In-silico modeling of the mitotic spindle assembly checkpoint.
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.


RESULTS
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.


CONCLUSIONS
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.
Ibrahim
Bashar
B
Bio System Analysis Group, Institute of Computer Science, Friedrich-Schiller-University Jena, Jena, Germany.
Diekmann
Stephan
S
Schmitt
Eberhard
E
Dittrich
Peter
P
D000705:Anaphase; D064173:Anaphase-Promoting Complex-Cyclosome; D002135:Calcium-Binding Proteins / Q000502:physiology; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology; D019295:Computational Biology / Q000379:methods*; D006801:Humans; D064246:Mad2 Proteins; D008677:Metaphase; D008954:Models, Biological; D046912:Multiprotein Complexes; D009687:Nuclear Proteins / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology; D008941:Spindle Apparatus; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism
D002135:Calcium-Binding Proteins; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; C501384:MAD1L1 protein, human; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D012097:Repressor Proteins; C577488:CDC20 protein, human; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome