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The cryptochrome inhibitor KS15 enhances E-box-mediated transcription by disrupting the feedback action of a circadian transcription-repressor complex
- The cryptochrome inhibitor KS15 enhances E-box-mediated transcription by disrupting the feedback action of a circadian transcription-repressor complex
- Jang, Jaebong; Chung, Sooyoung; Choi, Youjeong; Lim, Hye Young; Chun, Sung Kook; Son, Gi Hoon; Son, Yeongeon; Kim, Kyungjin; Suh, Young-Ger; Jung, Jong-Wha
- Ewha Authors
- SCOPUS Author ID
- Issue Date
- Journal Title
- LIFE SCIENCES
- 0024-3205; 1879-0631
- vol. 200, pp. 49 - 55
- Circadian rhythm; Circadian clock; Cryptochromes (CRYs); CLOCK:BMAL1 heterodimer; KS15; 2-Ethoxypropanoic acid
- PERGAMON-ELSEVIER SCIENCE LTD
- SCI; SCIE; SCOPUS
- 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.
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