Modeling dual pathways for the metazoan spindle assembly checkpoint

Proceedings of the National Academy of Sciences of the United States of America
Richard P Sear, Martin Howard

Abstract

Using computational modeling, we investigate mechanisms of signal transduction. We focus on the spindle assembly checkpoint, where a single unattached kinetochore is able to signal to prevent cell cycle progression. The 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 by the large volumes involved in open mitosis in metazoan cells. By 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 by active transport along spindle microtubules. We propose that both mechanisms may be operative in the metazoan spindle assembly checkpoint, with either ...Continue Reading

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Related Concepts

Cell Cycle Progression
Biochemical Pathway
Spindle
Cell Cycle Proteins
Mitotic Anaphase
Ubiquitin-Protein Ligase Complexes
Gene Amplification Technique
Microtubules
Anaphase-promoting complex
Cell Cycle

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