Induction of apoptosis by TNF receptor 2 in a T-cell hybridoma is FADD dependent and blocked by caspase-8 inhibitors
Induction of apoptosis by TNF receptor 2 in a T-cell hybridoma is FADD dependent and blocked by caspase-8 inhibitors
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DOI：
10.1242/jcs.01640
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发表时间：
2005-02-01
影响因子：
4
通讯作者：
Declercq, W
中科院分区：
文献类型：
--
作者：
Depuydt, B;Van Loo, G;Declercq, W
以前，我们报道了人TNFR 1和TNFR 2介导TNF诱导的细胞凋亡在转染的大鼠/小鼠T细胞杂交瘤PC60。我们在这里表明，TNFR 2介导的PVC 60细胞凋亡可以被广谱半胱天冬酶抑制剂zVAD-favor、半胱天冬酶-8抑制剂zIETD-favor和半胱天冬酶-1和半胱天冬酶-8的病毒抑制剂CrmA阻断。这表明caspase-8参与TNFR 2介导的细胞凋亡。caspase-8的上游衔接子FADD也参与TNFR 2诱导的细胞死亡，因为FADD的显性负缺失突变体的瞬时过表达抑制了该受体诱导的细胞凋亡。TNFR 2诱导的细胞凋亡不依赖于内源性TNF或其他死亡诱导配体的产生以及随后TNFR 1或其他死亡受体的激活。此外，TNFR 2刺激不会增强随后TNFR 1诱导的凋亡信号的敏感性，如Jurkat细胞所报道的那样。TRAF 2下调，这已被提出作为TNFR 2增强TNFR 1信号传导的机制，在PC 60细胞中观察到，但TNRF 1信号未被调节。这些数据证实了TNFR 2产生不依赖于TNFR 1的凋亡细胞死亡信号的能力。
Previously we reported that both human TNFR1 and TNFR2 mediate TNF-induced apoptosis in the transfected rat/mouse T cell hybridoma PC60. We show here that TNFR2-mediated apoptosis in PVC60 cells can be blocked by the broad-spectrum caspase inhibitor zVAD-fmk, the caspase-8 inhibitor zIETD-fmk and by CrmA, a viral inhibitor of caspase-1 and caspase-8. This suggests an involvement of caspase-8 in TNFR2-mediated apoptosis. The upstream adaptor of caspase-8, FADD, is also involved in TNFR2-induced cell death, since transient overexpression of a dominant negative deletion mutant of FADD inhibited apoptosis induced by this receptor. TNFR2-induced apoptosis is independent of endogenous TNF or other death-inducing ligand production and subsequent activation of TNFR1 or other death receptors. Furthermore, TNFR2 stimulation does not enhance sensitivity for a subsequent TNFR1-induced apoptotic signal, as has been reported for Jurkat cells. TRAF2 downregulation, which has been proposed as the mechanism by which TNFR2 enhances TNFR1 signaling, was observed in PC60 cells, but the TNRF1 signal was not modulated. These data confirm the capacity of TNFR2 to generate an apoptotic cell death signal independent of TNFR1.