Evaluating the role of p38 MAPK in the accelerated cell senescence of Werner syndrome fibroblasts

Davis, Terence, Brook, Amy, Rokicki, Michal, Bagley, Mark C and Kipling, David (2016) Evaluating the role of p38 MAPK in the accelerated cell senescence of Werner syndrome fibroblasts. Pharmaceuticals, 9 (2). p. 23. ISSN 1424-8247

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Abstract

Progeroid syndromes show features of accelerated ageing and are used as models for
human ageing, of which Werner syndrome (WS) is one of the most widely studied. WS fibroblasts
show accelerated senescence that may result from p38 MAP kinase activation since it is prevented by
the p38 inhibitor SB203580. Thus, small molecule inhibition of p38-signalling may be a therapeutic
strategy for WS. To develop this approach issues such as the in vivo toxicity and kinase selectivity
of existing p38 inhibitors need to be addressed, so as to strengthen the evidence that p38 itself
plays a critical role in mediating the effect of SB203580, and to find an inhibitor suitable for in vivo
use. In this work we used a panel of different p38 inhibitors selected for: (1) having been used
successfully in vivo in either animal models or human clinical trials; (2) different modes of binding
to p38; and (3) different off-target kinase specificity profiles, in order to critically address the role of
p38 in the premature senescence seen in WS cells. Our findings confirmed the involvement of p38 in
accelerated cell senescence and identified p38 inhibitors suitable for in vivo use in WS, with BIRB 796
the most effective.

Item Type: Article
Keywords: BIRB 796; cell ageing; fibroblasts; p38 MAP kinase; premature ageing; progeroid syndromes; SB203580; therapeutics; UR13756; VX-745
Schools and Departments: School of Life Sciences > Chemistry
Depositing User: Mark Bagley
Date Deposited: 29 Apr 2016 06:45
Last Modified: 11 Mar 2017 01:36
URI: http://sro.sussex.ac.uk/id/eprint/60652

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Project NameSussex Project NumberFunderFunder Ref
A combined genetic and small molecule approach to studying the role of the p38/MK2 stress signallingG0931ESRC-ECONOMIC & SOCIAL RESEARCH COUNCILES/G037205/1