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In-silico modeling of the mitotic spindle assembly checkpoint.

Ibrahim B, Diekmann S, Schmitt E, Dittrich P - PLoS ONE (2008)

Bottom Line: Our model is validated by simulation of ten perturbation experiments.Only in the controlled case, our models show (M)SAC behaviour at meta- to anaphase transition in agreement with experimental observations.Our simulations revealed that for (M)SAC activation, Cdc20 is not fully sequestered; instead APC is inhibited by MCC binding.

View Article: PubMed Central - PubMed

Affiliation: Bio System Analysis Group, Institute of Computer Science, Friedrich-Schiller-University Jena, Jena, Germany.

ABSTRACT

Background: The Mitotic Spindle Assembly Checkpoint ((M)SAC) is an evolutionary conserved mechanism that ensures the correct segregation of chromosomes by restraining cell cycle progression from entering anaphase until all chromosomes have made proper bipolar attachments to the mitotic spindle. Its malfunction can lead to cancer.

Principle findings: We have constructed and validated for the human (M)SAC mechanism an in silico dynamical model, integrating 11 proteins and complexes. The model incorporates the perspectives of three central control pathways, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. Originating from the biochemical reactions for the underlying molecular processes, non-linear ordinary differential equations for the concentrations of 11 proteins and complexes of the (M)SAC are derived. Most of the kinetic constants are taken from literature, the remaining four unknown parameters are derived by an evolutionary optimization procedure for an objective function describing the dynamics of the APC:Cdc20 complex. MCC:APC dissociation is described by two alternatives, namely the "Dissociation" and the "Convey" model variants. The attachment of the kinetochore to microtubuli is simulated by a switching parameter silencing those reactions which are stopped by the attachment. For both, the Dissociation and the Convey variants, we compare two different scenarios concerning the microtubule attachment dependent control of the dissociation reaction. Our model is validated by simulation of ten perturbation experiments.

Conclusion: Only in the controlled case, our models show (M)SAC behaviour at meta- to anaphase transition in agreement with experimental observations. Our simulations revealed that for (M)SAC activation, Cdc20 is not fully sequestered; instead APC is inhibited by MCC binding.

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Species concentration over time for the controlled Dissociation variant (A) and the controlled Convey variant (B).Spindle attachment occurs at t = 2000s (switching parameter u from 1 to 0 and u' from 0 to 1). Both variants show similar qualitative dynamics. However, quantitative differences can be observed for species like Cdc20:C-Mad2 and MCC. Parameters setting according to Table 2 (“wild type”).
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pone-0001555-g003: Species concentration over time for the controlled Dissociation variant (A) and the controlled Convey variant (B).Spindle attachment occurs at t = 2000s (switching parameter u from 1 to 0 and u' from 0 to 1). Both variants show similar qualitative dynamics. However, quantitative differences can be observed for species like Cdc20:C-Mad2 and MCC. Parameters setting according to Table 2 (“wild type”).

Mentions: In addition to the APC:Cdc20 concentration values, we also analyzed the time-dependent concentrations of all reaction components. We observed differences between the two pathways in the controlled case for sub-complexes like Cdc20:C-Mad2 and MCC (Figure 3).


In-silico modeling of the mitotic spindle assembly checkpoint.

Ibrahim B, Diekmann S, Schmitt E, Dittrich P - PLoS ONE (2008)

Species concentration over time for the controlled Dissociation variant (A) and the controlled Convey variant (B).Spindle attachment occurs at t = 2000s (switching parameter u from 1 to 0 and u' from 0 to 1). Both variants show similar qualitative dynamics. However, quantitative differences can be observed for species like Cdc20:C-Mad2 and MCC. Parameters setting according to Table 2 (“wild type”).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2215771&req=5

pone-0001555-g003: Species concentration over time for the controlled Dissociation variant (A) and the controlled Convey variant (B).Spindle attachment occurs at t = 2000s (switching parameter u from 1 to 0 and u' from 0 to 1). Both variants show similar qualitative dynamics. However, quantitative differences can be observed for species like Cdc20:C-Mad2 and MCC. Parameters setting according to Table 2 (“wild type”).
Mentions: In addition to the APC:Cdc20 concentration values, we also analyzed the time-dependent concentrations of all reaction components. We observed differences between the two pathways in the controlled case for sub-complexes like Cdc20:C-Mad2 and MCC (Figure 3).

Bottom Line: Our model is validated by simulation of ten perturbation experiments.Only in the controlled case, our models show (M)SAC behaviour at meta- to anaphase transition in agreement with experimental observations.Our simulations revealed that for (M)SAC activation, Cdc20 is not fully sequestered; instead APC is inhibited by MCC binding.

View Article: PubMed Central - PubMed

Affiliation: Bio System Analysis Group, Institute of Computer Science, Friedrich-Schiller-University Jena, Jena, Germany.

ABSTRACT

Background: The Mitotic Spindle Assembly Checkpoint ((M)SAC) is an evolutionary conserved mechanism that ensures the correct segregation of chromosomes by restraining cell cycle progression from entering anaphase until all chromosomes have made proper bipolar attachments to the mitotic spindle. Its malfunction can lead to cancer.

Principle findings: We have constructed and validated for the human (M)SAC mechanism an in silico dynamical model, integrating 11 proteins and complexes. The model incorporates the perspectives of three central control pathways, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. Originating from the biochemical reactions for the underlying molecular processes, non-linear ordinary differential equations for the concentrations of 11 proteins and complexes of the (M)SAC are derived. Most of the kinetic constants are taken from literature, the remaining four unknown parameters are derived by an evolutionary optimization procedure for an objective function describing the dynamics of the APC:Cdc20 complex. MCC:APC dissociation is described by two alternatives, namely the "Dissociation" and the "Convey" model variants. The attachment of the kinetochore to microtubuli is simulated by a switching parameter silencing those reactions which are stopped by the attachment. For both, the Dissociation and the Convey variants, we compare two different scenarios concerning the microtubule attachment dependent control of the dissociation reaction. Our model is validated by simulation of ten perturbation experiments.

Conclusion: Only in the controlled case, our models show (M)SAC behaviour at meta- to anaphase transition in agreement with experimental observations. Our simulations revealed that for (M)SAC activation, Cdc20 is not fully sequestered; instead APC is inhibited by MCC binding.

Show MeSH
Related in: MedlinePlus