Role Of C-Fos/JunD In Protecting Stress-induced Cell Death

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.