Limits...
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.

Show MeSH

Related in: MedlinePlus

Schematic network of the MSAC model.The arrows describe the interactions between the proteins and complexes. Red lines represent the Dissociation variant, green lines represents the Convey variant, while the black arrows are common to both. The switching parameter u models the effect of the attachment. We set u = 1 for the unattached case and u =  0 for the attached case. We set u′ = 1 for the uncontrolled scenario and u′ = 1−u for the controlled scenario (Table 1). The model incorporates three central control mechanisms, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. These sub-systems can be red from left to right. Nine biochemical reaction equations describe the interactions of 11 species: Mad1:C-Mad2, O-Mad2, Mad1:C-Mad2:O-Mad2*, Cdc20, Cdc20:C-Mad2, Bub3:BubR1, MCC, Bub3:BubR1:Cdc20, APC, MCC:APC, and APC:Cdc20. Below the network, the subunits of MCC as well as APC are depicted.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2215771&req=5

pone-0001555-g001: Schematic network of the MSAC model.The arrows describe the interactions between the proteins and complexes. Red lines represent the Dissociation variant, green lines represents the Convey variant, while the black arrows are common to both. The switching parameter u models the effect of the attachment. We set u = 1 for the unattached case and u =  0 for the attached case. We set u′ = 1 for the uncontrolled scenario and u′ = 1−u for the controlled scenario (Table 1). The model incorporates three central control mechanisms, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. These sub-systems can be red from left to right. Nine biochemical reaction equations describe the interactions of 11 species: Mad1:C-Mad2, O-Mad2, Mad1:C-Mad2:O-Mad2*, Cdc20, Cdc20:C-Mad2, Bub3:BubR1, MCC, Bub3:BubR1:Cdc20, APC, MCC:APC, and APC:Cdc20. Below the network, the subunits of MCC as well as APC are depicted.

Mentions: The Dissociation variant is defined by the following reaction rules (Figure 1, red lines):(1)(2)(3)(4)(5)(6)(7)(7a)(8)


In-silico modeling of the mitotic spindle assembly checkpoint.

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

Schematic network of the MSAC model.The arrows describe the interactions between the proteins and complexes. Red lines represent the Dissociation variant, green lines represents the Convey variant, while the black arrows are common to both. The switching parameter u models the effect of the attachment. We set u = 1 for the unattached case and u =  0 for the attached case. We set u′ = 1 for the uncontrolled scenario and u′ = 1−u for the controlled scenario (Table 1). The model incorporates three central control mechanisms, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. These sub-systems can be red from left to right. Nine biochemical reaction equations describe the interactions of 11 species: Mad1:C-Mad2, O-Mad2, Mad1:C-Mad2:O-Mad2*, Cdc20, Cdc20:C-Mad2, Bub3:BubR1, MCC, Bub3:BubR1:Cdc20, APC, MCC:APC, and APC:Cdc20. Below the network, the subunits of MCC as well as APC are depicted.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001555-g001: Schematic network of the MSAC model.The arrows describe the interactions between the proteins and complexes. Red lines represent the Dissociation variant, green lines represents the Convey variant, while the black arrows are common to both. The switching parameter u models the effect of the attachment. We set u = 1 for the unattached case and u =  0 for the attached case. We set u′ = 1 for the uncontrolled scenario and u′ = 1−u for the controlled scenario (Table 1). The model incorporates three central control mechanisms, namely Mad1/Mad2 induced Cdc20 sequestering based on the Template Model, MCC formation, and APC inhibition. These sub-systems can be red from left to right. Nine biochemical reaction equations describe the interactions of 11 species: Mad1:C-Mad2, O-Mad2, Mad1:C-Mad2:O-Mad2*, Cdc20, Cdc20:C-Mad2, Bub3:BubR1, MCC, Bub3:BubR1:Cdc20, APC, MCC:APC, and APC:Cdc20. Below the network, the subunits of MCC as well as APC are depicted.
Mentions: The Dissociation variant is defined by the following reaction rules (Figure 1, red lines):(1)(2)(3)(4)(5)(6)(7)(7a)(8)

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