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) extracellular signal-regulated kinases (ERK1/2), translocate into nuclei following activation and play critical roles in connecting the signal to gene expression and allowing cell-cycle entry. Here we found that the nuclear translocation of ERK1/2 in response to growth stimuli was significantly inhibited in senescent cells that were irreversibly growth arrested, compared with presenescent cells. The activation step of these enzymes was not impaired, since ERK1/2 were phosphorylated and activated in senescent cells as efficiently as in presenescent cells. By elaborately localizing ERK2 in the nuclei of senescent cells, we could restore c-fos transcriptional activity upon growth stimuli, which was repressed in senescent cells. Furthermore, the nuclear localization of ERK1/2 has been suggested to potentiate the proliferative activity of the senescent cells in collaboration with adenovirus E1A protein. More importantly, SV40 large T antigen, the strong inducer of DNA synthesis, had the inherent ability to restore nuclear relocalization of active ERK1/2 in senescent cells, which was essentially required for the reinitiation of DNA synthesis. Thus, manipulating the relocalization of ERK1/2 into nuclei was expected to open the way to overcome some of the senescent phenotypes.
Kim-Kaneyama
Department of Microbiology, Showa University School of Pharmaceutical Sciences, Hatanodai 1-5-8, Shinagawa-ku, Tokyo 142-8555, Japan.
Nose
K
K
Shibanuma
M
M
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000494:pharmacology; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000494:pharmacology; D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000494:pharmacology; D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics*; D004247:DNA / Q000096:biosynthesis*; D005347:Fibroblasts; D005455:Fluorescent Antibody Technique; D016762:Genes, fos / Q000235:genetics*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019913:Nuclear Localization Signals; D010766:Phosphorylation; D015533:Transcriptional Activation / Q000235:genetics*
D017500:Adenovirus E1A Proteins; D000952:Antigens, Polyomavirus Transforming; D000957:Antigens, Viral, Tumor; D019913:Nuclear Localization Signals; D004247:DNA; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases