p38 (MAPK) stress signalling in replicative senescence in fibroblasts from progeroid and genomic instability syndromes.

[werner syndrome]

Werner Syndrome (WS ) is a human segmental progeria resulting from mutations in a DNA helicase . WS fibroblasts have a shortened replicative capacity , an aged appearance , and activated p 38 MAPK , features that can be modulated by inhibition of the p 38 pathway . Loss of the WRNp RecQ helicase has been shown to result in replicative stress , suggesting that a link between faulty DNA repair and stress-induced premature cellular senescence may lead to premature ageing in WS . Other progeroid syndromes that share overlapping pathophysiological features with WS also show defects in DNA processing , raising the possibility that faulty DNA repair , leading to replicative stress and premature cellular senescence , might be a more widespread feature of premature ageing syndromes . We therefore analysed replicative capacity , cellular morphology and p 38 activation , and the effects of p 38 inhibition , in fibroblasts from a range of progeroid syndromes . In general , populations of young fibroblasts from non-WS progeroid syndromes do not have a high level of cells with an enlarged morphology and F-actin stress fibres , unlike young WS cells , although this varies between strains . p 38 activation and phosphorylated HSP 27 levels generally correlate well with cellular morphology , and treatment with the p 38 inhibitor SB 203580 effects cellular morphology only in strains with enlarged cells and phosphorylated HSP 27 . For some syndromes fibroblast replicative capacity was within the normal range , whereas for others it was significantly shorter (e .g . HGPS and DKC ). However , although in most cases SB 203580 extended replicative capacity , with the exception of WS and DKC the magnitude of the effect was not significantly different from normal dermal fibroblasts . This suggests that stress-induced premature cellular senescence via p 38 activation is restricted to a small subset of progeroid syndromes .

Diseases
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Diseases presenting "small subset" symptom

child syndrome

cushing syndrome

hereditary cerebral hemorrhage with amyloidosis

hodgkin lymphoma, classical

primary effusion lymphoma

werner syndrome

zellweger syndrome

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