The cryptochrome inhibitor KS15 enhances E-box-mediated transcription by disrupting the feedback action of a circadian transcription-repressor complex
- 주제(키워드) Circadian rhythm , Circadian clock , Cryptochromes (CRYs) , CLOCK:BMAL1 heterodimer , KS15 , 2-Ethoxypropanoic acid
- 주제(기타) Medicine, Research & Experimental; Pharmacology & Pharmacy
- 설명문(일반) [Jang, Jaebong] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA; [Jang, Jaebong] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA USA; [Chung, Sooyoung] Ewha Womans Univ, Scranton Coll, Dept Brain & Cognit Sci, Seoul, South Korea; [Choi, Youjeong; Son, Yeongeon; Jung, Jong-Wha] Kyungpook Natl Univ, Res Inst Pharmaceut Sci, Coll Pharm, Daegu, South Korea; [Lim, Hye Young; Son, Gi Hoon] Korea Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea; [Chun, Sung Kook; Kim, Kyungjin] DGIST, Dept Brain & Cognit Sci, Daegu, South Korea; [Chun, Sung Kook; Kim, Kyungjin] KBRI, Daegu, South Korea; [Suh, Young-Ger] Cha Univ, Coll Pharm, Pochen, South Korea
- 관리정보기술 faculty
- 등재 SCIE, SCOPUS
- 발행기관 PERGAMON-ELSEVIER SCIENCE LTD
- 발행년도 2018
- URI http://www.dcollection.net/handler/ewha/000000151842
- 본문언어 영어
- Published As http://dx.doi.org/10.1016/j.lfs.2018.03.022
초록/요약
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.
more