title: Origins of G1 arrest in senescent human fibroblasts.
abstract: Human diploid fibroblasts have a finite proliferative lifespan in culture, at the end of which they are arrested with G1 phase DNA contents. Upon serum stimulation, senescent cells are deficient in carrying out a subset of early signal transduction events such as activation of protein kinase C and induction of c-fos. Later in G1, they uniformly fail to express late G1 genes whose products are required for DNA synthesis, implying that they are unable to pass the R point. Failure to pass the R point may occur because senescent cells are unable to phosphorylate the retinoblastoma protein, owing to the accumulation of inactive complexes of cyclin E/Cdk2 and possibly cyclin D/Cdk4. Senescent cells contain high amounts of p21, a potent cyclin-dependent kinase inhibitor whose levels are also elevated in cells arrested in G1 following DNA damage, suggesting that both arrests might share a common mechanism. Cell aging is accompanied by a progressive shortening of chromosomal telomeres, which could be perceived by the cells as a form of DNA damage that gives rise to the signals that inactive the cell cycle machinery.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder 80309-0347, USA.
authors.forename: G H
authors.initials: GH
authors.lastname: Stein
authors.forename: V
authors.initials: V
authors.lastname: Dulić
mesh_terms: D002453:Cell Cycle; D016922:Cellular Senescence; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism; D004249:DNA Damage; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D016193:G1 Phase; D006801:Humans; D008954:Models, Biological
chemical_list: D016213:Cyclins; D004247:DNA; D018844:Cyclin-Dependent Kinases