Sheikh M S, Antinore M J, Huang Y, Fornace A J
Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Oncogene. 1998 Nov 19;17(20):2555-63. doi: 10.1038/sj.onc.1202292.
Ultraviolet (UV)-irradiation has been shown to induce jun N-terminal kinase activity via aggregation-mediated activation of tumor necrosis factor receptor 1 (TNFR1) but the role of TNFR1 in mediating UV-induced apoptosis has not been explored. Using p53-null cells, we demonstrate that UV-stimulated ligand independent activation of TNFR1 plays a major role in mediating the apoptotic effects of UV-irradiation. UV-irradiation and TNF alpha acted in a synergistic manner to induce apoptosis. UV-irradiation stimulated the aggregation-mediated activation of TNFR1 which was coupled with activation of caspase 8, the most proximal caspase in TNF alpha signaling pathway. CrmA and the dominant negative versions of FADD, caspase 8 and caspase 10, that block the apoptotic axis of TNFR1 at different levels, also independently inhibited the UV-induced apoptosis. The engagement of the membrane initiated events was specific for UV-irradiation since neither CrmA nor the dominant negative FADD, caspase 8 or caspase 10 blocked the ionizing radiation-induced apoptosis. Cisplatin and melphalan, the UV-mimetic agents known to elicit UV-type DNA damage, also induced apoptosis but differed from UV in that both of the former agents engaged the caspase cascade at a level distal to FADD. Consistent with these findings cisplatin also did not stimulate TNFR1 aggregation. Together these results indicate that DNA damage per se was not sufficient to activate the membrane TNFR1. Based on our results we propose that the plasma membrane initiated events play a predominant role in mediating UV-irradiation-induced apoptosis and that UV-irradiation appears to engage the apoptotic axis of TNFR1 and perhaps those of other membrane death receptors to transduce its apoptotic signals.
紫外线（UV）照射已被证明可通过聚集介导的肿瘤坏死因子受体1（TNFR1）激活来诱导Jun N端激酶活性，但TNFR1在介导紫外线诱导的细胞凋亡中的作用尚未得到探索。使用p53基因缺失的细胞，我们证明紫外线刺激的TNFR1配体非依赖性激活在介导紫外线照射的凋亡效应中起主要作用。紫外线照射和肿瘤坏死因子α以协同方式诱导细胞凋亡。紫外线照射刺激了聚集介导的TNFR1激活，这与半胱天冬酶8的激活相关联，半胱天冬酶8是肿瘤坏死因子α信号通路中最上游的半胱天冬酶。CrmA以及FADD、半胱天冬酶8和半胱天冬酶10的显性负性变体，它们在不同水平阻断TNFR1的凋亡轴，也独立抑制紫外线诱导的细胞凋亡。膜起始事件的参与对紫外线照射具有特异性，因为CrmA和显性负性FADD、半胱天冬酶8或半胱天冬酶10均不阻断电离辐射诱导的细胞凋亡。顺铂和美法仑是已知可引发紫外线型DNA损伤的紫外线模拟剂，它们也诱导细胞凋亡，但与紫外线不同的是，前两者均在FADD下游水平参与半胱天冬酶级联反应。与这些发现一致，顺铂也不刺激TNFR1聚集。这些结果共同表明，DNA损伤本身不足以激活膜TNFR1。基于我们的结果，我们提出质膜起始事件在介导紫外线照射诱导的细胞凋亡中起主要作用，并且紫外线照射似乎参与TNFR1的凋亡轴，也许还参与其他膜死亡受体的凋亡轴来转导其凋亡信号。
