title: Prevention of accelerated cell aging in Werner syndrome using a p38 mitogen-activated protein kinase inhibitor.
abstract: We investigated the role of p38 mitogen-activated protein kinase (MAPK) signalling in the accelerated aging of Werner Syndrome (WS) fibroblasts by use of SB203580, a cytokine-suppressive anti-inflammatory drug that targets p38 activity. SB203580 treatment reverts the aged morphology of young WS fibroblasts to that seen in young normal fibroblasts. In addition, SB203580 increases the life span and growth rate of WS fibroblasts to within the normal range. In young WS cells, p38 is activated coincident with an up-regulation of p21(WAF1), and a reduction in the levels of both activated p38 and p21(WAF1) are seen following treatment with SB203580. As these effects are not seen in young normal cells, our data suggest that the abbreviated replicative life span of WS cells is due to a stress-induced, p38-mediated growth arrest that is independent of telomere erosion. With some p38 inhibitors already in clinical trials, our data suggest a potential route to drug intervention in a premature aging syndrome.
authors.affiliation: D.Phil, Department of Pathology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Terence
authors.initials: T
authors.lastname: Davis
authors.forename: Duncan M
authors.initials: DM
authors.lastname: Baird
authors.forename: Michèle F
authors.initials: MF
authors.lastname: Haughton
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Jones
authors.forename: David
authors.initials: D
authors.lastname: Kipling
mesh_terms: D000199:Actins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D016615:Telomere; D014898:Werner Syndrome / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000199:Actins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580