Modulation of caspase-8 and FLICE-inhibitory protein expression as a potential mechanism of Epstein-Barr virus tumorigenesis in Burkitt's lymphoma
Modulation of caspase-8 and FLICE-inhibitory protein expression as a potential mechanism of Epstein-Barr virus tumorigenesis in Burkitt's lymphoma
复制标题
DOI：
10.1182/blood.v94.5.1727.417k03_1727_1737
复制
发表时间：
1999-09-01
期刊：
影响因子：
20.3
通讯作者：
Seldin, MF
中科院分区：
文献类型：
--
作者：
Tepper, CG;Seldin, MF
Fas受体的结扎诱导死亡诱导信号复合物（DISC）的形成；Caspase的激活和随后的几种细胞的凋亡死亡。eb病毒（EBV）阳性的III组伯基特淋巴瘤（BL）细胞系对Fas介导的细胞凋亡具有明显的抗性，尽管它们表达DISC成分、Fas/ apo -1相关死亡结构域蛋白（FADD）和caspase-8 （FLICE/MACH/Mch5）。由于神经酰胺类似物、staurosporine和颗粒酶B激活caspase-3并诱导凋亡，远端DISC的凋亡通路是完整的。Fas抗性不能用假定的死亡衰减caspase-8亚型来解释。然而，尽管来自敏感细胞的fas激活的细胞质提取物能够将procaspase-8和procaspase-3加工成活性亚基形式，但抗性细胞提取物不具有这两种活性。因此，逆转录聚合酶链反应（RT-PCR）分析显示，抗性细胞中flice抑制蛋白（FLIPL）的转录水平较高，竞争RT-PCR分析测量的caspase-8与FLIPL的比值与所有细胞系对fas介导的凋亡的易感性直接相关，此外，通过caspase-8或FLIPL过表达修饰caspase-8/FLIPL比值能够改变所测细胞系的易感性状态。我们的研究结果表明，caspase-8和FLIPL的相对水平是fas介导的细胞凋亡易感性的重要决定因素。(C) 1999年由美国血液病学会出版。
Ligation of the Fas receptor induces death inducing signaling complex (DISC) formation; caspase activation, and subsequent apoptotic death of several cell types. Epstein-Barr virus (EBV)-positive group III Burkitt's lymphoma (BL) cell lines have a marked resistance to Fas-mediated apoptosis, although expressing each of the DISC components, Fas/ APO-1-associated death domain protein (FADD), and caspase-8 (FLICE/MACH/Mch5). The apoptotic pathway distal to the DISC is intact because ceramide analogs, staurosporine, and granzyme B activate caspase-3 and induce apoptosis. Fas resistance was not explained by the putative death-attenuating caspase-8 isoforms. However, while Fas-activated cytosolic extracts from sensitive cells were capable of processing both procaspase-8 and procaspase-3 into active subunit forms, resistant cell extracts did not possess either of these activities. Accordingly, reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed higher transcript levels for the FLICE-inhibitory protein (FLIPL) in resistant cells and the ratio of caspase-8 to FLIPL measured by competition RT-PCR analysis directly correlated with susceptibility to Fas-mediated apoptosis of all cell lines, In addition, modification of the caspase-8/FLIPL ratio by caspase-8 or FLIPL overexpression was able to alter the susceptibility status of the cell lines tested. Our results imply that the relative levels of caspase-8 and FLIPL are an important determinant of susceptibility to Fas-mediated apoptosis. (C) 1999 by The American Society of Hematology.