Cell size at S phase initiation: an emergent property of the G1/S network.
Cell size at S phase initiation: an emergent property of the G1/S network.
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DOI：
10.1371/journal.pcbi.0030064
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发表时间：
2007-04-13
影响因子：
4.3
通讯作者：
Alberghina L
中科院分区：
文献类型：
--
作者：
Barberis M;Klipp E;Vanoni M;Alberghina L
真核细胞周期是使细胞分裂成两个子细胞的事件的重复序列。它分为四个阶段：G1，S，G2和M。细胞周期的通过受到分子相互作用网络的严格调节，其涉及周期蛋白的周期性合成和破坏，所述周期蛋白结合并激活以非限制量存在的周期蛋白依赖性激酶。细胞周期蛋白依赖性激酶抑制剂有助于细胞周期控制。芽殖酵母是细胞周期研究的一种模式生物，已有几种芽殖酵母细胞周期的数学模型。细胞周期控制中的一个主要相关领域是G1到S的转变。在任何给定的生长条件下，其特征在于需要特定的临界细胞大小PS才能进入S期。这种控制的分子基础仍在讨论中。作者报告了一个数学模型的G1到S网络，新考虑到核/细胞质定位，细胞周期蛋白依赖性激酶Sic 1在促进其同源Cdk 1-Clb 5，Whi 5控制，Sic 1和含Sic 1复合物的碳源调节的核进口的作用。该模型由一组描述所涉及的蛋白质和蛋白质复合物的浓度随时间变化的常微分方程来实现。该模型进行了测试，在几个遗传和营养的设置模拟，并发现与实验数据完全一致。为了估计PS，作者开发了一种混合模型，包括DNA复制起点激发的概率成分。PS的敏感性分析提供了一个新的相关结论：PS是一个紧急性质的G1到S网络，强烈依赖于增长率。活细胞的一个主要特性是它们在整个细胞分裂过程中保持质量稳态的能力。已经提出，为了实现这种稳态，细胞周期中的一些关键事件将仅在细胞生长超过临界细胞尺寸时发生。在芽殖酵母酿酒酵母（Saccharomyces cerevisiae）中，大量的证据表明，细胞必须达到临界大小才能开始复制其DNA并形成芽，这将产生子细胞。该临界细胞大小受生长速率调节，因此受营养条件和遗传物质的多样性（即，倍性）。作者提出了一个数学模型的调节分子网络作用于G1到S的过渡。与该过程的先前模型相比，该模型的主要新颖特征是（1）考虑细胞生长（即，细胞体积的增加）;（2）明确考虑到细胞具有细胞核和细胞质，并且关键的细胞周期调节分子必须在这些不同的区室之间移动，并且只有当它们在同一区室中时才能相互反应或调节;和（3）需要连续克服由细胞周期蛋白依赖性激酶/细胞周期蛋白和细胞周期蛋白依赖性激酶抑制剂给出的两个分子阈值。通过模拟不同生长条件或不同突变体的G1到S转变过程，并将结果与实验数据进行比较，对模型进行了检验。参数敏感性分析（即，当参数变化时，测试模型预测），新表明临界细胞大小是G1到S网络的一个紧急属性。该模型导致一个统一的解释，看似不同的实验观察，并作出预测，以实验验证。
The eukaryotic cell cycle is the repeated sequence of events that enable the division of a cell into two daughter cells. It is divided into four phases: G1, S, G2, and M. Passage through the cell cycle is strictly regulated by a molecular interaction network, which involves the periodic synthesis and destruction of cyclins that bind and activate cyclin-dependent kinases that are present in nonlimiting amounts. Cyclin-dependent kinase inhibitors contribute to cell cycle control. Budding yeast is an established model organism for cell cycle studies, and several mathematical models have been proposed for its cell cycle. An area of major relevance in cell cycle control is the G1 to S transition. In any given growth condition, it is characterized by the requirement of a specific, critical cell size, PS, to enter S phase. The molecular basis of this control is still under discussion. The authors report a mathematical model of the G1 to S network that newly takes into account nucleo/cytoplasmic localization, the role of the cyclin-dependent kinase Sic1 in facilitating nuclear import of its cognate Cdk1-Clb5, Whi5 control, and carbon source regulation of Sic1 and Sic1-containing complexes. The model was implemented by a set of ordinary differential equations that describe the temporal change of the concentration of the involved proteins and protein complexes. The model was tested by simulation in several genetic and nutritional setups and was found to be neatly consistent with experimental data. To estimate PS, the authors developed a hybrid model including a probabilistic component for firing of DNA replication origins. Sensitivity analysis of PS provides a novel relevant conclusion: PS is an emergent property of the G1 to S network that strongly depends on growth rate. A major property of living cells is their ability to maintain mass homeostasis throughout cell divisions. It has been proposed that in order to achieve such homeostasis, some critical event(s) in the cell cycle will take place only when the cell has grown beyond a critical cell size. In the budding yeast Saccharomyces cerevisiae, a widely used model for the study of the eukaryotic cell cycle, a large body of evidence indicates that cells have to reach a critical size before they start to replicate their DNA and to form bud, which will give rise to the daughter cell. This critical cell size is modulated by growth rate, hence by nutritional conditions and the multiplicity of genetic material (i.e., ploidy). The authors present a mathematical model of the regulatory molecular network acting at the G1 to S transition. The major novel features of this model compared with previous models of this process are (1) the accounting for cell growth (i.e., the increase in cell volume); (2) the explicit consideration of the fact that cells have a nucleus and a cytoplasm, and that key cell cycle regulatory molecules must move between these different compartments and can only react or regulate each other if they are in the same compartment; and (3) the requirement of sequential overcoming of two molecular thresholds given by a cyclin-dependent kinase/cyclin and a cyclin-dependent kinase inhibitor. The model was tested by simulating the processes during G1 to S transition for different growth conditions or for different mutants and by comparing the results with experimental data. A parameter sensitivity analysis (i.e., testing the model predictions when parameters are varied), newly indicates that the critical cell size is an emergent property of the G1 to S network. The model leads to a unified interpretation of seemingly disparate experimental observations and makes predictions to be experimentally verified.
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