The period of the circadian oscillator is primarily determined by the balance between casein kinase 1 and protein phosphatase 1
The period of the circadian oscillator is primarily determined by the balance between casein kinase 1 and protein phosphatase 1
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DOI：
10.1073/pnas.1107178108
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发表时间：
2011-09-27
影响因子：
11.1
通讯作者：
Lee, Choogon
中科院分区：
文献类型：
--
作者：
Lee, Hyeong-Min;Chen, Rongmin;Lee, Choogon
越来越多的证据表明，PERIOD（PER）蛋白在设定生物钟的速度（周期）和相位方面发挥着核心作用。药理学和遗传学研究表明，PER磷酸化动力学的变化与昼夜节律周期和相位的变化相关，这可能导致人类的睡眠障碍，如家族性睡眠相位提前综合征。我们和其他人已经表明，酪蛋白激酶1 δ和CK 1 δ/CK 2是必需的PER激酶，但很明显，其他未知的机制也是调节PER磷酸化动力学的关键。在这里，我们报告说，昼夜节律的周期性主要是通过PER磷酸化动力学CK 1d/e和蛋白磷酸酶1（PP 1）之间的平衡。在CK 1 δ/ε缺陷细胞中，PER磷酸化严重受损且无节律，PER蛋白质是组成性细胞质。然而，当PP 1被破坏时，PER磷酸化显著加速;当PP 2A被破坏时，没有看到相同的效果。我们的工作表明，PER磷酸化的速度和节律性是由CK 1d/e和PP 1之间的平衡控制的，这反过来又决定了昼夜节律振荡器的周期。因此，我们的研究结果为我们日常节奏的周期和阶段是如何确定的分子基础提供了清晰的见解。
Mounting evidence suggests that PERIOD (PER) proteins play a central role in setting the speed (period) and phase of the circadian clock. Pharmacological and genetic studies have shown that changes in PER phosphorylation kinetics are associated with changes in circadian rhythm period and phase, which can lead to sleep disorders such as Familial Advanced Sleep Phase Syndrome in humans. We and others have shown that casein kinase 1 delta and epsilon (CK1 delta/epsilon) are essential PER kinases, but it is clear that additional, unknown mechanisms are also crucial for regulating the kinetics of PER phosphorylation. Here we report that circadian periodicity is determined primarily through PER phosphorylation kinetics set by the balance between CK1d/e and protein phosphatase 1 (PP1). In CK1 delta/epsilon-deficient cells, PER phosphorylation is severely compromised and non-rhythmic, and the PER proteins are constitutively cytoplasmic. However, when PP1 is disrupted, PER phosphorylation is dramatically accelerated; the same effect is not seen when PP2A is disrupted. Our work demonstrates that the speed and rhythmicity of PER phosphorylation are controlled by the balance between CK1d/e and PP1, which in turn determines the period of the circadian oscillator. Thus, our findings provide clear insights into the molecular basis of how the period and phase of our daily rhythms are determined.