Role for ceramide as an endogenous mediator of Fas-induced cytotoxicity.
Role for ceramide as an endogenous mediator of Fas-induced cytotoxicity.
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DOI：
10.1073/pnas.92.18.8443
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发表时间：
1995-08
影响因子：
11.1
通讯作者：
C. Tepper;S. Jayadev;Bin Liu;A. Bielawska;R. A. Wolff;S. Yonehara;Y. Hannun;M. Seldin
中科院分区：
文献类型：
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作者：
C. Tepper;S. Jayadev;Bin Liu;A. Bielawska;R. A. Wolff;S. Yonehara;Y. Hannun;M. Seldin
Fas/APO-1细胞表面受体的触发通过未表征的事件链诱导细胞凋亡。Fas敏感细胞暴露于激动剂单克隆抗体诱导细胞死亡和200-300%的内源性鞘脂神经酰胺水平的升高，鞘脂神经酰胺是一种拟议的细胞内凋亡介质。相比之下，类似的治疗Fas耐药细胞引起神经酰胺水平的变化微不足道。由于抗性细胞系表达Fas抗原，这些结果表明这些细胞在导致神经酰胺产生的近端信号传导事件中存在缺陷。将耐药细胞系暴露于神经酰胺的合成类似物诱导细胞凋亡，从而绕过Fas耐药，并表明神经酰胺下游的信号传导途径是完整的。此外，激活蛋白激酶C与二酰基甘油类似物佛波醇12-肉豆蔻酸酯13-乙酸酯显着降低Fas诱导的细胞毒性，这表明神经酰胺和蛋白激酶C在调节细胞凋亡的相反作用。这些结果为神经酰胺作为Fas介导的细胞凋亡的必要和足够的脂质介质提供了证据，并表明这一过程可能通过激活额外的信号转导途径来调节。
Triggering of the Fas/APO-1 cell-surface receptor induces apoptosis through an uncharacterized chain of events. Exposure of Fas-sensitive cells to an agonist monoclonal antibody induced cell death and a 200-300% elevation in endogenous levels of the sphingolipid ceramide, a proposed intracellular mediator of apoptosis. In contrast, similar treatment of Fas-resistant cells caused insignificant changes in ceramide levels. Because resistant cell lines expressed the Fas antigen, these results indicate that these cells have a defect in the proximal signaling events leading to ceramide generation. Exposure of the resistant cell lines to a synthetic analog of ceramide induced apoptosis, thus bypassing Fas resistance and indicating that the signaling pathways downstream of ceramide were intact. Furthermore, activation of protein kinase C with the diacylglycerol analog phorbol 12-myristate 13-acetate significantly reduced Fas-induced cytotoxicity, suggesting opposing roles for ceramide and protein kinase C in regulation of apoptosis. These results provide evidence for ceramide as a necessary and sufficient lipid mediator of Fas-mediated apoptosis and suggest this process may be modulated via activation of additional signal-transduction pathways.