Ibrahim2008 - Mitotic Spindle Assembly Checkpoint - Dissociation variant

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Model Identifier
BIOMD0000000186
Short description
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.

Format
SBML (L2V3)
Related Publication
  • In-silico modeling of the mitotic spindle assembly checkpoint.
  • Ibrahim B, Diekmann S, Schmitt E, Dittrich P
  • PloS one , 2/ 2008 , Volume 3 , pages: e1555 , PubMed ID: 18253502
  • Bio System Analysis Group, Institute of Computer Science, Friedrich-Schiller-University Jena, Jena, Germany.
  • 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.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.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.
Contributors
Bashar Ibrahim

Metadata information

is
BioModels Database MODEL6655615431
BioModels Database BIOMD0000000186
isDescribedBy
PubMed 18253502
isDerivedFrom
PubMed 15694304
hasTaxon
Taxonomy Homo sapiens
isPartOf

Curation status
Curated

Tags
Name Description Size Actions

Model files

BIOMD0000000186_url.xml SBML L2V3 representation of Ibrahim2008 - Mitotic Spindle Assembly Checkpoint - Dissociation variant 37.01 KB Preview | Download

Additional files

BIOMD0000000186-biopax2.owl Auto-generated BioPAX (Level 2) 29.90 KB Preview | Download
BIOMD0000000186.svg Auto-generated Reaction graph (SVG) 25.88 KB Preview | Download
BIOMD0000000186.pdf Auto-generated PDF file 187.06 KB Preview | Download
BIOMD0000000186.vcml Auto-generated VCML file 61.84 KB Preview | Download
BIOMD0000000186.png Auto-generated Reaction graph (PNG) 71.25 KB Preview | Download
BIOMD0000000186.sci Auto-generated Scilab file 67.00 bytes Preview | Download
BIOMD0000000186-biopax3.owl Auto-generated BioPAX (Level 3) 41.77 KB Preview | Download
BIOMD0000000186.xpp Auto-generated XPP file 4.19 KB Preview | Download
BIOMD0000000186.m Auto-generated Octave file 6.29 KB Preview | Download
BIOMD0000000186_urn.xml Auto-generated SBML file with URNs 35.72 KB Preview | Download

  • Model originally submitted by : Bashar Ibrahim
  • Submitted: 03-Sep-2008 16:42:16
  • Last Modified: 28-May-2014 00:06:28
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 28-May-2014 00:06:28
    • Submitted by: Bashar Ibrahim
    • With comment: Current version of Ibrahim2008 - Mitotic Spindle Assembly Checkpoint - Dissociation variant
  • Version: 1 public model Download this version
    • Submitted on: 03-Sep-2008 16:42:16
    • Submitted by: Bashar Ibrahim
    • With comment: Original import of Mitotic Spindle Assembly Checkpoint (dissociation, controlled)
Legends
: Variable used inside SBML models


Species
Reactions
Reactions Rate Parameters
(Cdc20:C-Mad2) => (Cdc20 + O-Mad2)

([Mitotic spindle assembly checkpoint protein MAD2A; Cell division cycle protein 20 homolog]) => ([Cell division cycle protein 20 homolog] + [Mitotic spindle assembly checkpoint protein MAD2A])
k3f*Cdc20_CMad2*Cytoplasm

k3f*[Mitotic spindle assembly checkpoint protein MAD2A; Cell division cycle protein 20 homolog]*Cytoplasm
k3f = 0.01 per second
(Mad1:C-Mad2 + O-Mad2) => (Mad1:C-Mad2:O-Mad2*)

([protein complex; Mitotic spindle assembly checkpoint protein MAD2A; Mitotic spindle assembly checkpoint protein MAD1] + [Mitotic spindle assembly checkpoint protein MAD2A]) => ([Mitotic spindle assembly checkpoint protein MAD2A; Mitotic spindle assembly checkpoint protein MAD1; protein complex])
Cytoplasm*(u*k1f*Mad1_CMad2*OMad2-k1r*Mad1_CMad2_OMad2)

