Essential roles of CKIdelta and CKIepsilon in the mammalian circadian clock.

Proceedings of the National Academy of Sciences of the United States of America
Hyeongmin LeeChoogon Lee

Abstract

Circadian rhythms in mammals are generated by a negative transcriptional feedback loop in which PERIOD (PER) is rate-limiting for feedback inhibition. Casein kinases Idelta and Iepsilon (CKIdelta/epsilon) can regulate temporal abundance/activity of PER by phosphorylation-mediated degradation and cellular localization. Despite their potentially crucial effects on PER, it has not been demonstrated in a mammalian system that these kinases play essential roles in circadian rhythm generation as does their homolog in Drosophila. To disrupt both CKIdelta/epsilon while avoiding the embryonic lethality of CKIdelta disruption in mice, we used CKIdelta-deficient Per2(Luc) mouse embryonic fibroblasts (MEFs) and overexpressed a dominant-negative mutant CKIepsilon (DN-CKIepsilon) in the mutant MEFs. CKIdelta-deficient MEFs exhibited a robust circadian rhythm, albeit with a longer period, suggesting that the cells possess a way to compensate for CKIdelta loss. When CKIepsilon activity was disrupted by the DN-CKIepsilon in the mutant MEFs, circadian bioluminescence rhythms were eliminated and rhythms in endogenous PER abundance and phosphorylation were severely compromised, demonstrating that CKIdelta/epsilon are indeed essential kinases for t...Continue Reading

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Citations

Oct 23, 2012·Cell Reports·Craig C JolleyHiroki R Ueda
Aug 11, 2010·Proceedings of the National Academy of Sciences of the United States of America·Qing-Jun MengAndrew S I Loudon
Sep 21, 2011·Proceedings of the National Academy of Sciences of the United States of America·Hyeong-min LeeChoogon Lee
Dec 21, 2011·Proceedings of the National Academy of Sciences of the United States of America·Zheng ChenJoseph S Takahashi
Jan 5, 2011·The Journal of Biological Chemistry·Yongjin LeeChoogon Lee
Aug 13, 2013·PloS One·Gerben van OoijenAndrew J Millar
May 9, 2012·Genetics Research International·Chengwei LiXiaodong Li
Jan 5, 2014·Canadian Journal of Physiology and Pharmacology·Roberto Refinetti
Mar 23, 2011·The Journal of Cell Biology·Yoshimi Endo Greer, Jeffrey S Rubin
Dec 1, 2015·Nature Communications·Matthew D'AlessandroChoogon Lee
Dec 6, 2012·Molecular Systems Biology·Jae Kyoung Kim, Daniel B Forger
Jul 19, 2013·CPT: Pharmacometrics & Systems Pharmacology·J K KimK M Walton
Nov 8, 2014·Proceedings of the National Academy of Sciences of the United States of America·Lorena Aguilar-Arnal, Paolo Sassone-Corsi
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