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

Title: Essential roles of CKIdelta and CKIepsilon in the mammalian circadian clock.
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Name(s): Lee, Hyeongmin, author
Chen, Rongmin, author
Lee, Yongjin, author
Yoo, Seunghee, author
Lee, Choogon, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2009-12-15
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: 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 the clockwork. This is further supported by abolition of circadian rhythms when physical interaction between PER and CKIdelta/epsilon was disrupted by overexpressing the CKIdelta/epsilon binding domain of PER2 (CKBD-P2). Interestingly, CKBD-P2 overexpression led to dramatically low levels of endogenous PER, while PER-binding, kinase-inactive DN-CKIepsilon did not, suggesting that CKIdelta/epsilon may have a non-catalytic role in stabilizing PER. Our results show that an essential role of CKIdelta/epsilon is conserved between Drosophila and mammals, but CKIdelta/epsilon and DBT may have divergent non-catalytic functions in the clockwork as well.
Identifier: FSU_pmch_19948962 (IID), 10.1073/pnas.0906651106 (DOI), PMC2795500 (PMCID), 19948962 (RID), 19948962 (EID), 0906651106 (PII)
Grant Number: R01 NS053616, NS-053616
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2795500.
Subject(s): Animals
Casein Kinase Idelta/deficiency
Casein Kinase Idelta/metabolism
Casein Kinase Idelta/physiology
Casein Kinase Iepsilon/metabolism
Casein Kinase Iepsilon/physiology
Cell Line
Circadian Rhythm
Drosophila
Fibroblasts/cytology
Mice
Mice, Knockout
Mutation
Period Circadian Proteins/metabolism
Protein Binding
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_19948962
Host Institution: FSU
Is Part Of: Proceedings of the National Academy of Sciences of the United States of America.
1091-6490
Issue: iss. 50, vol. 106

Choose the citation style.
Lee, H., Chen, R., Lee, Y., Yoo, S., & Lee, C. (2009). Essential roles of CKIdelta and CKIepsilon in the mammalian circadian clock. Proceedings Of The National Academy Of Sciences Of The United States Of America. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_19948962