Novak B, Csikasz-Nagy A, Gyorffy B, Nasmyth K, Tyson J J
Department of Agricultural Chemical Technology, Technical University of Budapest, Hungary.
Philos Trans R Soc Lond B Biol Sci. 1998 Dec 29;353(1378):2063-76. doi: 10.1098/rstb.1998.0352.
Progress through the division cycle of present day eukaryotic cells is controlled by a complex network consisting of (i) cyclin-dependent kinases (CDKs) and their associated cyclins, (ii) kinases and phosphatases that regulate CDK activity, and (iii) stoichiometric inhibitors that sequester cyclin-CDK dimers. Presumably regulation of cell division in the earliest ancestors of eukaryotes was a considerably simpler affair. Nasmyth (1995) recently proposed a mechanism for control of a putative, primordial, eukaryotic cell cycle, based on antagonistic interactions between a cyclin-CDK and the anaphase promoting complex (APC) that labels the cyclin subunit for proteolysis. We recast this idea in mathematical form and show that the model exhibits hysteretic behaviour between alternative steady states: a Gl-like state (APC on, CDK activity low, DNA unreplicated and replication complexes assembled) and an S/M-like state (APC off, CDK activity high, DNA replicated and replication complexes disassembled). In our model, the transition from G1 to S/M ('Start') is driven by cell growth, and the reverse transition ('Finish') is driven by completion of DNA synthesis and proper alignment of chromosomes on the metaphase plate. This simple and effective mechanism for coupling growth and division and for accurately copying and partitioning a genome consisting of numerous chromosomes, each with multiple origins of replication, could represent the core of the eukaryotic cell cycle. Furthermore, we show how other controls could be added to this core and speculate on the reasons why stoichiometric inhibitors and CDK inhibitory phosphorylation might have been appended to the primitive alternation between cyclin accumulation and degradation.
当今真核细胞通过分裂周期的进程由一个复杂的网络控制，该网络由以下部分组成：（i）细胞周期蛋白依赖性激酶（CDK）及其相关的细胞周期蛋白；（ii）调节CDK活性的激酶和磷酸酶；（iii）隔离细胞周期蛋白 - CDK二聚体的化学计量抑制剂。据推测，真核生物最早祖先的细胞分裂调控要简单得多。纳斯米斯（1995年）最近基于细胞周期蛋白 - CDK与后期促进复合体（APC）之间的拮抗相互作用，提出了一种控制假定的原始真核细胞周期的机制，后期促进复合体将细胞周期蛋白亚基标记为进行蛋白水解。我们将这个想法以数学形式重新表述，并表明该模型在不同的稳态之间表现出滞后行为：一种类似G1期的状态（APC开启，CDK活性低，DNA未复制且复制复合体组装完成）和一种类似S/M期的状态（APC关闭，CDK活性高，DNA已复制且复制复合体已解体）。在我们的模型中，从G1期到S/M期（“起始”）的转变由细胞生长驱动，而反向转变（“结束”）由DNA合成的完成以及染色体在中期板上的正确排列驱动。这种将生长与分裂耦合以及精确复制和分配由众多染色体组成的基因组（每个染色体都有多个复制起点）的简单而有效的机制，可能代表了真核细胞周期的核心。此外，我们展示了如何将其他控制添加到这个核心，并推测了为什么化学计量抑制剂和CDK抑制性磷酸化可能被附加到细胞周期蛋白积累与降解之间的原始交替过程中的原因。
