Modeling the temporal evolution of the spindle assembly checkpoint and role of Aurora B kinase.
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.
Mistry
Hitesh B
HB
Division of Mathematics, University of Dundee, Dundee DD1 4HN, Scotland.
MacCallum
David E
DE
Jackson
Robert C
RC
Chaplain
Mark A J
MA
Davidson
Fordyce A
FA
D064107:Aurora Kinase B; D064127:Aurora Kinases; D020090:Chromosome Segregation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D018386:Kinetochores / Q000378:metabolism; D008677:Metaphase; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis; D008954:Models, Biological; D008962:Models, Theoretical; D009369:Neoplasms / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008941:Spindle Apparatus / Q000378:metabolism*
D004791:Enzyme Inhibitors; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases