title: Activation of p38 MAP kinase and stress signalling in fibroblasts from the progeroid Rothmund-Thomson syndrome.
abstract: Rothmund-Thomson fibroblasts had replicative lifespans and growth rates within the range for normal fibroblasts; however, they show elevated levels of the stress-associated p38 MAP kinase, suggestive of stress during growth. Treatment with the p38 MAP kinase inhibitor SB203580 increased both lifespan and growth rate, as did reduction of oxidative stress using low oxygen in some strains. At replicative senescence p53, p21(WAF1) and p16(INK4A) levels were elevated, and abrogation of p53 using shRNA knockdown allowed the cells to bypass senescence. Ectopic expression of human telomerase allowed Rothmund-Thomson fibroblasts to bypass senescence. However, activated p38 was still present, and continuous growth for some telomerised clones required either a reduction in oxidative stress or SB203580 treatment. Overall, the evidence suggests that replicative senescence in Rothmund-Thomson cells resembles normal senescence in that it is telomere driven and p53 dependent. However, the lack of RECQL4 leads to enhanced levels of stress during cell growth that may lead to moderate levels of stress-induced premature senescence. As replicative senescence is believed to underlie human ageing, a moderate level of stress-induced premature senescence and p38 activity may play a role in the relatively mild ageing phenotype seen in Rothmund-Thomson.
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK, davist2@cardiff.ac.uk.
authors.forename: Terence
authors.initials: T
authors.lastname: Davis
authors.forename: Hannah S E
authors.initials: HS
authors.lastname: Tivey
authors.forename: Amy J C
authors.initials: AJ
authors.lastname: Brook
authors.forename: Julia W
authors.initials: JW
authors.lastname: Grimstead
authors.forename: Michal J
authors.initials: MJ
authors.lastname: Rokicki
authors.forename: David
authors.initials: D
authors.lastname: Kipling
mesh_terms: D000293:Adolescent; D000375:Aging / Q000235:genetics*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D018384:Oxidative Stress / Q000235:genetics; D010641:Phenotype; D011725:Pyridines / Q000494:pharmacology; D012313:RNA / Q000235:genetics*; D011038:Rothmund-Thomson Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D012313:RNA; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580