title: Replicative senescence in sheep fibroblasts is a p53 dependent process.
abstract: Studies on telomere and telomerase biology are fundamental to the understanding of human ageing, and age-related diseases such as cancer. However, human studies are hampered by the lack of fully reflective animal model systems. Here we describe basic studies of telomere length and telomerase activity in sheep tissues and cells. Terminal restriction fragment lengths from sheep tissues ranged from 9 to 23 kb, with telomerase activity present in testis but suppressed in somatic tissues. Sheep fibroblasts had a finite lifespan in culture, after which the cells entered senescence. During in vitro growth the mean terminal restriction fragment lengths decreased in size at a rate of 210 and 350 bp per population doubling (PD). Senescent skin fibroblasts had increased levels of p53 and p21WAF1 compared to young cells. Incubation of senescent cells with siRNA duplexes specific for p53 suppressed p53 expression and allowed the cells to re-enter the cell cycle. Five PDs beyond senescence the siRNA-treated cells reached a second proliferative barrier. This study shows that telomere biology in sheep is similar to that in humans, with senescence in sheep GM03550 fibroblasts being a telomere-driven, p53-(p21WAF1)-dependent process. Therefore sheep may represent an alternative model system for studying telomere biology, replicative senescence, and by implication human ageing.
authors.affiliation: Department of Pathology, School of Medicine, University of Cardiff, Heath Park, Cardiff CF14 4XN, Wales, UK.
authors.forename: Terence
authors.initials: T
authors.lastname: Davis
authors.forename: Julia W
authors.initials: JW
authors.lastname: Skinner
authors.forename: Richard G A
authors.initials: RG
authors.lastname: Faragher
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Jones
authors.forename: David
authors.initials: D
authors.lastname: Kipling
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D023421:Models, Animal; D034741:RNA, Small Interfering / Q000235:genetics; D012756:Sheep; D019098:Telomerase / Q000378:metabolism; D016615:Telomere; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D019098:Telomerase