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

Tivey, Hannah S. E., Rokicki, Michal Jaroslaw, Barnacle, James R., Rogers, Mathew James, Bagley, Mark C., Kipling, David Glyn and Davis, Terence 2013. Small molecule inhibition of p38 MAP kinase extends the replicative life span of human ATR-Seckel syndrome fibroblasts. The Journals of Gerontology. Series A: Biological Sciences and Medical Sciences 68 (9) , pp. 1001-1009. 10.1093/gerona/gls336

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Abstract

Ataxia-telangiectasia and rad3 (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 p38 mitogen-activated protein kinase and phosphorylated HSP27. These phenotypes are prevented using p38 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 p53 abrogation. Young ATR-Seckel fibroblasts show elevated levels of p21WAF1, p16INK4A, phosphorylated actin-binding protein cofilin, and phosphorylated caveolin-1, with small molecule drug inhibition of p38 reducing p16INK4A and caveolin-1 phosphorylation. In conclusion, ATR-Seckel fibroblasts undergo accelerated aging via stress-induced premature senescence and p38 activation that may underlie certain clinical features of Seckel syndrome, and our data suggest a novel target for pharmacological intervention in this human syndrome.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > RB Pathology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords:	Progeroid syndromes ; Telomeres ; p53 ; ATR ; Premature aging ; Werner syndrome ; Fragile sites ; Chromosome instability ; Replication stress ; Caveolin-1
Publisher:	Oxford University Press
ISSN:	1079-5006
Date of First Compliant Deposit:	30 March 2016
Last Modified:	08 Jan 2020 03:27
URI:	http://orca.cf.ac.uk/id/eprint/46606

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