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BIOMD0000000186 - Ibrahim2008 - Mitotic Spindle Assembly Checkpoint - Dissociation variant

 

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Reference Publication
Publication ID: 18253502
Ibrahim B, Diekmann S, Schmitt E, Dittrich P.
In-silico modeling of the mitotic spindle assembly checkpoint.
PLoS ONE 2008; 3(2): e1555
Bio System Analysis Group, Institute of Computer Science, Friedrich-Schiller-University Jena, Jena, Germany.  [more]
Model
Original Model: BIOMD0000000186.origin
Submitter: Bashar Ibrahim
Submission ID: MODEL6655615431
Submission Date: 03 Sep 2008 15:42:16 UTC
Last Modification Date: 27 May 2014 23:06:28 UTC
Creation Date: 02 Sep 2008 15:06:57 UTC
Encoders:  Lukas Endler
   Eberhard Schmitt
   Peter Dittrich
   Stephan Diekmann
   Bashar Ibrahim
set #1
bqmodel:isDerivedFrom PubMed 15694304
set #2
bqbiol:isPartOf KEGG Pathway Cell cycle - Homo sapiens (human)
bqbiol:isVersionOf Reactome REACT_2137.2
Gene Ontology mitotic spindle assembly checkpoint
bqbiol:hasTaxon Taxonomy Homo sapiens
Notes
Ibrahim2008 - Mitotic Spindle Assembly Checkpoint - Dissociation variant

The Mitotic Spindle Assembly Checkpoint ((M)SAC) is an evolutionary conserved mechanism. This 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. MCC:APC dissociation is described by two alternatives models, namely the "Dissociation" and the "Convey" model variants. Both these model are available in BioModels Database. This model corresponds to the "Dissociation" variant.

This model is described in the article:

Ibrahim B, Diekmann S, Schmitt E, Dittrich P
PLoS One. 2008 Feb 6;3(2):e1555.

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.

This model describes the controlled dissociation variant of the mitotic spindle assembly checkpoint. If the tool you use has problems with events, you can uncomment the assignment rules for u and u_prime and comment out the list of events.

In accordance with the authors due to typos in the original publication some initial conditions and parameters were slightly changed in the model:

article model
[O-Mad2] 1.5e-7 M 1.3e-7 M
[BubR1:Bub3] 1.30e-7 M 1.27e-7 M
k -4 0.01 M -1 s -1 0.02 M -1 s -1
k -5 0.1 M -1 s -1 0.2 M -1 s -1

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 18253502 Submission Date: 03 Sep 2008 15:42:16 UTC Last Modification Date: 27 May 2014 23:06:28 UTC Creation Date: 02 Sep 2008 15:06:57 UTC
Mathematical expressions
Reactions
R1 R2 R3 R4
R5 R6 R7 R7a
R8      
Events
Microtubule attachment      
Physical entities
Compartments Species
Cytoplasm Mad1:C-Mad2 O-Mad2 Mad1:C-Mad2:O-Mad2*
Cdc20 Cdc20:C-Mad2 Bub3:BubR1
MCC Bub3:BubR1:Cdc20 APC
MCC:APC APC:Cdc20  
Global parameters
k1f k1r k2f k3f
k4f k4r k5f k5r
kf6 k7f k7r k8f
k8r u u_prime const_val_0
const_val_1      
Reactions (9)
 
 R1 [Mad1:C-Mad2] + [O-Mad2] ↔ [Mad1:C-Mad2:O-Mad2*];  
 
 R2 [Mad1:C-Mad2:O-Mad2*] + [Cdc20] → [Mad1:C-Mad2] + [Cdc20:C-Mad2];  
 
 R3 [Cdc20:C-Mad2] → [Cdc20] + [O-Mad2];  
 
 R4 [Cdc20:C-Mad2] + [Bub3:BubR1] ↔ [MCC];  
 
 R5 [Bub3:BubR1] + [Cdc20] ↔ [Bub3:BubR1:Cdc20];  
 
 R6 [O-Mad2] + [Cdc20] → [Cdc20:C-Mad2];  
 
 R7 [MCC] + [APC] → [MCC:APC];  
 
 R7a [MCC:APC] → [MCC] + [APC];  
 
 R8 [APC] + [Cdc20] ↔ [APC:Cdc20];  
 
Events (1)
 
 Microtubule attachment
u = const_val_0
u_prime = const_val_1
 
 Cytoplasm Spatial dimensions: 3.0  Compartment size: 1.0
 
 Mad1:C-Mad2
Compartment: Cytoplasm
Initial concentration: 5.0E-8  (Units: mole)
 
 O-Mad2
Compartment: Cytoplasm
Initial concentration: 1.3E-7  (Units: mole)
 
 Mad1:C-Mad2:O-Mad2*
Compartment: Cytoplasm
Initial concentration: 0.0  (Units: mole)
 
 Cdc20
Compartment: Cytoplasm
Initial concentration: 2.2E-7  (Units: mole)
 
 Cdc20:C-Mad2
Compartment: Cytoplasm
Initial concentration: 0.0  (Units: mole)
 
 Bub3:BubR1
Compartment: Cytoplasm
Initial concentration: 1.27E-7  (Units: mole)
 
 MCC
Compartment: Cytoplasm
Initial concentration: 0.0  (Units: mole)
 
 Bub3:BubR1:Cdc20
Compartment: Cytoplasm
Initial concentration: 0.0  (Units: mole)
 
 APC
Compartment: Cytoplasm
Initial concentration: 9.0E-8  (Units: mole)
 
 MCC:APC
Compartment: Cytoplasm
Initial concentration: 0.0  (Units: mole)
 
 APC:Cdc20
Compartment: Cytoplasm
Initial concentration: 0.0  (Units: mole)
 
Global Parameters (17)
 
   k1f
Value: 200000.0   (Units: liter per mole per second)
Constant
 
   k1r
Value: 0.2   (Units: per second)
Constant
 
   k2f
Value: 1.0E8   (Units: liter per mole per second)
Constant
 
   k3f
Value: 0.01   (Units: per second)
Constant
 
   k4f
Value: 1.0E7   (Units: liter per mole per second)
Constant
 
   k4r
Value: 0.02   (Units: per second)
Constant
 
   k5f
Value: 10000.0   (Units: liter per mole per second)
Constant
 
   k5r
Value: 0.2   (Units: per second)
Constant
 
   kf6
Value: 1000.0   (Units: liter per mole per second)
Constant
 
   k7f
Value: 1.0E8   (Units: liter per mole per second)
Constant
 
   k7r
Value: 0.08   (Units: per second)
Constant
 
   k8f
Value: 5000000.0   (Units: liter per mole per second)
Constant
 
   k8r
Value: 0.08   (Units: per second)
Constant
 
 u
Value: 1.0   (Units: dimensionless)
 
 u_prime  
 
   const_val_0
Constant
 
   const_val_1
Value: 1.0   (Units: dimensionless)
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000186

Curator's comment: (updated: 03 Sep 2008 16:41:13 BST)

Reproduction of fig 3b from the article

Integration performed using SBML ODESolver (20080507)

Plot created using Xmgrace

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