Significance of nuclear relocalization of ERK1/2 in reactivation of c-fos transcription and DNA synthesis in senescent fibroblasts

Two of mitogen-activated protein kinases (MAPK) p44(mapk)/p42(mapk) extrace llular signal-regulated kinases (ERK1/2), translocate into nuclei following activation and play critical roles in connecting the signal to gene expres sion and allowing cell-cycle entry. Here we found that the nuclear transloc ation of ERK1/2 in response to growth stimuli was significantly inhibited i n senescent cells that were irreversibly growth arrested, compared with pre senescent cells. The activation step of these enzymes was not impaired, sin ce ERK1/2 were phosphorylated and activated in senescent cells as efficient ly as in presenescent cells. By elaborately localizing ERK2 in the nuclei o f senescent cells, we could restore c-fos transcriptional activity upon gro wth stimuli, which was repressed in senescent cells. Furthermore, the nucle ar localization of ERK1/2 has been suggested to potentiate the proliferativ e activity of the senescent cells in collaboration with adenovirus E1A prot ein. More importantly, SV40 large T antigen, the strong inducer of DNA synt hesis, had the inherent ability to restore nuclear relocalization of active ERK1/2 in senescent cells, which was essentially required for the reinitia tion of DNA synthesis. Thus, manipulating the relocalization of ERK1/2 into nuclei was expected to open the way to overcome some of the senescent phen otypes.