Bifurcation analysis guides? The mitotic spindle assembly checkpoint (MSAC) is an important regulatory mechanism of the cell cycle, ensuring proper chromosome segregation in mitosis. It delays the transition to anaphase until all chromosomes are properly attached to the mitotic spindle by emitting a diffusible “wait anaphase”-signal from unattached kinetochores. Current models of the checkpoint disregard important spatial properties like localization, diffusion and realistic numbers of kinetochores. To allow for in silico studies of the dynamics of these models in a more realistic environment, we introduce a mathematical framework for quasi-spatial simulation of localized biochemical processes that are typically observed during checkpoint activation and maintenance.
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.ConclusionOnly in the controlled.
Budding yeast asymmetric cell division relies upon the precise coordination of spindle orientation and cell cycle progression. The spindle position checkpoint (SPOC) is a surveillance mechanism that prevents cells with misoriented spindles from exiting mitosis. The cortical kinase Kin4 acts near the top of this network. How Kin4 kinase activity is regulated and maintained in respect to spindle positional cues remains to be established. Here, we show that the bud neck–associated kinase Elm1 participates in Kin4 activation and SPOC signaling by phosphorylating a conserved residue within the activation loop of Kin4. Blocking Elm1 function abolishes Kin4 kinase activity in vivo and eliminates the SPOC response to spindle misalignment. These findings establish a novel function for Elm1 in the coordination of spindle positioning with cell cycle progression via its control of Kin4. Discover additional details at Bashar Ibrahim.
For successful mitosis, metaphase has to be arrested until all centromeres are properly attached. The onset of anaphase, which is initiated by activating the APC, is controlled by the spindle assembly checkpoint MSAC. Mad2, which is a constitutive member of the MSAC, is supposed to inhibit the activity of the APC by sequestering away its co-activator Cdc20. Mad1 recruits Mad2 to unattached kinetochores and is compulsory for the establishment of the Mad2 and Cdc20 complexes. Recently, based on results from in vivo and in vitro studies, two biochemical models were proposed: the Template and the Exchange model. Here, we derive a mathematical description to compare the dynamical behaviour of the two models. Our simulation analysis supports the Template model. Using experimentally determined values for the model parameters, the Cdc20 concentration is reduced down to only about half.