Evaluating the role of p38 MAP kinase in growth of Werner syndrome fibroblasts.
The accelerated aging of Werner syndrome (WS) fibroblasts can be prevented by treatment with the p38 kinase inhibitor SB203580. If accelerated cellular senescence underlies the premature ageing features seen in this human aging model, then p38 inhibitors may have therapeutic potential in WS. However, SB203580 can inhibit in vitro several kinases that are involved in control of cellular growth, in particular, c-Raf1, CK1, and RIPK2. Thus, a better understanding of the role of this inhibitor in WS cells is required. Here we use a combination of kinase inhibitors and small intefering RNA-induced gene knockdown to show that it is inhibition of the stress-induced p38 MAP kinase that is the most plausible explanation for the effects of SB203580 on the growth of WS cells. As the development of highly selective p38 inhibitors with low toxicity is a major effort of the pharmaceuticals sector, these studies help pave the way for possible therapeutics for WS.
Davis
Terence
T
Department of Pathology, Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom. davist2@cardiff.ac.uk
Bachler
Marcus A
MA
Wyllie
Fiona S
FS
Bagley
Mark C
MC
Kipling
David
D
D000375:Aging / Q000187:drug effects / Q000235:genetics; D019588:Aging, Premature / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects*; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006128:Growth / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D014898:Werner Syndrome / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580