Prevention of accelerated cell aging in the Werner syndrome.
In the Werner syndrome (WS) fibroblasts have an increased life span and growth rate when treated with the p38 inhibitor SB203580. Additionally, the cellular morphology reverts to that seen in young normal fibroblasts. The p38 pathway is activated in young WS cells, associated with high levels of p21(WAF1) leading to cell cycle arrest, and is suppressed by SB203580. As these changes are also seen in telomerized WS cells, these data show that the growth problems seen in WS cells, and perhaps the accelerated in vivo aging, are due to a telomere-independent premature senescence mechanism. The suppression of this mechanism by SB203580 treatment suggests a route whereby WS may be amenable to therapeutic intervention.
Davis
Terence
T
Department of Pathology, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Wales, UK. davist2@cardiff.ac.uk
Haughton
Michèle F
MF
Jones
Christopher J
CJ
Kipling
David
D
D000199:Actins / Q000378:metabolism; D019588:Aging, Premature / Q000517:prevention & control*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014898:Werner Syndrome / Q000235:genetics* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D000199:Actins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases; D019098:Telomerase; C093642:SB 203580