Assessing the role of stress signalling via p38 MAP kinase in the premature senescence of ataxia telangiectasia and Werner syndrome fibroblasts.
The premature ageing ataxia telangiectasia (AT) and Werner syndromes (WS) are associated with accelerated cellular ageing. Young WS fibroblasts have an aged appearance and activated p38 MAP kinase, and treatment with the p38 inhibitor SB230580 extends their lifespan to within the normal range. SB203580 also extends the replicative lifespan of normal adult dermal fibroblasts, however, the effect is much reduced when compared to WS cells, suggesting that WS fibroblasts undergo a form of stress-induced premature senescence (SIPS). A small lifespan extension is seen in AT cells, which is not significant compared to normal fibroblasts, and the majority of young AT cells do not have an aged appearance and lack p38 activation, suggesting that the premature ageing does not result from SIPS. The lack of p38 activation is supported by the clinical manifestation, since AT is not associated with inflammatory disease, whereas WS individuals are predisposed to atherosclerosis, type II diabetes and osteoporosis, conditions known to be associated with p38 activation.
Davis
Terence
T
Department of Pathology, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK. davist2@cardiff.ac.uk
Kipling
David
D
D019588:Aging, Premature / Q000201:enzymology / Q000473:pathology*; D001260:Ataxia Telangiectasia / Q000201:enzymology / Q000473:pathology*; D049109:Cell Proliferation; D048430:Cell Shape; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological; D013997:Time Factors; D014898:Werner Syndrome / Q000201:enzymology / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases