title: Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway.
abstract: BACKGROUND
  Cellular senescence is a state of irreversible growth arrest shown by normal cells, and has been most extensively studied in replicative senescence caused by telomere shortening. Several conditions, including oncogenic Ras over-expression and inappropriate culture conditions, also induce senescence without telomere shortening. However, it remains unclear how a common set of senescence phenotypes is indistinguishably induced in various types of senescence.
  
  
  RESULTS
  We demonstrate that p38 mitogen-activated protein kinase (MAPK) plays important causative roles in senescent cells following telomere shortening, Ras-Raf activation, oxidative stress or inappropriate culture conditions. By monitoring the kinetics of p38 activation, we suggest that p38 is activated not directly by the initial stimuli, but in response to unidentified cellular conditions caused by these stimuli. Importantly, this p38-activating condition appears to be defined quantitatively as a sum of continuous and low-level stresses, and remains even after the initial stimuli are withdrawn, which may explain the well-known irreversible nature of cellular senescence. We also show that papilloma virus E7 abolishes the p38-induced growth arrest but not other senescence-associated phenotypes, indicating the differential role of pRb in the downstream of p38.
  
  
  CONCLUSIONS
  These results indicate that p38 comprises the senescence-executing pathway in response to diverse stimuli.
authors.affiliation: Laboratory of Molecular and Cellular Assembly, Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Iwasa
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
authors.forename: Fuyuki
authors.initials: F
authors.lastname: Ishikawa
mesh_terms: D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D011905:Genes, ras; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D018384:Oxidative Stress; D027383:Papillomaviridae / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D016160:Retinoblastoma Protein; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019098:Telomerase; D018631:ras Proteins; C093642:SB 203580