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Novak2004 - A Model for Restriction Point Control of the Mammalian Cell Cycle

ABSTRACT: Inhibition of protein synthesis by cycloheximide blocks subsequent division of a mammalian cell, but only if the cell is exposed to the drug before the "restriction point" (i.e. within the first several hours after birth). If exposed to cycloheximide after the restriction point, a cell proceeds with DNA synthesis, mitosis and cell division and halts in the next cell cycle. If cycloheximide is later removed from the culture medium, treated cells will return to the division cycle, showing a complex pattern of division times post-treatment, as first measured by Zetterberg and colleagues. We simulate these physiological responses of mammalian cells to transient inhibition of growth, using a set of nonlinear differential equations based on a realistic model of the molecular events underlying progression through the cell cycle. The model relies on our earlier work on the regulation of cyclin-dependent protein kinases during the cell division cycle of yeast. The yeast model is supplemented with equations describing the effects of retinoblastoma protein on cell growth and the synthesis of cyclins A and E, and with a primitive representation of the signaling pathway that controls synthesis of cyclin D.

SUBMITTER: Ahmad Zyoud

PROVIDER: MODEL2006080001 | BioModels | 2024-01-25

REPOSITORIES: BioModels

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A model for restriction point control of the mammalian cell cycle.

Novák Béla B Tyson John J JJ

Journal of theoretical biology 20041001 4

Inhibition of protein synthesis by cycloheximide blocks subsequent division of a mammalian cell, but only if the cell is exposed to the drug before the "restriction point" (i.e. within the first several hours after birth). If exposed to cycloheximide after the restriction point, a cell proceeds with DNA synthesis, mitosis and cell division and halts in the next cell cycle. If cycloheximide is later removed from the culture medium, treated cells will return to the division cycle, showing a comple ...[more]

PMID: 15363676

Similar Datasets

Project description:This model is from the article: Restriction point control of the mammalian cell cycle via the cyclin E/Cdk2:p27 complex. Conradie R, Bruggeman FJ, Ciliberto A, Csikász-Nagy A, Novák B, Westerhoff HV, Snoep JL FEBS J.2010 Jan; 277(2): 357-67 20015233, Abstract: Numerous top-down kinetic models have been constructed to describe the cell cycle. These models have typically been constructed, validated and analyzed using model species (molecular intermediates and proteins) and phenotypic observations, and therefore do not focus on the individual model processes (reaction steps). We have developed a method to: (a) quantify the importance of each of the reaction steps in a kinetic model for the positioning of a switch point [i.e. the restriction point (RP)]; (b) relate this control of reaction steps to their effects on molecular species, using sensitivity and co-control analysis; and thereby (c) go beyond a correlation towards a causal relationship between molecular species and effects. The method is generic and can be applied to responses of any type, but is most useful for the analysis of dynamic and emergent responses such as switch points in the cell cycle. The strength of the analysis is illustrated for an existing mammalian cell cycle model focusing on the RP [Novak B, Tyson J (2004) J Theor Biol230, 563-579]. The reactions in the model with the highest RP control were those involved in: (a) the interplay between retinoblastoma protein and E2F transcription factor; (b) those synthesizing the delayed response genes and cyclin D/Cdk4 in response to growth signals; (c) the E2F-dependent cyclin E/Cdk2 synthesis reaction; as well as (d) p27 formation reactions. Nine of the 23 intermediates were shown to have a good correlation between their concentration control and RP control. Sensitivity and co-control analysis indicated that the strongest control of the RP is mediated via the cyclin E/Cdk2:p27 complex concentration. Any perturbation of the RP could be related to a change in the concentration of this complex; apparent effects of other molecular species were indirect and always worked through cyclin E/Cdk2:p27, indicating a causal relationship between this complex and the positioning of the RP. The rate constants presented in the paper have units [per tenth of an hour] and have been changed here to [per hour] (e.g. k16 = 0.25 not 0.025); for further confirmation of the correctness of this change, see the original model (Novak, J Theor Biol 2004 230:563).

Project description:This 89-node Boolean model of mammalian growth factor signaling can reproduce oscillations in PI3K signaling in cycling cells, and links these oscillations to the regulatory networks that drive each phase of cell cycle progression, as well as apoptosis. It builds on our previous work on modeling cell cycle progression as the interaction of two linked multi-stable switches (Deritei et al, Sci Rep 6:21957, 2016) and extends it to capture the role of Plk1 in cell cycle progression. The resulting model reproduces the following experimentally documented cell behaviors: — cyclic PI3K/AKT1 activity in dividing cells, which remain in sync with the cell cycle — apoptosis in response to prolonged mitosis or mitotic catastrophe — four distinct, experimentally documented cell fates caused by Plk1 inhibition, depending on the timing of Plk1 loss; namely, G2 arrest, mitotic catastrophe, premature anaphase and chromosome mis-segregation leading to aneuploidy, and failure to complete cytokinesis following telophase, which can lead to genome duplication — failure of cytokinesis and accumulation of binucleate telophase cells driven by hyperactive PI3K, hyperactive Ak1, or FoxO inhibition. — the effect of a large number of knockdown / forced activation mutations Testable predictions: — PI3K degradation in response to high PI3K activation is driven by the Neddl4 ubiquitin ligase activated by PLCγ, while its re-synthesis requires nuclear re-accumulation of FoxO3. — The degradation/re-synthesis cycle of PI3K occurs twice per division cycle, synchronized by Plk1-mediated inhibition of FoxO3 during metaphase/anaphase. — Cells in which PI3K is inhibited after the start of DNA synthesis can nevertheless pre-commit to another cell cycle in the presence of saturating growth stimulation (passing the restriction point in late metaphase), albeit at lower rates than wild-type cells. — Cell cycle defects in response to PI3K/Ak1 over-activation or FoxO knockdown are driven by a loss of Plk1 in telophase.