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Modeling dual pathways for the metazoan spindle assembly checkpoint

Sear, Richard and Howard, M (2006) Modeling dual pathways for the metazoan spindle assembly checkpoint PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 103 (45). pp. 16758-16763.

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Using computational modelling, we investigate mechanisms of signal transduction focusing on the spindle assembly checkpoint where a single unattached kinetochore is able to signal to prevent cell cycle progression. This inhibitory signal switches off rapidly once spindle microtubules have attached to all kinetochores. This requirement tightly constrains the possible mechanisms. Here we investigate two possible mechanisms for spindle checkpoint operation in metazoan cells, both supported by recent experiments. The first involves the free diffusion and sequestration of cell-cycle regulators. This mechanism is severely constrained both by experimental fluorescence recovery data and also by the large volumes involved in open mitosis in metazoan cells. Using a simple mathematical analysis and computer simulation, we find that this mechanism can generate the inhibition found in experiment but likely requires a two stage signal amplification cascade. The second mechanism involves spatial gradients of a short-lived inhibitory signal that propagates first by diffusion but then primarily via active transport along spindle microtubules. We propose that both mechanisms may be operative in the metazoan spindle assembly checkpoint, with either able to trigger anaphase onset even without support from the other pathway.

Item Type: Article
Divisions : Faculty of Engineering and Physical Sciences > Physics
Authors :
Howard, M
Date : 7 November 2006
DOI : 10.1073/pnas.0603174103
Uncontrolled Keywords : Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, kinetochore, mathematical modeling, signal transduction, concentration gradients, ANAPHASE-PROMOTING COMPLEX, VERTEBRATE SOMATIC-CELLS, LIVING CELLS, MAMMALIAN-CELLS, PROTEIN BUBR1, MAD2, DYNAMICS, INHIBITION, BINDING, KINETOCHORES
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Additional Information : Copyright 2006 NATL ACAD SCIENCES. This is the author's version of the paper, which appears here with permission of the publisher.
Depositing User : Symplectic Elements
Date Deposited : 02 Jan 2013 09:54
Last Modified : 16 Jan 2019 16:40

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