title: 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.
abstract: 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.
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, 388 Yuhang Tang Road, Hangzhou 310058, PR China.
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Wang
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Jiang
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Fan
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Huang
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.forename: Hongyan
authors.initials: H
authors.lastname: Qi
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Xiangyun
authors.initials: X
authors.lastname: Lu
authors.forename: Jimin
authors.initials: J
authors.lastname: Shao
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D009153:Mutagens / Q000633:toxicity*; D010766:Phosphorylation
chemical_list: D015852:Eukaryotic Initiation Factor-2; D009153:Mutagens; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide