Bid participates in genotoxic drug-induced apoptosis of HeLa cells and is essential for death receptor ligands' apoptotic and synergistic effects.
Bid participates in genotoxic drug-induced apoptosis of HeLa cells and is essential for death receptor ligands' apoptotic and synergistic effects.
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DOI：
10.1371/journal.pone.0002844
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发表时间：
2008-07-30
期刊：
影响因子：
3.7
通讯作者：
Prehn JH
中科院分区：
文献类型：
--
作者：
Köhler B;Anguissola S;Concannon CG;Rehm M;Kögel D;Prehn JH
BH 3-only蛋白Bid是死亡受体介导的半胱天冬酶激活的重要组成部分。Bid被半胱天冬酶-8或-10切割成t-Bid，其易位到线粒体并触发半胱天冬酶激活因子的释放。Bid也被报道被其他蛋白酶切割。为了检验这一假设，投标是一个中央调解人的压力诱导的细胞凋亡，我们研究了小分子投标抑制剂的影响，压力诱导的细胞凋亡，并产生HeLa细胞缺乏投标。bid的稳定敲低导致对Fas/CD 95和TRAIL诱导的半胱天冬酶活化和凋亡的显著抗性，并显著增加克隆形成存活。虽然BID缺陷细胞对ER应激诱导的细胞凋亡同样敏感，但它们显示出中度但显著降低的细胞凋亡水平，以及对遗传毒性药物依托泊苷、奥沙利铂和阿霉素的反应增加的克隆形成存活。使用Bid抑制剂BI 6C 9观察到类似的效果。有趣的是，当亚毒性浓度的ER应激物、依托泊苷或奥沙利铂与亚毒性浓度的TRAIL组合时，Bid缺陷细胞被显著保护免于凋亡。我们的数据表明，Bid是中央死亡受体诱导的细胞死亡，并参与抗癌药物诱导的人宫颈癌HeLa细胞凋亡。他们还表明，TRAIL与ER应激物或遗传毒性抗癌药物组合的协同效应几乎完全通过增加Bid诱导的细胞凋亡信号传导的活化来介导。
The BH3-only protein Bid is an important component of death receptor-mediated caspase activation. Bid is cleaved by caspase-8 or -10 into t-Bid, which translocates to mitochondria and triggers the release of caspase-activating factors. Bid has also been reported to be cleaved by other proteases. To test the hypothesis that Bid is a central mediator of stress-induced apoptosis, we investigated the effects of a small molecule Bid inhibitor on stress-induced apoptosis, and generated HeLa cells deficient for Bid. Stable knockdown of bid lead to a pronounced resistance to Fas/CD95- and TRAIL-induced caspase activation and apoptosis, and significantly increased clonogenic survival. While Bid-deficient cells were equally sensitive to ER stress-induced apoptosis, they showed moderate, but significantly reduced levels of apoptosis, as well as increased clonogenic survival in response to the genotoxic drugs Etoposide, Oxaliplatin, and Doxorubicin. Similar effects were observed using the Bid inhibitor BI6C9. Interestingly, Bid-deficient cells were dramatically protected from apoptosis when subtoxic concentrations of ER stressors, Etoposide or Oxaliplatin were combined with subtoxic TRAIL concentrations. Our data demonstrate that Bid is central for death receptor-induced cell death and participates in anti-cancer drug-induced apoptosis in human cervical cancer HeLa cells. They also show that the synergistic effects of TRAIL in combination with either ER stressors or genotoxic anti-cancer drugs are nearly exclusively mediated via an increased activation of Bid-induced apoptosis signalling.
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影响因子：
8
作者：
Concannon, C. G.;Koehler, B. F.;Prehn, J. H. M.
通讯作者：
Prehn, J. H. M.
影响因子：
4.8
作者：
Gao, ZH;Shao, YF;Jiang, XJ
通讯作者：
Jiang, XJ
DOI：
10.1073/pnas.0603460103
发表时间：
2006-08-15
影响因子：
11.1
作者：
Becattini, Barbara;Culmsee, Carsten;Pellecchia, Maurizio
通讯作者：
Pellecchia, Maurizio
影响因子：
11.2
作者：
Jiang, Chen Chen;Chen, Li Hua;Hersey, Peter
通讯作者：
Hersey, Peter
影响因子：
12.4
作者：
Ganten, TM;Haas, TL;Walczak, H
通讯作者：
Walczak, H