CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Jiao Tong University School of Medicine, Shanghai Institute of Nutrition and Health, Shanghai Institute for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
Institute of Neuroscience, CAS Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China.
Biochem Biophys Res Commun. 2019 Jun 11;513(4):967-973. doi: 10.1016/j.bbrc.2019.04.043. Epub 2019 Apr 17.
Circadian clock and cell cycle are vital cellular programs acting in a timely-regulated, cyclic manner. The two cellular oscillators are coupled in various ways to facilitate biological processes. Here we report CDK9, a kinase belongs to the CDK family in regulating cell cycle and RNA Pol II activity, can serve as a modulator for circadian clock. We identified CDK inhibitor LY2857785 potently blocked PER2:LUC expression in MEFs from a screen of 17 commonly-used CDK inhibitors. We further analyzed the possible targets of LY2857785 by siRNA approach, and confirmed CDK9 as the main effector. LY2857785 treatment, as well as Cdk9 knock-down, led to lowered expression of Bmal1 in accordance with elevated expression of Rev-Erbα. CDK9 associated with REV-ERBα thus attenuated REV-ERBα binding to the RORE for Bmal1 suppression. To conform the circadian-modulating activity of CDK9 in vivo, we knocked down CDK9 in mice at the anterior hypothalamus covering the central oscillator SCN, and found the respiratory exchange ratio, daily activity and circadian period were altered in the Cdk9-knockdown mice. Together, our finding designated CDK9 as a novel modulator in circadian clock. CDK9 may serve as a vital basis to understand circadian- and cell cycle-misregulated ailments such as cancer.
生物钟和细胞周期是至关重要的细胞程序，以定时调节、周期性的方式发挥作用。这两个细胞振荡器以各种方式耦合，以促进生物过程。在这里，我们报告 CDK9，一种属于细胞周期蛋白依赖性激酶家族的激酶，可调节细胞周期和 RNA Pol II 活性，可作为生物钟的调节剂。我们从 17 种常用 CDK 抑制剂的筛选中发现，CDK 抑制剂 LY2857785 可有效阻断 MEFs 中 PER2:LUC 的表达。我们进一步通过 siRNA 方法分析 LY2857785 的可能靶标，并确认 CDK9 为主要效应物。LY2857785 处理以及 Cdk9 敲低导致 Bmal1 表达降低，同时 Rev-Erbα 表达升高。因此，CDK9 与 REV-ERBα 结合，减弱了 REV-ERBα 对 Bmal1 的抑制作用。为了在体内证实 CDK9 的生物钟调节活性，我们在前脑下丘脑（覆盖中央振荡器 SCN）敲低 CDK9，发现 Cdk9 敲低小鼠的呼吸交换率、每日活动和昼夜节律周期发生改变。总之，我们的发现将 CDK9 确定为生物钟的一个新的调节剂。CDK9 可能是理解生物钟和细胞周期失调疾病（如癌症）的重要基础。
