The kinetic origins of the restriction point in the mammalian cell cycle

Cell Prolif. 1999 Oct;32(5):321-35. doi: 10.1046/j.1365-2184.1999.3250321.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CDC2-CDC28 Kinases*
  • Cell Cycle / physiology*
  • Cell Cycle Proteins*
  • Computer Simulation
  • Cyclin E / physiology
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / physiology
  • Feedback
  • G1 Phase / physiology
  • Humans
  • Kinetics
  • Microtubule-Associated Proteins / physiology
  • Models, Biological*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / physiology
  • Retinoblastoma Protein / physiology
  • S Phase / physiology
  • Tumor Suppressor Proteins*
  • cdc25 Phosphatases / physiology

Substances

  • Cell Cycle Proteins
  • Cyclin E
  • Microtubule-Associated Proteins
  • Retinoblastoma Protein
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • CDC25A protein, human
  • cdc25 Phosphatases