title: The kinetic origins of the restriction point in the mammalian cell cycle.
abstract: A detailed model mechanism for the G1/S transition in the mammalian cell cycle is presented and analysed by computer simulation to investigate whether the kinetic origins of the restriction point (R-point) can be identified. The R-point occurs in mid-to-late G1 phase and marks the transition between mitogen-dependent to mitogen-independent progression of the cell cycle. For purposes of computer simulations, the R-point is defined as the first point in time after mitosis where cutting off mitogen stimulation does not prevent the cell reaching the threshold activity of cyclin-E/cdk2 required for entry into S phase. The key components of the network that generate a dynamic switching behaviour associated with the R-point include a positive feedback loop between cyclin-E/cdk2 and Cdc25A, along with the mutually negative interaction between the cdk inhibitor p27Kip1 and cyclin-E/cdk2. Simulations of the passage through the R-point were carried out and the factors affecting the position of the R-point in G1 are determined. The detailed model also shows various points in the network where the activation of cyclin-E/cdk2 can be initiated with or without the involvement of the retinoblastoma protein.
authors.affiliation: Department of Chemistry & Biochemistry, Laurentian University, Sudbury, Ontario, Canada. daguda@nickel.laurentian.ca
authors.forename: B D
authors.initials: BD
authors.lastname: Aguda
authors.forename: Y
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000818:Animals; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D003198:Computer Simulation; D019927:Cyclin E / Q000502:physiology; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000502:physiology; D005246:Feedback; D016193:G1 Phase / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008869:Microtubule-Associated Proteins / Q000502:physiology; D008954:Models, Biological; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D016160:Retinoblastoma Protein / Q000502:physiology; D016196:S Phase / Q000502:physiology; D025521:Tumor Suppressor Proteins; D020687:cdc25 Phosphatases / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D019927:Cyclin E; D008869:Microtubule-Associated Proteins; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases