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The cryptochrome inhibitor KS15 enhances E-box-mediated transcription by disrupting the feedback action of a circadian transcription-repressor complex

Title
The cryptochrome inhibitor KS15 enhances E-box-mediated transcription by disrupting the feedback action of a circadian transcription-repressor complex
Authors
Jang J.Chung S.Choi Y.Lim H.Y.Son Y.Chun S.K.Son G.H.Kim K.Suh Y.-G.Jung J.-W.
Ewha Authors
정수영
SCOPUS Author ID
정수영scopus
Issue Date
2018
Journal Title
Life Sciences
ISSN
0024-3205JCR Link
Citation
Life Sciences vol. 200, pp. 49 - 55
Keywords
2-Ethoxypropanoic acid; Circadian clock; Circadian rhythm; CLOCK:BMAL1 heterodimer; Cryptochromes (CRYs); KS15
Publisher
Elsevier Inc.
Indexed
SCI; SCIE; SCOPUS WOS scopus
Document Type
Article
Abstract
Aims: 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. Main methods: 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. Key findings: 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. Significance: 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. © 2018 Elsevier Inc.
DOI
10.1016/j.lfs.2018.03.022
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스크랜튼대학 > 융합학부 > Journal papers
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