CDK9 modulates circadian clock by attenuating REV-ERB alpha activity
CDK9 modulates circadian clock by attenuating REV-ERB alpha activity
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CDK9 通过减弱 REV-ERB α 活性来调节生物钟
DOI：
10.1016/j.bbrc.2019.04.043
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发表时间：
2019
影响因子：
3.1
通讯作者：
Tang Yun-Chi
中科院分区：
文献类型：
--
作者：
Ou Jiali;Li Huilin;Qiu Peiyuan;Li Qing;Chang Hung-Chun;Tang Yun-Chi
生物钟和细胞周期是重要的细胞程序，以时间调节的循环方式发挥作用。两个细胞振荡器以各种方式耦合以促进生物过程。本文报道了CDK 9作为CDK家族的一个成员，在细胞周期和RNA PolII活性的调控中发挥生物钟调节剂的作用。我们从17种常用的CDK抑制剂的筛选中鉴定出CDK抑制剂LY 2857785有效地阻断MEFs中PER 2：LUC的表达。我们进一步通过siRNA方法分析了LY 2857785的可能靶点，证实CDK 9是主要效应子。LY 2857785处理以及Cdk 9敲低导致Bmal 1表达降低，与Rev-Erb α表达升高一致。因此，与REV-ERBα相关的CDK 9减弱了REV-ERBα与RORE的结合，从而抑制Bmal 1。为了证实CDK 9在体内的昼夜节律调节活性，我们在覆盖中央振荡器SCN的小鼠下丘脑前部敲除CDK 9，发现Cdk 9敲除小鼠的呼吸交换率、日常活动和昼夜节律周期发生改变。总之，我们的发现指定CDK 9作为一种新的生物钟调节剂。CDK 9可以作为理解昼夜节律和细胞周期失调疾病（如癌症）的重要基础。
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 asCdk9knock-down, led to lowered expression ofBmal1in accordance with elevated expression ofRev-Erbα. CDK9 associated with REV-ERBα thus attenuated REV-ERBα binding to the RORE forBmal1suppression. To conform the circadian-modulating activity of CDK9in 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 theCdk9-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.