title: Escape from senescence in human diploid fibroblasts induced directly by mutant p53.
abstract: Cellular senescence is thought to be a key restraint on the progression of human tumours, escape from which involves loss of function of tumour suppressor genes. The number and nature of the genes involved however is uncertain, in particular the role of p53 mutation, which is commonly correlated with tumour progression. To address this question, we used the novel approach of directly assessing the effect of mutant p53 on 'pre-aged' human diploid fibroblasts (HDF), thereby avoiding the uncertainty of additional cooperating events, inherent in transgenic models. HDF were passaged till near-senescent and then infected with an amphotropic retroviral vector encoding an ala143 human mutant p53. The results show conclusively that p53 mutation alone is sufficient to extend the proliferative lifespan of normal fibroblasts by approximately 17 population doublings, but has no phenotypic effect on 'young' fibroblasts. We conclude that a key tumour-limiting function of wild-type p53 is to mediate growth arrest after a given number of cell divisions, in agreement with data implicating a p53-regulated gene, WAF-1/sdi-1, in cellular senescence. This may be reconciled with its 'guardian of the genome' role, if telomere erosion, a key change in senescence, is perceived by the cell as a form of DNA 'damage'.
authors.affiliation: Department of Pathology, University of Wales College of Medicine, Health Park, Cardiff, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Bond
authors.forename: F S
authors.initials: FS
authors.lastname: Wyllie
authors.forename: D
authors.initials: D
authors.lastname: Wynford-Thomas
mesh_terms: D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D004171:Diploidy; D005347:Fibroblasts / Q000166:cytology; D016158:Genes, p53; D005822:Genetic Vectors; D006801:Humans; D009154:Mutation; D012190:Retroviridae / Q000235:genetics; D014162:Transfection