Activation of apoptosis by Apo-2 ligand is independent of FADD but blocked by CrmA
Activation of apoptosis by Apo-2 ligand is independent of FADD but blocked by CrmA
复制标题
DOI：
10.1016/s0960-9822(09)00456-4
复制
发表时间：
1996-06-01
期刊：
影响因子：
9.2
通讯作者：
Ashkenazi, A
中科院分区：
文献类型：
--
作者：
Marsters, SA;Pitti, RM;Ashkenazi, A
肿瘤坏死因子（TNF）细胞因子家族的新成员，命名为Apo-2配体（Apo-2L）[1]或TRAIL [2]，最近已显示可诱导各种肿瘤细胞系的凋亡;然而，其生物学作用尚不清楚。在这里，我们表明，载脂蛋白PL激活的外周血淋巴细胞的T细胞富集培养物中的细胞凋亡的白细胞介素-2（IL-2）刺激，但不是在未受刺激的细胞。这一发现表明，与Fas/Apo-1配体和TNF [3-5]一样，Apo-2L可能在调节成熟淋巴细胞的刺激后凋亡中发挥作用。对Apo-2L作用机制的研究表明，在将Apo-2L加入肿瘤细胞的几分钟内，细胞膜出现明显的气泡，这是细胞凋亡的标志。FADD的显性负突变体的异位表达，FADD是一种通过Fas/Apo-1和TNF受体1型（TNFR 1）介导死亡信号的细胞质蛋白[6-9]，抑制抗Fas/Apo-1抗体诱导细胞凋亡，但对Apo-2L功能几乎没有影响。相反，CrmA（Ced-3样蛋白酶ICE [10]和CPP 32/Yama [11，12]的牛痘病毒衍生的抑制剂）的表达阻断了Apo-2L或抗Fas/Apo-1抗体对凋亡的诱导。非FADD依赖性途径触发细胞死亡程序，需要ICE或CPP 32/Yama等半胱氨酸蛋白酶的功能。
A new member of the tumor necrosis factor (TNF) cytokine family, designated Apo-2 ligand (Apo-2L) [1] or TRAIL [2], has been shown recently to induce apoptosis in various tumor cell lines; however, its biological role is unknown. Here, we show that Apo-PL activated apoptosis in T-cell-enriched cultures of peripheral blood lymphocytes stimulated by interleukin-2 (IL-2), but not in unstimulated cells. This finding suggests that, like Fas/Apo-1 ligand and TNF [3-5], Apo-2L may play a role in regulating post-stimulation apoptosis of mature lymphocytes. Studies on the mechanism of Apo-2L action demonstrated marked membrane blebbing, a hallmark of apoptosis, within a few minutes of the addition of Apo-2L to tumor cells, Ectopic expression of a dominant negative mutant of FADD, a cytoplasmic protein that mediates death signalling by Fas/Apo-1 and by TNF receptor type 1 (TNFR1) [6-9], inhibited the induction of apoptosis by anti-Fas/Apo-1 antibody, but had little effect on Apo-2L function, In contrast, expression of CrmA, a cowpox virus-derived inhibitor of the Ced-3-like proteases ICE [10] and CPP32/Yama [11,12], blocked the induction of apoptosis by either Apo-2L or anti-Fas/Apo-1 antibody These results suggest that Apo-PL activates a rapid, FADD-independent pathway to trigger a cell-death programme that requires the function of cysteine proteases such as ICE or CPP32/Yama.