Modeling the temporal evolution of the spindle assembly checkpoint and role of Aurora B kinase

Abstract

Faithful separation of chromosomes prior to cell division at mitosis is a highly regulated process. One family of serine/threonine kinases that plays a central role in regulation is the Aurora family. Aurora B plays a role in the spindle assembly checkpoint, in part, by destabilizing the localization of BubR1 and Mad2 at centrosomes and responds to changes in tension caused by aberrant microtubule kinetochore attachments. Aurora B is overexpressed in a subset of cancers and is required for mitosis, making it an attractive anticancer target. Here, we use mathematical modeling to extend a current model of the spindle assembly checkpoint to incorporate all signaling kinetochores within a cell rather than just one and the role of Aurora B within the resulting model. We find that the current model of the spindle assembly checkpoint is robust to variation in its key diffusion-limited parameters. Furthermore, when Aurora B inhibition is considered within the model, for a certain range of inhibitor concentrations, a prolonged prometaphase/metaphase is observed. This level of inhibitor concentrations has not yet been studied experimentally, to the authors' best knowledge. Therefore, experimental verification of the results discussed here could provide a deeper understanding of how kinetochores and Aurora B cooperate in the spindle assembly checkpoint. mathematical | mitosis | kinetochore | metazoan | cell cycle

An integrated pharmacokinetic–pharmacodynamic model for an Aurora kinase inhibitor

“…In order to gain a better insight into the complex interplay between pharmacokinetics, measurable biomarkers and cell fate required the construction of a novel integrated mathematical model, which we present here. This model builds on the core SAC models developed in [21,22]. To the authors' best knowledge, these were the first such models to be used to investigate the action of AK inhibition on the spindle assembly checkpoint, albeit from a functional point of view in which the source of inhibition was not explicitly detailed.…”

“…We first describe the model construction by briefly reviewing the attachment and spindle assembly checkpoint models developed in [21,22]. We then discuss the inhibition of AK activity by CYC116 and thus the effects of such inhibition on parameters in the new integrated PK-PD model presented here.…”

“…1a. A model of the temporal evolution of attachment type was developed in [21] and full details of the derivation can be found there. A brief overview of the main points follows.…”

“…The spindle assembly checkpoint model, proposed in [5] and subsequently extended in [21], concerns the wait signal generated by the temporal evolution of kinetochore-microtubule attachments. A brief summary of this model is as follows.…”

“…It is assumed that the inhibited complex e * can catalyse the production of further inhibited complexes of e denoted by c * with a possible candidate being the Cdc20-BubR1 complex, at a diffusion limited protein-protein interaction rate, k. It is assumed that these complexes, c * , cannot catalyse further complexation. Species g * is associated with inhibitory complexes of Cdc20 generated prior to prometaphase and by a different mechanism during prophase [21]. These inhibitory complexes decay releasing the Cdc20 at rate a.…”