title: Reduced Geminin levels promote cellular senescence.
abstract: Cellular senescence is a permanent out-of-cycle state regulated by molecular circuits acting during the G1 phase of the cell cycle. Cdt1 is a central regulator of DNA replication licensing acting during the G1 phase and it is negatively controlled by Geminin. Here, we characterize the cell cycle expression pattern of Cdt1 and Geminin during successive passages of primary fibroblasts and compare it to tumour-derived cell lines. Cdt1 and Geminin are strictly expressed in distinct subpopulations of young fibroblasts, similarly to cancer cells, with Geminin accumulating shortly after the onset of S phase. Cdt1 and Geminin are down-regulated when primary human and mouse fibroblasts undergo replicative or stress-induced senescence. RNAi-mediated Geminin knock-down in human cells enhances the appearance of phenotypic and molecular features of senescence. Mouse embryonic fibroblasts heterozygous for Geminin exhibit accelerated senescence compared to control fibroblasts. In contrast, ectopic expression of Geminin in mouse embryonic fibroblasts delays the appearance of the senescent phenotype. Taken together, our data suggest that changes in Geminin expression levels affect the establishment of senescence pathways.
authors.affiliation: Laboratory of General Biology, School of Medicine, University of Patras, Rio, Patras, Greece.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Iliou
authors.forename: Panorea
authors.initials: P
authors.lastname: Kotantaki
authors.forename: Dimitris
authors.initials: D
authors.lastname: Karamitros
authors.forename: Magda
authors.initials: M
authors.lastname: Spella
authors.forename: Stavros
authors.initials: S
authors.lastname: Taraviras
authors.forename: Zoi
authors.initials: Z
authors.lastname: Lygerou
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D016922:Cellular Senescence / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D016193:G1 Phase / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016196:S Phase / Q000502:physiology*; D055532:SMN Complex Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C498645:Ris2 protein, mouse; D055532:SMN Complex Proteins