Cell Cycle Control: The Restriction Point


The current understanding of the mechanism and kinetics of the G1 checkpoint called the restriction point (R‐point) in mammalian cells is discussed. The core mechanism involves a network of interactions among transcription factors (Myc and E2F) and cyclin‐dependendent kinases (CcnD/Cdk4,6 and CcnE/Cdk2). This network contains many positive feedback loops that generate a bistable switch in E2F activity which is similar to a toggle switch and explains the transition from growth‐factor‐dependent to growth‐factor‐independent transition of cell cycle progression at the R‐point.

Key Concepts

  • The restriction point (R‐point) marks the transition from growth‐factor‐dependent to growth‐factor‐independent cell cycle progression.
  • The R‐point has been experimentally demonstrated to be governed by a bistable switch involving the transcription factor E2F.
  • A bistable switch is similar to a toggle switch that no longer requires the initial switching stimulus once it is flipped on.
  • The network of gene and molecular interactions that generate the R‐point switch includes several positive feedback loops among transcription factors, kinases and phosphatases.

Keywords: cell cycle checkpoint; restriction point; bistable switch; E2F; Myc; cyclin‐dependent kinase; Cdk2; Cdk4; Cdk6; initiation of DNA replication

Figure 1. A network model involving growth‐factor (GF) signalling that stimulates the expression of Myc and CcnD, and leads to increase in E2F transcriptional activity and induction of positive feedback loops of CDK activation that ultimately drive the assembly and activation of replisomes. An arrow means ‘activate’ or ‘upregulate’, while a hammerhead means ‘inhibit’ or ‘downregulate’. Dashed lines represent gene expressions and solid lines indicate protein and enzymatic interactions.
Figure 2. A plot of the steady states of E2F activity as a function of serum concentration. Three steady states coexist in the range of serum concentrations between A and B. Solid upper and lower branches represent stable steady states, and the dashed middle branch represents unstable steady states. Vertical dashed arrows at A and B indicate transitions between the stable branches. Adapted from Yao et al. (2008) reproduced under the Creative Commons Attribution‐Share Alike 3.0 Unported license. http://creativecommons.org/licenses/by/3.0/.
Figure 3. DNA damage signalling in G1. Figure adapted from Bartek and Lukas (2001) © Elsevier.
Figure 4. (a) Positively coupled phosphorylation‐dephosphorylation cycles of Cdc25A and Cdk2. Species marked with asterisk (*) are active enzymes. (b) Top graph: steady state of active Cdk2 as a function of E2 (=sum of [Cdk2] and [Cdk2*]); bottom graph: steady state of active Cdk2 as a function of E1 (=sum of [Cdc25A] and [Cdc25A*]). Solid lines and curves represent stable steady states. Horizontal dashed line to the right of T represents zero unstable steady state. See Aguda () for details of the mathematical analysis.


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Further Reading

Alfieri R, Barberis M, Chiaradonna F, et al. (2009) Towards a systems biology approach to mammalian cell cycle: modeling the entrance into S phase of quiescent fibroblasts after serum stimulation. BMC Bioinformatics 10 (Suppl 12): S16.

Weis MC, Avva J, Jacobberger JW and Sreenath SN (2014) A data‐driven, mathematical model of mammalian cell cycle regulation. PLoS One 9: e97130.

Yao G, Tan C, West M, Nevins JR and You L (2008) Origin of bistability underlying mammalian cell cycle entry. Molecular Systems Biology 7: 485.

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Aguda, Baltazar D(Apr 2015) Cell Cycle Control: The Restriction Point. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005993.pub2]