer drug etoposide, and gamma-radiation induce apoptosis in the human T cell line Jurkat. Variant clones selected for resistance to CD95-induced apoptosis proved cross-resistant to etoposide- and radiation-induced apoptosis, suggesting that the apoptosis pathways induced by these distinct stimuli have critical component(s) in common. The pathways do not converge at the level of CD95 ligation or caspase-8 signaling. Whereas caspase-8 function was required for CD95-mediated cytochrome c release, effector caspase activation, and apoptosis, these responses were unaffected in etoposide-treated and irradiated cells when caspase-8 was inhibited by FLIPL. Both effector caspase processing and cytochrome c release were inhibited in the resistant variant cells as well as in Bcl-2 transfectants, suggesting that, in Jurkat cells, the apoptosis signaling pathways activated by CD95, etoposide, and gamma-radiation are under common mitochondrial control. All three stimuli induced ceramide production in wild-type cells, but not in resistant variant cells. Exogenous ceramide bypassed apoptosis resistance in the variant cells, but not in Bcl-2-transfected cells, suggesting that apoptosis signaling induced by CD95, etoposide, and gamma-radiation is subject to common regulation at a level different from that targeted by Bcl-2.