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 ORCID: https://orcid.org/0000-0003-2780-0262 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

Preview

PDF - Published Version Available under License Creative Commons Attribution Non-commercial. Download (706kB) | Preview

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:	05 Jan 2024 03:13
URI:	https://orca.cardiff.ac.uk/id/eprint/46606

Citation Data

Cited 16 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item