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- 저자 : Son Yeongeon (검색결과 1 건)
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Jang, Jaebong,Chung, Sooyoung,Choi, Youjeong,Lim, Hye Young,Son, Yeongeon,Chun, Sung Kook,Son, Gi Hoon,Kim, Kyungjin,Suh, Young-Ger,Jung, Jong-Wha Elsevier 2018 Life sciences Vol.200 No.-
<P><B>Abstract</B></P> <P><B>Aims</B></P> <P>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.</P> <P><B>Main methods</B></P> <P>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.</P> <P><B>Key findings</B></P> <P>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.</P> <P><B>Significance</B></P> <P>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.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
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