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
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Diseases presenting "elevated levels" symptom

22q11.2 deletion syndrome

adrenal incidentaloma

adrenomyeloneuropathy

alexander disease

aniridia

cadasil

canavan disease

congenital adrenal hyperplasia

epidermolysis bullosa simplex

erythropoietic protoporphyria

esophageal carcinoma

fabry disease

familial hypocalciuric hypercalcemia

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inclusion body myositis

kabuki syndrome

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phenylketonuria

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scrub typhus

sneddon syndrome

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

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