Henze 2017

  public model
Short description
The spindle assembly checkpoint (SAC) is an evolutionarily conserved mechanism, exclusively sensitive to the states of kinetochores attached to microtubules. During metaphase, the anaphase-promoting complex/cyclosome (APC/C) is inhibited by the SAC but it rapidly switches to its active form following proper attachment of the final spindle. It had been thought that APC/C activity is an all-or-nothing response, but recent findings have demonstrated that it switches steadily. In this study, we develop a detailed mathematical model that considers all 92 human kinetochores and all major proteins involved in SAC activation and silencing. We perform deterministic and spatially-stochastic simulations and find that certain spatial properties do not play significant roles. Furthermore, we show that our model is consistent with in-vitro mutation experiments of crucial proteins as well as the recently-suggested rheostat switch behavior, measured by Securin or CyclinB concentration. Considering an autocatalytic feedback loop leads to an all-or-nothing toggle switch in the underlying core components, while the output signal of the SAC still behaves like a rheostat switch. The results of this study support the hypothesis that the SAC signal varies with increasing number of attached kinetochores, even though it might still contain toggle switches in some of its components.
Format
SBML (L2V4)
Related Publication
  • A Dynamical Model for Activating and Silencing the Mitotic Checkpoint.
  • Henze R, Dittrich P, Ibrahim B
  • Scientific reports , 6/ 2017 , Volume 7 , Issue 1 , pages: 3865
  • Department of Mathematics and Computer Science, Friedrich Schiller University Jena, 07743, Jena, Germany.
  • The spindle assembly checkpoint (SAC) is an evolutionarily conserved mechanism, exclusively sensitive to the states of kinetochores attached to microtubules. During metaphase, the anaphase-promoting complex/cyclosome (APC/C) is inhibited by the SAC but it rapidly switches to its active form following proper attachment of the final spindle. It had been thought that APC/C activity is an all-or-nothing response, but recent findings have demonstrated that it switches steadily. In this study, we develop a detailed mathematical model that considers all 92 human kinetochores and all major proteins involved in SAC activation and silencing. We perform deterministic and spatially-stochastic simulations and find that certain spatial properties do not play significant roles. Furthermore, we show that our model is consistent with in-vitro mutation experiments of crucial proteins as well as the recently-suggested rheostat switch behavior, measured by Securin or CyclinB concentration. Considering an autocatalytic feedback loop leads to an all-or-nothing toggle switch in the underlying core components, while the output signal of the SAC still behaves like a rheostat switch. The results of this study support the hypothesis that the SAC signal varies with increasing number of attached kinetochores, even though it might still contain toggle switches in some of its components.
Contributors
Ashley Xavier

Metadata information

Curation status
Non-curated
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Model files

Henze2017.xml SBML file 144.45 KB Preview | Download

  • Model originally submitted by : Ashley Xavier
  • Submitted: Dec 21, 2018 1:59:16 PM
  • Last Modified: Dec 21, 2018 1:59:16 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Dec 21, 2018 1:59:16 PM
    • Submitted by: Ashley Xavier
    • With comment: Edited model metadata online.