Stoichiometric Relationship among Clock Proteins Determines Robustness of Circadian Rhythms
Stoichiometric Relationship among Clock Proteins Determines Robustness of Circadian Rhythms
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DOI：
10.1074/jbc.m110.207217
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发表时间：
2011-03-04
影响因子：
4.8
通讯作者：
Lee, Choogon
中科院分区：
文献类型：
--
作者：
Lee, Yongjin;Chen, Rongmin;Lee, Choogon
哺乳动物的昼夜节律振荡器主要由一个基本的负反馈回路驱动，该负反馈回路包括一个正分量（CLOCK-BMAL 1复合物）和一个负分量（PER-CRY复合物）。许多研究表明，反馈抑制时钟BMAL 1介导的时间依赖性物理相互作用与其直接靶基因产物PER和CRY，这表明负和正复合物之间的比例必须是重要的分子振荡器和节奏的产生。我们通过改变Per 2（Luc）和Per突变小鼠（一种广泛用于研究体内时钟机制的细胞系统）成纤维细胞中时钟成分的表达来探索这一想法。我们的数据表明，化学计量的时钟组件之间的关系是至关重要的昼夜节律的鲁棒性，并提供洞察负反馈回路的机械组织。我们的研究结果可以解释为什么某些突变小鼠或细胞是节律性的，而另一些则是节律性的，并表明即使在野生型细胞中，也可以通过调节化学计量来增加昼夜节律的鲁棒性。
The mammalian circadian oscillator is primarily driven by an essential negative feedback loop comprising a positive component, the CLOCK-BMAL1 complex, and a negative component, the PER-CRY complex. Numerous studies suggest that feedback inhibition of CLOCK-BMAL1 is mediated by time-dependent physical interaction with its direct target gene products PER and CRY, suggesting that the ratio between the negative and positive complexes must be important for the molecular oscillator and rhythm generation. We explored this idea by altering expression of clock components in fibroblasts derived from Per2(Luc) and Per mutant mice, a cell system extensively used to study in vivo clock mechanisms. Our data demonstrate that the stoichiometric relationship between clock components is critical for the robustness of circadian rhythms and provide insights into the mechanistic organization of the negative feedback loop. Our findings may explain why certain mutant mice or cells are arrhythmic, whereas others are rhythmic, and suggest that robustness of circadian rhythms can be increased even in wild-type cells by modulating the stoichiometry.