Distinct signaling pathways in TRAIL- versus tumor necrosis factor-induced apoptosis
Distinct signaling pathways in TRAIL- versus tumor necrosis factor-induced apoptosis
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DOI：
10.1128/mcb.00257-06
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发表时间：
2006-11-01
影响因子：
5.3
通讯作者：
El-Deiry, Wafik S.
中科院分区：
文献类型：
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作者：
Jin, Zhaoyu;El-Deiry, Wafik S.
三聚体肿瘤坏死因子（TNF）结合导致TRADD募集至TNFR 1。在目前的模型中，TRADD募集RIP、TRAF 2和FADD以激活NF-κ B、Jun N-末端蛋白激酶（JNK）和凋亡。使用稳定的短发夹RNA（shRNA）敲低（KD）细胞靶向这些衔接子，TNF死亡诱导信号复合物免疫沉淀证明TRADD和RIP与TNFR 1的竞争性结合，而TRAF 2的招募需要TRADD。KD细胞的分析表明，FADD是必需的Fas-L-或TRAIL-，但不是TNF-诱导的凋亡。有趣的是，TRADD是不稳定的，而RIP是TNF诱导的人肿瘤细胞凋亡所必需的。TRADD是TNF暴露后c-Jun磷酸化所必需的。RIP KD消除了TNF暴露后复合物11的形成，而TRADD KD允许有效的RIP-半胱天冬酶8缔合。用TRAIL处理还诱导含有FADD、RIP、IKK α和半胱天冬酶8和10的复合物11的形成，导致半胱天冬酶8的活化。我们的数据表明，TNF触发细胞凋亡的方式不同于Fas-L或TRAIL。
Trimeric tumor necrosis factor (TNF) binding leads to recruitment of TRADD to TNFR1. In current models, TRADD recruits RIP, TRAF2, and FADD to activate NF-kappa B, Jun N-terminal protein kinase (JNK), and apoptosis. Using stable short-hairpin RNA (shRNA) knockdown (KD) cells targeting these adaptors, TNF death-inducing signaling complex immunoprecipitation demonstrates competitive binding of TRADD and RIP to TNFR1, whereas TRAF2 recruitment requires TRADD. Analysis of KD cells indicates that FADD is necessary for Fas-L- or TRAIL- but not TNF-induced apoptosis. Interestingly, TRADD is dispensable, while RIP is required for TNF-induced apoptosis in human tumor cells. TRADD is required for c-Jun phosphorylation upon TNF exposure. RIP KD abrogates formation of complex 11 following TNF exposure, whereas TRADD KD allows efficient RIP-caspase 8 association. Treatment with TRAIL also induces formation of a complex 11 containing FADD, RIP, IKK alpha, and caspase 8 and 10, leading to activation of caspase 8. Our data suggest that TNF triggers apoptosis in a manner distinct from that of Fas-L or TRAIL.