title: Small molecule inhibition of p38 MAP kinase extends the replicative life span of human ATR-Seckel syndrome fibroblasts.
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 p21(WAF1), p16(INK4A), phosphorylated actin-binding protein cofilin, and phosphorylated caveolin-1, with small molecule drug inhibition of p38 reducing p16(INK4A) 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.
authors: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, Wales, UK.
authors: Hannah S E
authors: HS
authors: Tivey
authors: Michal J
authors: MJ
authors: Rokicki
authors: James R
authors: JR
authors: Barnacle
authors: Matthew J
authors: MJ
authors: Rogers
authors: Mark C
authors: MC
authors: Bagley
authors: David
authors: D
authors: Kipling
authors: Terence
authors: T
authors: Davis
mesh_terms: D000199:Actins / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D051242:Caveolin 1 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D004392:Dwarfism / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D019066:Facies; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016158:Genes, p53; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008831:Microcephaly / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D019098:Telomerase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000199:Actins; C495540:CAV1 protein, human; D051242:Caveolin 1; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C509186:TERT protein, human; D019098:Telomerase
keywords: ATR; Caveolin-1.; Chromosome instability; Fragile sites; Premature aging; Progeroid syndromes; Replication stress; Telomeres; Werner syndrome; p53
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