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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, JaebongChung, SooyoungChoi, YoujeongLim, Hye YoungChun, Sung KookSon, Gi HoonSon, YeongeonKim, KyungjinSuh, Young-GerJung, Jong-Wha
Ewha Authors
정수영
SCOPUS Author ID
정수영scopus
Issue Date
2018
Journal Title
LIFE SCIENCES
ISSN
0024-3205JCR Link1879-0631JCR Link
Citation
vol. 200, pp. 49 - 55
Keywords
Circadian rhythmCircadian clockCryptochromes (CRYs)CLOCK:BMAL1 heterodimerKS152-Ethoxypropanoic acid
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Indexed
SCI; SCIE; SCOPUS WOS scopus
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.
DOI
10.1016/j.lfs.2018.03.022
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스크랜튼대학 > 융합학부 > Journal papers
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