dorsal/arxiv
View SchemaModeling Dual Pathways for the Metazoan Spindle Assembly Checkpoint
| Authors | Richard P. Sear, Martin Howard |
|---|---|
| Categories | |
| ArXiv ID | q-bio/0610054 |
| URL | https://arxiv.org/abs/q-bio/0610054 |
| DOI | 10.1073/pnas.0603174103 |
| Journal | Proc. Natl. Acad. Sci. 103 16758-16763 (2006) |
Abstract
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.
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"abstract": "Using computational modelling, we investigate mechanisms of signal\ntransduction focusing on the spindle assembly checkpoint where a single\nunattached kinetochore is able to signal to prevent cell cycle progression.\nThis inhibitory signal switches off rapidly once spindle microtubules have\nattached to all kinetochores. This requirement tightly constrains the possible\nmechanisms. Here we investigate two possible mechanisms for spindle checkpoint\noperation in metazoan cells, both supported by recent experiments. The first\ninvolves the free diffusion and sequestration of cell-cycle regulators. This\nmechanism is severely constrained both by experimental fluorescence recovery\ndata and also by the large volumes involved in open mitosis in metazoan cells.\nUsing a simple mathematical analysis and computer simulation, we find that this\nmechanism can generate the inhibition found in experiment but likely requires a\ntwo stage signal amplification cascade. The second mechanism involves spatial\ngradients of a short-lived inhibitory signal that propagates first by diffusion\nbut then primarily via active transport along spindle microtubules. We propose\nthat both mechanisms may be operative in the metazoan spindle assembly\ncheckpoint, with either able to trigger anaphase onset even without support\nfrom the other pathway.",
"arxiv_id": "q-bio/0610054",
"authors": [
"Richard P. Sear",
"Martin Howard"
],
"categories": [
"q-bio.SC",
"cond-mat.stat-mech"
],
"doi": "10.1073/pnas.0603174103",
"journal_ref": "Proc. Natl. Acad. Sci. 103 16758-16763 (2006)",
"title": "Modeling Dual Pathways for the Metazoan Spindle Assembly Checkpoint",
"url": "https://arxiv.org/abs/q-bio/0610054"
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