c-Fos/JunD异源二聚体对应激条件下细胞的保护作用
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摘要
组织细胞在受到包括创伤在内的各种外界刺激作用下发生应激反应。应激反应诱导哺乳动物细胞内立早基因例如c-fos和c-jun的表达以及转录因子激活剂蛋白-1(AP-1)的活化。我们研究了两种立早基因的产物c-Fos和JunD在应激条件诱导的细胞死亡中所起的作用。研究发现对原代培养的小鼠胚胎成纤维细胞(MEF)进行短波紫外线(UV-C)或者过氧化氢(H2O2)的刺激,细胞内c-Fos和JunD的蛋白表达明显上升,而且,这两种蛋白相互作用形成的异源二聚体AP-1的活性也上升。更重要的是,过表达JunD或者同时过表达c-Fos和JunD能够降低UV-C或者H2O2这两种刺激引起的细胞内caspase 3的活性,缓解细胞死亡。同时,UV-C激活了有丝分裂原激动蛋白激酶-细胞外信号调节激酶(MAPK/ERK1/2)信号通路。为了进一步研究UV-C诱导的情况下,细胞内ERK1/2的活化对c-Fos和JunD的蛋白表达的作用,我们使用了ERK激酶MEK1的特异性抑制剂PD98059预处理细胞。研究发现,在UV-C诱导的细胞中,抑制MEK1/ERK1/2的活性能够加强c-Fos和JunD的蛋白表达以及caspase 3的活性,缓解细胞死亡。我们的研究结果表明在原代培养的MEF中,UV或者H2O2诱导的c-Fos/JunD异源二聚体的活化缓解了这两种刺激引起的细胞死亡,而且,UV-C诱导c-Fos/JunD的表达上升是由MAPK/ERK1/2信号通路的活化所介导的。
The exposure of mammalian cells to extracellular stress induces the expression of immediate early genes such as c-fos and c-jun and activates the transcription factors activator protein-1 (AP-1). In the present study, we investigated the role of c-Fos and JunD in stress-induced cell death. We found that the exposure of primary cultured mouse embryonic fibroblast (MEF) cells to ultraviolet (UV-C) or hydrogen peroxide (H2O2) caused a significant increase in c-Fos and JunD protein levels. In addition, these two proteins heterodimerized with each other and contributed to the activation of AP-1 transcription complex. More importantly, in both stress conditions, overexpression of JunD alone or overexpression both c-Fos and JunD reduced caspase 3 activity and cell death. At the same time, UV irradiation activated MAPK/ERK1/2 signaling pathway. To further investigate the effect of UV-induced ERK1/2 activation on the protein expression of c-Fos and JunD, PD98059, a specific inhibitor of MEK1, was used to pre-treat cells before UV irradiation. The suppression of MEK1/ERK1/2 activation inhibited UV-induced expression of c-Fos and JunD. In addition, inhibition of ERK1/2 increased caspase 3 activity and cell death. Our results suggest that both UV and H2O2 induce the activation of c-Fos/JunD heterodimers resulting in the prevention of cell death. Moreover, UV irradiation-induced increases in c-Fos/JunD expression in primary MEF cells are mediated through activation of MAPK/ERK1/2 signaling pathway.
The exposure of mammalian cells to extracellular stress induces the expression of immediate early genes such as c-fos and c-jun and activates the transcription factors activator protein-1 (AP-1). In the present study, we investigated the role of c-Fos and JunD in stress-induced cell death. We found that the exposure of primary cultured mouse embryonic fibroblast (MEF) cells to ultraviolet (UV-C) or hydrogen peroxide (H2O2) caused a significant increase in c-Fos and JunD protein levels. In addition, these two proteins heterodimerized with each other and contributed to the activation of AP-1 transcription complex. More importantly, in both stress conditions, overexpression of JunD alone or overexpression both c-Fos and JunD reduced caspase 3 activity and cell death. At the same time, UV irradiation activated MAPK/ERK1/2 signaling pathway. To further investigate the effect of UV-induced ERK1/2 activation on the protein expression of c-Fos and JunD, PD98059, a specific inhibitor of MEK1, was used to pre-treat cells before UV irradiation. The suppression of MEK1/ERK1/2 activation inhibited UV-induced expression of c-Fos and JunD. In addition, inhibition of ERK1/2 increased caspase 3 activity and cell death. Our results suggest that both UV and H2O2 induce the activation of c-Fos/JunD heterodimers resulting in the prevention of cell death. Moreover, UV irradiation-induced increases in c-Fos/JunD expression in primary MEF cells are mediated through activation of MAPK/ERK1/2 signaling pathway.
引文
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