Doncic Andreas, Ben-Jacob Eshel, Barkai Naama
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Proc Natl Acad Sci U S A. 2005 May 3;102(18):6332-7. doi: 10.1073/pnas.0409142102. Epub 2005 Apr 25.
The mitotic spindle checkpoint halts the cell cycle until all chromosomes are attached to the mitotic spindles. Evidence suggests that the checkpoint prevents cell-cycle progression by inhibiting the activity of the APC-Cdc20 complex, but the precise mechanism underlying this inhibition is not yet known. Here, we use mathematical modeling to compare several mechanisms that could account for this inhibition. We describe the interplay between the capacities to strongly inhibit cell-cycle progression before spindle attachment on one hand and to rapidly resume cell-cycle progression once the last kinetochore is attached on the other hand. We find that inhibition that is restricted to the kinetochore region is not sufficient for supporting both requirements when realistic diffusion constants are considered. A mechanism that amplifies the checkpoint signal through autocatalyzed inhibition is also insufficient. In contrast, amplifying the signal through the release of a diffusible inhibitory complex can support reliable checkpoint function. Our results suggest that the design of the spindle checkpoint network is limited by physical constraints imposed by realistic diffusion constants and the relevant spatial and temporal dimensions where computation is performed.
有丝分裂纺锤体检查点会使细胞周期停滞，直到所有染色体都附着到有丝分裂纺锤体上。有证据表明，该检查点通过抑制后期促进复合体（APC）-Cdc20复合物的活性来阻止细胞周期进程，但其抑制的精确机制尚不清楚。在此，我们使用数学建模来比较几种可能解释这种抑制作用的机制。我们描述了一方面在纺锤体附着前强烈抑制细胞周期进程的能力与另一方面在最后一个动粒附着后迅速恢复细胞周期进程的能力之间的相互作用。我们发现，当考虑实际扩散常数时，仅限于动粒区域的抑制不足以满足这两个要求。通过自催化抑制放大检查点信号的机制也不充分。相比之下，通过释放可扩散抑制复合物来放大信号能够支持可靠的检查点功能。我们的结果表明，纺锤体检查点网络的设计受到实际扩散常数以及进行计算的相关空间和时间维度所施加的物理限制。
