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

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posted on 2023-06-09, 01:04 authored by Terence Davis, Amy Brook, Michal Rokicki, Mark BagleyMark Bagley, David Kipling
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.

Funding

A combined genetic and small molecule approach to studying the role of the p38/MK2 stress signalling; G0931; ESRC-ECONOMIC & SOCIAL RESEARCH COUNCIL; ES/G037205/1

History

Publication status

  • Published

File Version

  • Published version

Journal

Pharmaceuticals

ISSN

1424-8247

Publisher

MDPI

Issue

2

Volume

9

Page range

23

Department affiliated with

  • Chemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2016-04-29

First Open Access (FOA) Date

2016-04-29

First Compliant Deposit (FCD) Date

2016-04-28

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