Mitotic kinases: The key to duplication, segregation, and cytokinesis errors, chromosomal instability, and oncogenesis

Li, Jonathan J.; Li, Sara Antonia

doi:10.1016/j.pharmthera.2006.02.006

Cited by 118 publications

(117 citation statements)

References 92 publications

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“…It becomes localized to the centrosome in the late G 2 and has peak activity at the G 2 /M transition. Plk1 is involved in the regulation of various cell cycle checkpoints that ensure the timing and order of cell cycle events, such as DNA repair, bipolar spindle formation, chromosome segregation, and mitotic exit (10). Aurora-A kinase is also implicated in centrosome separation, spindle assembly, and spindle maintenance.…”

mentioning

confidence: 99%

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Cell Cycle-dependent Expression of Centrosomal Ninein-like Protein in Human Cells Is Regulated by the Anaphase-promoting Complex

Wang

Zhan

2007

Journal of Biological Chemistry

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mentioning

confidence: 99%

“…Aurora-A kinase is also implicated in centrosome separation, spindle assembly, and spindle maintenance. Deregulated expression of Aurora-A kinase results in centrosome hypertrophy and leads to cell transformation (10). Both of the two kinases have emerged as the key regulators of centrosome maturation in a variety of different organisms.…”

mentioning

confidence: 99%

Cell Cycle-dependent Expression of Centrosomal Ninein-like Protein in Human Cells Is Regulated by the Anaphase-promoting Complex

Wang

Zhan

2007

Journal of Biological Chemistry

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“…Failure to do so correctly may lead to genomic instability, aneuploidy, and cancer (1)(2)(3). Chromosome segregation requires the formation of a microtubule network that connects the spindle poles located at either end of the cell, originating in centrosomes, with kinetochores (protein structures located at the centromeres of each chromosome) (4).…”

Section: Mathematical | Mitosis | Kinetochore | Metazoan | Cell Cyclementioning

confidence: 99%

“…Chromosome segregation requires the formation of a microtubule network that connects the spindle poles located at either end of the cell, originating in centrosomes, with kinetochores (protein structures located at the centromeres of each chromosome) (4). This is a highly regulated process involving the interactions between multiple protein complexes and signaling pathways (3,5). One family of serine/threonine kinases that plays a central role in regulation is the Aurora family consisting of 3 forms in metazoans: Aurora A, Aurora B, and Aurora C. In bakers' yeast and budding yeast only one homologue is found (Ark1 and Ipl1, respectively) (6)(7)(8).…”

Section: Mathematical | Mitosis | Kinetochore | Metazoan | Cell Cyclementioning

confidence: 99%

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

Mistry

MacCallum

Jackson

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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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

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“…Unattached kinetochores generate diffusible checkpoint complexes that comprise a wait signal, which inhibits the activation of the anaphase-promoting complex/cyclosome (APC/C) and delays the irreversible transition from metaphase to anaphase until all kinetochores become appropriately attached. Even one unattached kinetochore is considered to be enough to prevent the onset of anaphase [1,2,3,4].…”

Section: Introductionmentioning

confidence: 99%

An integrated pharmacokinetic–pharmacodynamic model for an Aurora kinase inhibitor

Kamei

Jackson

Zheleva

et al. 2010

J Pharmacokinet Pharmacodyn

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The spindle assembly checkpoint is a cell cycle surveillance mechanism that ensures the proper separation of chromosomes prior to cell division at mitosis. Aurora kinases play critical roles in mitotic progression and hence small-molecule inhibitors of Aurora kinases have been developed as a new class of potential anticancer drugs. In this paper we present for the first time an integrated pharmacokinetic-pharmacodynamic model of the functional effects of CYC116 (a known inhibitor of Aurora kinases A and B) on the spindle assembly checkpoint. We use the model to simulate two common experimental systems: cell culture and p.o. dosing of mice and present predictions of the effects of CYC116 for a range of doses and drug scheduling regimes. The model reveals that a critical peak drug concentration is required to cause aberrant kinetochore-microtubule attachments. The model also predicts that provided this threshold concentration is exceeded, a high total oral dose causes a high number of aberrant attachments within any given damaged cell. However, the proportion of cells which enter anaphase with aberrant attachments is associated with the total length of time for which the plasma concentration is maintained above the threshold. Moreover, our model reveals that the length of prometaphase/metaphase is a nonlinear function of drug dose and this time period can be extended or shortened. Finally, a strong saturation effect on CYC116 efficacy is predicted by the model. We discuss how these predictions may have implications for further drug trials using CYC116 and other similar AK inhibitors.

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Mitotic kinases: The key to duplication, segregation, and cytokinesis errors, chromosomal instability, and oncogenesis

Cited by 118 publications

References 92 publications

Cell Cycle-dependent Expression of Centrosomal Ninein-like Protein in Human Cells Is Regulated by the Anaphase-promoting Complex

Cell Cycle-dependent Expression of Centrosomal Ninein-like Protein in Human Cells Is Regulated by the Anaphase-promoting Complex

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

An integrated pharmacokinetic–pharmacodynamic model for an Aurora kinase inhibitor

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