Sear Richard P, Howard Martin
Department of Physics, University of Surrey, Guildford, Surrey GU2 7XH, United Kingdom.
Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16758-63. doi: 10.1073/pnas.0603174103. Epub 2006 Oct 25.
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 able to trigger anaphase onset even without support from the other pathway.
我们运用计算建模来研究信号转导机制。我们聚焦于纺锤体组装检验点，在此处，单个未附着的动粒能够发出信号以阻止细胞周期进程。一旦纺锤体微管附着到所有动粒上，抑制信号会迅速关闭。这一要求严格限制了可能的机制。在此，我们研究了后生动物细胞中纺锤体检验点运作的两种可能机制，二者均得到了近期实验的支持。第一种机制涉及细胞周期调节因子的自由扩散和隔离。该机制受到实验荧光恢复数据以及后生动物细胞开放有丝分裂所涉及的大量空间的严重限制。通过简单的数学分析和计算机模拟，我们发现这种机制能够产生实验中所发现的抑制现象，但可能需要一个两阶段的信号放大级联反应。第二种机制涉及一种短暂存在的抑制信号的空间梯度，该信号首先通过扩散传播，但随后主要通过沿纺锤体微管的主动运输进行传播。我们提出，这两种机制可能在后生动物纺锤体组装检验点中都发挥作用，其中任何一种机制都能够在没有另一条途径支持的情况下触发后期起始。
