A Dynamical Framework for the All-or-None G1/S Transition.
A Dynamical Framework for the All-or-None G1/S Transition.
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DOI：
10.1016/j.cels.2016.01.001
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发表时间：
2016-01-27
期刊：
影响因子：
9.3
通讯作者：
Novák B
中科院分区：
文献类型：
--
作者：
Barr AR;Heldt FS;Zhang T;Bakal C;Novák B
从G1期到DNA复制期（S期）的转变是细胞周期蛋白依赖性激酶（Cdks）、Cdk抑制剂（CKIs）和后期促进复合物/细胞周期体（APC/C）之间动态和复杂相互作用的结果。理解细胞决定进入S期需要对这些相互作用进行定量描述。我们应用单个人类细胞的定量成像来跟踪G1/S调节剂的表达，并使用这些数据来参数化G1/S过渡的随机数学模型。我们发现，一个快速的，蛋白水解，双负反馈之间的Cdk 2：细胞周期蛋白和Cdk抑制剂p27 Kip 1驱动开关样进入S期的循环。此外，我们的模型预测，在整个S期增加的G1/S水平是至关重要的，在保持G1/S过渡的不可逆性，我们验证使用G1/S报告基因的G1/S敲低和实时成像。这项工作深入了解了控制细胞周期阶段之间时间突然转变的信号网络的一般设计原则。人类G1/S转换的模型来自关键调节因子的单细胞成像Cdk 2：CycE和p27之间的双负反馈驱动开关样转换APC/C抑制剂p53 1确保G1/S转换保持不可逆建模提供了对癌症和正常细胞之间Cdk 2活性差异的深入了解哺乳动物细胞对细胞周期阶段之间开关样和不可逆转换的基本原理知之甚少。巴尔等人使用定量实时成像技术对单个人类细胞中G1-to-S转换的调节因子进行了研究，以开发一种机制模型来显示该网络如何驱动细胞周期进程的快速和不可逆承诺。
The transition from G1 into DNA replication (S phase) is an emergent behavior resulting from dynamic and complex interactions between cyclin-dependent kinases (Cdks), Cdk inhibitors (CKIs), and the anaphase-promoting complex/cyclosome (APC/C). Understanding the cellular decision to commit to S phase requires a quantitative description of these interactions. We apply quantitative imaging of single human cells to track the expression of G1/S regulators and use these data to parametrize a stochastic mathematical model of the G1/S transition. We show that a rapid, proteolytic, double-negative feedback loop between Cdk2:Cyclin and the Cdk inhibitor p27Kip1 drives a switch-like entry into S phase. Furthermore, our model predicts that increasing Emi1 levels throughout S phase are critical in maintaining irreversibility of the G1/S transition, which we validate using Emi1 knockdown and live imaging of G1/S reporters. This work provides insight into the general design principles of the signaling networks governing the temporally abrupt transitions between cell-cycle phases. A model of the human G1/S transition is derived from single-cell imaging of key regulators Double-negative feedback between Cdk2:CycE and p27 drives a switch-like transition The APC/C inhibitor Emi1 ensures that the G1/S transition is kept irreversible Modeling provides insight into the differences in Cdk2 activity between cancer and normal cells The principles underlying switch-like and irreversible transitions between cell-cycle phases are poorly understood in mammalian cells. Barr et al. have used quantitative real-time imaging of regulators of the G1-to-S transition in single human cells to develop a mechanistic model to show how this network drives rapid and irreversible commitment to cell-cycle progression.