Linke Christian, Chasapi Anastasia, González-Novo Alberto, Al Sawad Istabrak, Tognetti Silvia, Klipp Edda, Loog Mart, Krobitsch Sylvia, Posas Francesc, Xenarios Ioannis, Barberis Matteo
Synthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, 1098 XH The Netherlands.
Max Planck Institute for Molecular Genetics, Berlin, 14195 Germany.
NPJ Syst Biol Appl. 2017 Mar 6;3:7. doi: 10.1038/s41540-017-0008-1. eCollection 2017.
Precise timing of cell division is achieved by coupling waves of cyclin-dependent kinase (Cdk) activity with a transcriptional oscillator throughout cell cycle progression. Although details of transcription of cyclin genes are known, it is unclear which is the transcriptional cascade that modulates their expression in a timely fashion. Here, we demonstrate that a Clb/Cdk1-mediated regulation of the Fkh2 transcription factor synchronizes the temporal mitotic expression in budding yeast. A simplified kinetic model of the cyclin/Cdk network predicts a linear cascade where a Clb/Cdk1-mediated regulation of an activator molecule drives and expression. Experimental validation highlights Fkh2 as modulator of transcript levels, besides its role in regulating expression. A Boolean model based on the minimal number of interactions needed to capture the information flow of the Clb/Cdk1 network supports the role of an activator molecule in the sequential activation, and oscillatory behavior, of mitotic Clb cyclins. This work illustrates how transcription and phosphorylation networks can be coupled by a Clb/Cdk1-mediated regulation that synchronizes them.
通过在整个细胞周期进程中，将细胞周期蛋白依赖性激酶（Cdk）活性波与转录振荡器相耦合，实现了细胞分裂的精确时间调控。尽管细胞周期蛋白基因转录的细节已为人所知，但尚不清楚是哪种转录级联反应能及时调节它们的表达。在此，我们证明了Clb/Cdk1介导的Fkh2转录因子调控可使芽殖酵母中的有丝分裂表达在时间上同步。细胞周期蛋白/Cdk网络的简化动力学模型预测了一个线性级联反应，其中Clb/Cdk1介导的激活分子调控驱动了和表达。实验验证突出了Fkh2除了在调控表达中的作用外，还是转录水平的调节因子。基于捕获Clb/Cdk1网络信息流所需的最少相互作用数量构建的布尔模型，支持了激活分子在有丝分裂Clb细胞周期蛋白的顺序激活和振荡行为中的作用。这项工作说明了转录和磷酸化网络如何通过Clb/Cdk1介导的调控相互耦合并实现同步。
