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Life Sci. 2018 May 1;200:49-55. doi: 10.1016/j.lfs.2018.03.022. Epub 2018 Mar 10.

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

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
2
Department of Brain and Cognitive Sciences, Scranton College, Ewha Womans University, Seoul, Republic of Korea.
3
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea.
4
Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, Republic of Korea.
5
Department of Brain and Cognitive Sciences, Daegu-Gyeongbuk Institute of Science & Technology (DGIST), Daegu, Republic of Korea; Korea Brain Research Institute (KBRI), Daegu, Republic of Korea.
6
College of Pharmacy, Cha University, Pochen, Republic of Korea. Electronic address: ygsuh@cha.ac.kr.
7
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea. Electronic address: jungj@knu.ac.kr.

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.

KEYWORDS:

2-Ethoxypropanoic acid; CLOCK:BMAL1 heterodimer; Circadian clock; Circadian rhythm; Cryptochromes (CRYs); KS15

PMID:
29534992
DOI:
10.1016/j.lfs.2018.03.022
[Indexed for MEDLINE]

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