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
Validation

Diseases presenting "high level" symptom

22q11.2 deletion syndrome

aniridia

cadasil

carcinoma of the gallbladder

cohen syndrome

congenital toxoplasmosis

cutaneous mastocytosis

cystinuria

dedifferentiated liposarcoma

dentinogenesis imperfecta

erdheim-chester disease

erythropoietic protoporphyria

esophageal carcinoma

esophageal squamous cell carcinoma

familial hypocalciuric hypercalcemia

familial mediterranean fever

hodgkin lymphoma, classical

inclusion body myositis

liposarcoma

lymphangioleiomyomatosis

omenn syndrome

oral submucous fibrosis

pyomyositis

scrub typhus

waldenstrÃ¶m macroglobulinemia

well-differentiated liposarcoma

werner syndrome

x-linked adrenoleukodystrophy

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