Small molecule inhibition of p38 MAP kinase extends the replicative life span of human ATR-Seckel syndrome fibroblasts.

[werner syndrome]

Ataxia-telangiectasia and rad 3 (ATR )-related Seckel syndrome is associated with growth retardation and premature aging features . ATR -Seckel fibroblasts have a reduced replicative capacity in vitro and an aged morphology that is associated with activation of stress-associated p 38 mitogen-activated protein kinase and phosphorylated HSP 27 . These phenotypes are prevented using p 38 inhibitors , with replicative capacity restored to the normal range . However , this stressed phenotype is retained in telomerase-immortalized ATR -Seckel fibroblasts , indicating that it is independent of telomere erosion . As with normal fibroblasts , senescence in ATR -Seckel is bypassed by p 53 abrogation . Young ATR -Seckel fibroblasts show elevated levels of p 21 (WAF 1 ), p 16 (INK 4 A ), phosphorylated actin-binding protein cofilin , and phosphorylated caveolin-1 , with small molecule drug inhibition of p 38 reducing p 16 (INK 4 A ) and caveolin-1 phosphorylation . In conclusion , ATR -Seckel fibroblasts undergo accelerated aging via stress-induced premature senescence and p 38 activation that may underlie certain clinical features of Seckel syndrome , and our data suggest a novel target for pharmacological intervention in this human syndrome .

Diseases
Validation

Diseases presenting "phosphorylated actin-binding protein cofilin" symptom

werner syndrome

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