首页> 外文OA文献 >Sustained Activation of p38 Mitogen-Activated Protein Kinase and c-Jun N-Terminal Kinase Pathways by Hepatitis B Virus X Protein Mediates Apoptosis via Induction of Fas/FasL and Tumor Necrosis Factor (TNF) Receptor 1/TNF-α Expression
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Sustained Activation of p38 Mitogen-Activated Protein Kinase and c-Jun N-Terminal Kinase Pathways by Hepatitis B Virus X Protein Mediates Apoptosis via Induction of Fas/FasL and Tumor Necrosis Factor (TNF) Receptor 1/TNF-α Expression

机译:乙型肝炎病毒X蛋白持续激活p38丝裂原活化蛋白激酶和c-Jun N末端激酶途径通过诱导Fas / FasL和肿瘤坏死因子(TNF)受体1 /TNF-α表达介导细胞凋亡。

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摘要

Activation of the cellular stress pathways (c-Jun N-terminal kinase [JNK] and p38 mitogen-activated protein [MAP] kinase) is linked to apoptosis. However, whether both pathways are required for apoptosis remains unresolved. Hepatitis B virus X protein (pX) activates p38 MAP kinase and JNK pathways and, in response to weak apoptotic signals, sensitizes hepatocytes to apoptosis. Employing hepatocyte cell lines expressing pX, which was regulated by tetracycline, we investigated the mechanism of apoptosis by p38 MAP kinase and JNK pathway activation. Inhibition of the p38 MAP kinase pathway rescues by 80% the initiation of pX-mediated apoptosis, whereas subsequent apoptotic events involve both pathways. pX-mediated activation of p38 MAP kinase and JNK pathways is sustained, inducing the transcription of the death receptor family genes encoding Fas/FasL and tumor necrosis factor receptor 1 (TNFR1)/TNF-α and the p53-regulated Bax and Noxa genes. The pX-dependent expression of Fas/FasL and TNFR1/TNF-α mediates caspase 8 activation, resulting in Bid cleavage. In turn, activated Bid, acting with pX-induced Bax and Noxa, mediates the mitochondrial release of cytochrome c, resulting in the activation of caspase 9 and apoptosis. Combined antibody neutralization of FasL and TNF-α reduces by 70% the initiation of pX-mediated apoptosis. These results support the importance of the pX-dependent activation of both the p38 MAP kinase and JNK pathways in pX-mediated apoptosis and suggest that this mechanism of apoptosis occurs in vivo in response to weak apoptotic signals.
机译:细胞应激途径的激活(c-Jun N端激酶[JNK]和p38丝裂原活化蛋白[MAP]激酶)与细胞凋亡相关。然而,凋亡是否同时需要两条途径仍未解决。乙型肝炎病毒X蛋白(pX)激活p38 MAP激酶和JNK通路,并响应弱的凋亡信号,使肝细胞对凋亡敏感。利用表达由四环素调节的pX的肝细胞系,我们研究了p38 MAP激酶和JNK途径激活的凋亡机制。对p38 MAP激酶途径的抑制可将pX介导的细胞凋亡的发生率提高80%,而随后的凋亡事件则涉及这两个途径。 pX介导的p38 MAP激酶和JNK途径的激活得以持续,从而诱导了编码Fas / FasL和肿瘤坏死因子受体1(TNFR1)/TNF-α的死亡受体家族基因以及p53调控的Bax和Noxa基因的转录。 Fas / FasL和TNFR1 /TNF-α的pX依赖性表达介导caspase 8激活,导致Bid切割。反过来,激活的Bid与pX诱导的Bax和Noxa相互作用,介导细胞色素c的线粒体释放,导致caspase 9的激活和凋亡。 FasL和TNF-α的结合抗体中和使pX介导的细胞凋亡的启动减少了70%。这些结果支持pX介导的凋亡中p38 MAP激酶和JNK途径的依赖于pX的激活的重要性,并表明这种凋亡机制是在体内对弱凋亡信号的响应中发生的。

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