Glutathione peroxidase-1 protects from CD95-induced apoptosis
Glutathione peroxidase-1 protects from CD95-induced apoptosis
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DOI：
10.1074/jbc.m203067200
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发表时间：
2002-11-08
影响因子：
4.8
通讯作者：
Levade, T
中科院分区：
文献类型：
--
作者：
Gouazé, V;Andrieu-Abadie, N;Levade, T
通过诱导细胞凋亡，CD 95在免疫应答和消除癌细胞中起着至关重要的作用。CD 95受体的连接激活了一个复杂的信号网络，似乎涉及活性氧（ROS）的产生。本研究探讨了ROS产生在CD 95介导的细胞凋亡中的作用以及抗氧化酶谷胱甘肽过氧化物酶-1（GPx 1）的作用。抗CD 95抗体在人乳腺癌T47 D细胞中触发了ROS的早期产生，该ROS被GPx 1的过表达和起始剂caspase活化的抑制所阻断。GPxl的增强表达也导致抑制CD 95诱导的效应物半胱天冬酶活化、DNA片段化和凋亡性细胞死亡。对CD 95介导的细胞凋亡的抵抗不是由于抗凋亡分子表达的增加，并且可以通过谷胱甘肽耗竭剂逆转。此外，尽管抗凋亡蛋白Bcl-xL阻止了MCF-7细胞中CD 95诱导的凋亡，但它并不抑制早期ROS的产生。此外，Bcl-xL而不是GPx 1过表达可以抑制星形孢菌素诱导的ROS晚期产生和随后的细胞死亡。总而言之，这些发现表明GPx 1在线粒体事件上游发挥作用，抑制CD 95连接诱导的早期活性氧产生和细胞凋亡。最后，过表达GPx 1的转基因小鼠部分地免受抗CD 95的致死作用，这是过氧化物形成（和GPx 1）在CD 95触发的细胞凋亡中的重要性的基础。
Through the induction of apoptosis, CD95 plays a crucial role in the immune response and the elimination of cancer cells. Ligation of CD95 receptor activates a complex signaling network that appears to implicate the generation of reactive oxygen species (ROS). This study investigated the place of ROS production in CD95-mediated apoptosis and the role of the antioxidant enzyme glutathione peroxidase-1 (GPx1). Anti-CD95 antibodies triggered an early generation of ROS in human breast cancer T47D cells that was blocked by overexpression of GPx1 and inhibition of initiator caspase activation. Enforced expression of GPxl also resulted in inhibition of CD95-induced effector caspase activation, DNA fragmentation, and apoptotic cell death. Resistance to CD95-mediated apoptosis was not due to an increased expression of anti-apoptotic molecules and could be reversed by glutathione-depleting agents. In addition, whereas the anti-apoptotic protein Bcl-xL prevented CD95-induced apoptosis in MCF-7 cells, it did not inhibit the early ROS production. Moreover, Bcl-xL but not GPx1 overexpression could suppress the staurosporine-induced late generation of ROS and subsequent cell death. Altogether, these findings suggest that GPx1 functions upstream of the mitochondrial events to inhibit the early ROS production and apoptosis induced by CD95 ligation. Finally, transgenic mice overexpressing GPx1 were partially protected from the lethal effect of antiCD95, underlying the importance of peroxide formation (and GPx1) in CD95-triggered apoptosis.