Cytoplasm*(u*k1f*[protein complex; Mitotic spindle assembly checkpoint protein MAD2A; Mitotic spindle assembly checkpoint protein MAD1]*[Mitotic spindle assembly checkpoint protein MAD2A]-k1r*[Mitotic spindle assembly checkpoint protein MAD2A; Mitotic spindle assembly checkpoint protein MAD1; protein complex])
k1f = 200000.0 liter per mole per second; k1r = 0.2 per second; u = 1.0 dimensionless
(Mad1:C-Mad2:O-Mad2* + Cdc20) => (Mad1:C-Mad2 + Cdc20:C-Mad2)

([Mitotic spindle assembly checkpoint protein MAD2A; Mitotic spindle assembly checkpoint protein MAD1; protein complex] + [Cell division cycle protein 20 homolog]) => ([protein complex; Mitotic spindle assembly checkpoint protein MAD2A; Mitotic spindle assembly checkpoint protein MAD1] + [Mitotic spindle assembly checkpoint protein MAD2A; Cell division cycle protein 20 homolog])
u*k2f*Mad1_CMad2_OMad2*Cytoplasm*Cdc20

u*k2f*[Mitotic spindle assembly checkpoint protein MAD2A; Mitotic spindle assembly checkpoint protein MAD1; protein complex]*Cytoplasm*[Cell division cycle protein 20 homolog]
k2f = 1.0E8 liter per mole per second; u = 1.0 dimensionless
(Bub3:BubR1 + Cdc20) => (Bub3:BubR1:Cdc20)

([Vdx protein; Mitotic checkpoint protein BUB3] + [Cell division cycle protein 20 homolog]) => ([Cell division cycle protein 20 homolog; Vdx protein; Mitotic checkpoint protein BUB3])
Cytoplasm*(u*k5f*Bub3_BubR1*Cdc20-k5r*Bub3_BubR1_Cdc20)

Cytoplasm*(u*k5f*[Vdx protein; Mitotic checkpoint protein BUB3]*[Cell division cycle protein 20 homolog]-k5r*[Cell division cycle protein 20 homolog; Vdx protein; Mitotic checkpoint protein BUB3])
k5r = 0.2 per second; k5f = 10000.0 liter per mole per second; u = 1.0 dimensionless
(O-Mad2 + Cdc20) => (Cdc20:C-Mad2)

([Mitotic spindle assembly checkpoint protein MAD2A] + [Cell division cycle protein 20 homolog]) => ([Mitotic spindle assembly checkpoint protein MAD2A; Cell division cycle protein 20 homolog])
kf6*OMad2*Cdc20*Cytoplasm

kf6*[Mitotic spindle assembly checkpoint protein MAD2A]*[Cell division cycle protein 20 homolog]*Cytoplasm
kf6 = 1000.0 liter per mole per second
(Cdc20:C-Mad2 + Bub3:BubR1) => (MCC)

([Mitotic spindle assembly checkpoint protein MAD2A; Cell division cycle protein 20 homolog] + [Vdx protein; Mitotic checkpoint protein BUB3]) => ([Cell division cycle protein 20 homolog; Mitotic spindle assembly checkpoint protein MAD2A; Vdx protein; Mitotic checkpoint protein BUB3; mitotic checkpoint complex])
Cytoplasm*(u*k4f*Cdc20_CMad2*Bub3_BubR1-k4r*MCC)

Cytoplasm*(u*k4f*[Mitotic spindle assembly checkpoint protein MAD2A; Cell division cycle protein 20 homolog]*[Vdx protein; Mitotic checkpoint protein BUB3]-k4r*[Cell division cycle protein 20 homolog; Mitotic spindle assembly checkpoint protein MAD2A; Vdx protein; Mitotic checkpoint protein BUB3; mitotic checkpoint complex])
k4r = 0.02 per second; u = 1.0 dimensionless; k4f = 1.0E7 liter per mole per second
Curator's comment:
(added: 03 Sep 2008, 16:41:13, updated: 03 Sep 2008, 16:41:13)
Reproduction of fig 3b from the article
Integration performed using SBML ODESolver (20080507)
Plot created using Xmgrace