The positive circadian regulators CLOCK and BMAL1 control G2/M cell cycle transition through Cyclin B1
The positive circadian regulators CLOCK and BMAL1 control G2/M cell cycle transition through Cyclin B1
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昼夜节律正调节因子 CLOCK 和 BMAL1 通过 Cyclin B1 控制 G2/M 细胞周期转换
DOI：
10.1080/15384101.2018.1558638
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发表时间：
2019-01-02
期刊：
影响因子：
4.3
通讯作者：
van der Horst, Gijsbertus T. J.
中科院分区：
文献类型：
--
作者：
Farshadi, Elham;Yan, Jie;van der Horst, Gijsbertus T. J.
我们之前发现了生物钟和细胞周期之间紧密的双向相位耦合。为了了解CLOCK/BMAL1复合物的作用，我们在NIH3T33C小鼠成纤维细胞（携带时钟和细胞周期的荧光报告细胞）中敲除BMAL1或CLOCK，并分析了单个细胞和细胞群体中细胞分裂的时间。Bmal1的失活导致昼夜节律性的丧失和细胞周期的延长，起源于延迟的G2/M转换。随后的分子分析显示，抑制Bmal1基因表达后，细胞周期蛋白B1 （G2/M的重要调节因子）水平降低。与这些实验观察结果完全一致，在哺乳动物生物钟和细胞周期振荡器耦合的计算模型中模拟Bmal1敲低（现在纳入了Bmal1诱导的Cyclin B1）显示细胞周期延长。敲除Clock基因表达后也获得了类似的数据。综上所述，CLOCK/BMAL1复合物通过调节Cyclin B1的表达，在G2/M过渡水平上控制细胞周期进程。
ABSTRACT We previously identified a tight bidirectional phase coupling between the circadian clock and the cell cycle. To understand the role of the CLOCK/BMAL1 complex, representing the main positive regulator of the circadian oscillator, we knocked down Bmal1 or Clock in NIH3T33C mouse fibroblasts (carrying fluorescent reporters for clock and cell cycle phase) and analyzed timing of cell division in individual cells and cell populations. Inactivation of Bmal1 resulted in a loss of circadian rhythmicity and a lengthening of the cell cycle, originating from delayed G2/M transition. Subsequent molecular analysis revealed reduced levels of Cyclin B1, an important G2/M regulator, upon suppression of Bmal1 gene expression. In complete agreement with these experimental observations, simulation of Bmal1 knockdown in a computational model for coupled mammalian circadian clock and cell cycle oscillators (now incorporating Cyclin B1 induction by BMAL1) revealed a lengthening of the cell cycle. Similar data were obtained upon knockdown of Clock gene expression. In conclusion, the CLOCK/BMAL1 complex controls cell cycle progression at the level of G2/M transition through regulation of Cyclin B1 expression.