Phosphorylation of the α-subunit of the eukaryotic initiation factor-2 (eIF2α) alleviates benzo[a]pyrene-7,8-diol-9,10-epoxide induced cell cycle arrest and apoptosis in human cells.
Phosphorylation of the α-subunit of the eukaryotic initiation factor-2 (eIF2α) alleviates benzo[a]pyrene-7,8-diol-9,10-epoxide induced cell cycle arrest and apoptosis in human cells.
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真核起始因子 2 (eIF2α) α 亚基的磷酸化可减轻苯并[a]芘-7,8-二醇-9,10-环氧化物诱导的人类细胞细胞周期停滞和细胞凋亡。
DOI：
10.1016/j.etap.2010.08.005
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发表时间：
2011
影响因子：
4.3
通讯作者：
Jimin Shao
中科院分区：
文献类型：
--
作者：
Qiaoling Wang;Hongjuan Jiang;Yanfeng Fan;Xiaobin Huang;Jing Shen;H. Qi;Qian Li;Xiangyun Lu;Jimin Shao
苯并[a]芘-7，8-二醇-9，10-环氧化物(BPDE)是一种致癌物质，可引起大量的DNA加合物损伤，并诱导广泛的细胞反应，调节细胞周期、细胞存活和细胞凋亡。然而，细胞对BPDE暴露的反应机制还不完全清楚。在这项研究中，我们证明了真核细胞起始因子-2α亚单位(eIF2α)的磷酸化参与了细胞对BPDE的反应，并探讨了eIF2α磷酸化在细胞应激调节中的作用。在正常羊膜上皮细胞系中，eIF2α的磷酸化被诱导，并且eIF2α磷酸化的下游保守转录因子ATF4的表达在BPDE作用后上调，但已知的eIF2α磷酸化的四个主要激酶(GCN2、HRI、PKR和PERK)并未被激活。在BPDE诱导FL细胞发生严重的细胞周期停滞和细胞凋亡并降低细胞存活率的同时，选择性的eIF2α去磷酸化抑制剂salubrine维持eif2α的磷酸化，减轻细胞周期停滞和细胞凋亡，促进细胞存活。结果表明，当BPDE引起细胞损伤时，它也会诱导eIF2α的磷酸化，从而产生促进生存和抗凋亡的作用，从而减轻细胞损伤。因此，本研究提出了一种在环境诱变剂和致癌物攻击中的新的细胞防御机制。
Benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE) is a carcinogen causing bulky-adduct DNA damage and inducing extensive cell responses regulating cell cycle, cell survival and apoptosis. However, the mechanism of cellular responses to BPDE exposure is not fully understood. In this study, we demonstrated the involvement of the phosphorylation of the α-subunit of the eukaryotic initiation factor-2 (eIF2α) in the cellular response to BPDE exposure and addressed the role of eIF2α phosphorylation in the regulation of the cellular stress. Phosphorylation of eIF2α was induced in a normal human FL amnion epithelial cell line, and the expression of ATF4, a conserved downstream transcriptional factor of eIF2α phosphorylation, was up-regulated after BPDE exposure; however, the four known primary kinases for eIF2α phosphorylation (GCN2, HRI, PKR, and PERK) were not found activated. While BPDE induced severe cell cycle arrest and apoptosis and decreased cell viability in FL cells, salubrinal, a selective inhibitor of eIF2α dephosphorylation, maintained the eIF2α phosphorylation and attenuated cell cycle arrest and apoptosis and promoted cell survival. The findings reveal that when BPDE causes cellular damages, it induces eIF2α phosphorylation as well, which produces a pro-survival and anti-apoptotic effect to alleviate the cellular damages. Thus, the present study proposes a new cellular defensive mechanism during the environmental mutagen and carcinogen attack.
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DOI：
10.1074/jbc.m011476200
发表时间：
2001
期刊：
The Journal of biological chemistry
影响因子：
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作者：
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DOI：
--
发表时间：
2002
期刊：
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research
影响因子：
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作者：
Guo,Ning;Faller,DouglasV;Vaziri,Cyrus
通讯作者：
Vaziri,Cyrus