In this work, we study period control of the mammalian cell cycle via coupling with the cellular clock. For this, we make use of the oscillators’ synchronization dynamics and investigate methods of slowing down the cell cycle with the use of clock inputs. Clock control of the cell cycle is well established via identified molecular mechanisms, such as the CLOCK:BMAL1-mediated induction of the wee1 gene, resulting in the WEE1 kinase that represses the active form of mitosis promoting factor (MPF), the essential cell cycle component. To investigate the coupling dynamics of these systems, we use previously developed models of the clock and cell cycle oscillators and center our studies on unidirectional clock [Formula: see text] cell cycle coupling. Moreover, we propose an hypothesis of a Growth Factor (GF)-responsive clock, involving a pathway of the non-essential cell cycle complex cyclin D/CDK4. We observe a variety of rational ratios of clock to cell cycle period, such as: 1:1, 3:2, 4:3, and 5:4. Finally, our protocols of period control are successful in effectively slowing down the cell cycle by the use of clock modulating inputs, some of which correspond to existing drugs.

中文翻译：

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通过调制时钟输入来控制单元周期周期

在这项工作中，我们通过与细胞时钟耦合来研究哺乳动物细胞周期的周期控制。为此，我们利用振荡器的同步动力学并研究使用时钟输入减慢细胞周期的方法。细胞周期的时钟控制通过已确定的分子机制得到了很好的建立，例如 CLOCK:BMAL1 介导的 wee1 基因诱导，导致 WEE1 激酶抑制有丝分裂促进因子 (MPF) 的活性形式，这是必需的细胞周期零件。为了研究这些系统的耦合动力学，我们使用先前开发的时钟和细胞周期振荡器模型，并将我们的研究集中在单向时钟[公式：见文本]细胞周期耦合上。此外，我们提出了一个生长因子（GF）响应时钟的假设，涉及非必需细胞周期复合物cyclin D/CDK4的通路。我们观察到时钟与细胞周期周期的各种合理比率，例如：1:1、3:2、4:3 和 5:4。最后，我们的周期控制协议通过使用时钟调制输入成功地有效减缓了细胞周期，其中一些对应于现有药物。