隐色素
抄写(语言学)
电箱
转录因子
抑制因子
昼夜节律
细胞生物学
生物
转录调控
生物钟
调节器
化学
生物化学
内分泌学
基因
增强子
哲学
语言学
作者
Jaebong Jang,Sooyoung Chung,Youjeong Choi,Hye Young Lim,Yeongeon Son,Sung Kook Chun,Gi Hoon Son,Kyungjin Kim,Young‐Ger Suh,Jong‐Wha Jung
出处
期刊:Life Sciences
[Elsevier]
日期:2018-03-10
卷期号:200: 49-55
被引量:27
标识
DOI:10.1016/j.lfs.2018.03.022
摘要
We have previously identified a chemical scaffold possessing 2-ethoxypropanoic acid (designated as KS15) that directly binds to the C-terminal region of cryptochromes (CRYs: CRY1 and CRY2) and enhances E-box-mediated transcription. However, it is still unclear how KS15 impairs the feedback actions of the CRYs and which chemical moieties are functionally important for its actions. The E-box-mediated transcriptional activities were mainly used to examine the effects of KS15 and its derivatives. Co-immunoprecipitation assays accompanied by immunoblotting were employed to monitor protein-protein associations. We also examined the effects of KS15 and selected derivatives on circadian molecular rhythms in cultured cells. The present study shows that KS15 inhibits the interaction between CRYs and Brain-Muscle-Arnt-Like protein 1 (BMAL1), thereby impairing the feedback actions of CRYs on E-box-dependent transcription by CLOCK:BMAL1 heterodimer, an indispensable transcriptional regulator of the mammalian circadian clock. Subsequent structure-activity relationship analyses using a well-designed panel of derivatives identified the structural requirements for the effects of KS15 on CRY-evoked regulation of E-box-mediated transcription. We found that KS15 and several derivatives significantly reduce the amplitude and delayed the phase of molecular circadian rhythms in fibroblast cultures. Taken together, our results provide valuable information on the molecular mode-of-action as well as the chemical components of the CRYs inhibitor that pharmacologically impact on the transcriptional activity of the CLOCK:BMAL1 heterodimer.
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