ECRG4 is a negative regulator of caspase-8-mediated apoptosis in human T-leukemia cells
ECRG4 is a negative regulator of caspase-8-mediated apoptosis in human T-leukemia cells
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DOI：
10.1093/carcin/bgs118
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发表时间：
2012-05-01
期刊：
影响因子：
4.7
通讯作者：
Sato, Noriyuki
中科院分区：
文献类型：
--
作者：
Matsuzaki, Junichi;Torigoe, Toshihiko;Sato, Noriyuki
我们以前从人类T细胞白血病细胞系Jurkat和SUP-T13中建立了Fas抗性变异克隆。Fas抗性克隆和Fas敏感克隆的比较基因表达分析显示，在Fas抗性克隆中有几个基因表达异常。其中一个基因，食道癌相关基因4(ECRG4)，含有一个类似VDAC2的结构域，可能与细胞凋亡信号有关。在本研究中，我们研究了ECRG4在Fas介导的细胞凋亡中的亚细胞定位和功能。共聚焦荧光显微镜检测到ECRG4-EGFP融合蛋白存在于转基因HeLa细胞的线粒体、内质网和高尔基体中。在Fas敏感的Jurkat细胞中过表达ECRG4抑制线粒体膜通透性转换，从而抵抗Fas诱导的细胞凋亡。在ECRG4过表达的Jurkat细胞中，肿瘤坏死因子-α诱导的细胞凋亡也被抑制。免疫沉淀实验证明ECRG4与前天冬氨酸蛋白酶-8结合。其作用机制包括抑制caspase-8活性和Bid裂解。由于ECRG4在活化的T细胞中表达下调，我们的结果提示ECRG4是一个新的抗凋亡基因，它参与了caspase-8介导的T细胞凋亡的负调控。
We previously established Fas-resistant variant clones from the human T-cell leukemia lines Jurkat and SUP-T13. Comparative gene expression analysis of the Fas-resistant and Fas-sensitive clones revealed several genes that were aberrantly expressed in the Fas-resistant clones. One of the genes, esophageal cancer-related gene 4 (ECRG4), contained a VDAC2-like domain that might be associated with apoptotic signals. In the present study, we examined the subcellular localization and function of ECRG4 in Fas-mediated apoptosis. By confocal fluorescence microscopy, ECRG4-EGFP fusion protein was detected in mitochondria, endoplasmic reticulum and the Golgi apparatus in gene-transfected HeLa cells. Overexpression of ECRG4 in Fas-sensitive Jurkat cells inhibited mitochondrial membrane permeability transition, leading to resistance against Fas-induced apoptosis. Tumor necrosis factor-alpha-induced apoptosis was also suppressed in ECRG4-overexpressing Jurkat cells. Immunoprecipitation assay demonstrated that ECRG4 is associated with procaspase-8. The inhibitory mechanism included the inhibition of caspase-8 activity and Bid cleavage. Since ECRG4 expression is downregulated in activated T cells, our results suggest that ECRG4 is a novel antiapoptotic gene which is involved in the negative regulation of caspase-8-mediated apoptosis in T cells.