Ectodomain shedding of TNF receptor 1 induced by protein synthesis inhibitors regulates TNF-α-mediated activation of NF-κB and caspase-8
Ectodomain shedding of TNF receptor 1 induced by protein synthesis inhibitors regulates TNF-α-mediated activation of NF-κB and caspase-8
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DOI：
10.1016/j.yexcr.2008.01.019
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发表时间：
2008-04-01
影响因子：
3.7
通讯作者：
Kataoka, Takao
中科院分区：
文献类型：
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作者：
Ogura, Hirotsugu;Tsukumo, Yoshinori;Kataoka, Takao
转录因子核因子 kappa B (NF-kappa B) 在诱导性抵抗死亡受体介导的细胞凋亡中发挥着重要作用。现已确定，蛋白质合成抑制剂放线菌酮 (CHX) 可使多种类型的细胞对肿瘤坏死因子 (TNF)-α 诱导的细胞凋亡敏感，这主要是由于其能够阻断细胞 FLICE 抑制蛋白 (c-FLIP) 的从头合成。然而，我们令人惊讶地发现，CHX 及其结构类似物乙酰氧基放线菌酮 (Ac-CHX) 可以阻止人肺癌 A549 细胞中 TNF-α 介导的 NF-κ B 和 caspase-8 的激活。 CHX 和 Ac-CHX 均以剂量依赖性方式降低细胞表面 TNF 受体 1 (TNF-R1) 的表达，而 Ac-CHX 的效果比 CHX 大约高 100 倍。与这一观察结果一致，Ac-CHX 诱导 TNF-R1 的蛋白水解裂解并将其释放到培养基中。 CHX 和 Ac-CHX 显着降低了 c-FLIP 的组成型和诱导型表达，而这些化合物仅在存在金属蛋白酶抑制剂时才增强 TNF-α 诱导的 caspase-8 激活。因此，我们的结果表明，蛋白质合成抑制剂诱导的 TNF-R1 胞外域脱落调节 TNF-α 介导的 NF-κ B 和 caspase-8 激活。 (C) 2008 Elsevier Inc. 保留所有权利。
The transcription factor nuclear factor kappa B (NF-kappa B) plays a major role in the inducible resistance to death receptor-mediated apoptosis. it has been established that the protein synthesis inhibitor cycloheximide (CHX) sensitizes many types of cells to tumor necrosis factor (TNF)-alpha-induced apoptosis, mainly due to its ability to block de novo synthesis of cellular FLICE-inhibitory protein (c-FLIP). Nevertheless, we have surprisingly found that CHX, as well as its structural analogue acetoxycycloheximide (Ac-CHX), prevents TNF-alpha-mediated activation of NF-kappa B and caspase-8 in human lung carcinoma A549 cells. Both CHX and Ac-CHX reduced the expression of cell surface TNF receptor 1 (TNF-R1) in a dose-dependent manner, while Ac-CHX was approximately 100-fold more effective than CHX. Consistent with this observation, Ac-CHX induced the proteolytic cleavage of TNF-R1 and its release into the culture medium. CHX and Ac-CHX profoundly decreased constitutive and inducible expression of c-FLIP, whereas these compounds potentiated TNF-alpha-induced caspase-8 activation only when metalloprotease inhibitors were present. Thus, our results indicate that ectodomain shedding of TNF-R1 induced by protein synthesis inhibitors regulates TNF-alpha-mediated activation of NF-kappa B and caspase-8. (C) 2008 Elsevier Inc. All rights reserved.