Home LiteratureArticle Details
PMID: 11875063 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iepsilon.

The Journal of biological chemistry ·Vol. 277 ·No. 19 ·2002-05-10 ·Pages 17248-54

Eide EJ, Vielhaber EL, Hinz WA, Virshup DM

Abstract

The serine/threonine protein kinase casein kinase I epsilon (CKIepsilon) is a key regulator of metazoan circadian rhythm. Genetic and biochemical data suggest that CKIepsilon binds to and phosphorylates the PERIOD proteins. However, the PERIOD proteins interact with a variety of circadian regulators, suggesting the possibility that CKIepsilon may interact with and phosphorylate additional clock components as well. We find that CRY1 and BMAL1 are phosphoproteins in cultured cells. Mammalian PERIOD proteins act as a scaffold with distinct domains that simultaneously bind CKIepsilon and mCRY1 and mCRY2 (mCRY). mCRY is phosphorylated by CKIepsilon only when both proteins are bound to mammalian PERIOD proteins. BMAL1 is also a substrate for CKIepsilon in vitro, and CKIepsilon kinase activity positively regulates BMAL1-dependent transcription from circadian promoters in reporter assays. We conclude that CKIepsilon phosphorylates multiple circadian substrates and may exert its effects on circadian rhythm in part by a direct effect on BMAL1-dependent transcription.

MeSH Terms
ARNTL Transcription Factors Animals Basic Helix-Loop-Helix Transcription Factors Binding Sites Casein Kinases Cell Line Cryptochromes Drosophila Proteins Eye Proteins Flavoproteins/metabolism Humans Microscopy, Fluorescence Phosphorylation Photoreceptor Cells, Invertebrate Precipitin Tests Promoter Regions, Genetic Protein Binding Protein Kinases/metabolism,physiology Protein Structure, Tertiary Receptors, G-Protein-Coupled Transcription Factors/metabolism Transcription, Genetic Transfection
Chemicals
ARNTL Transcription Factors ARNTL protein, human Basic Helix-Loop-Helix Transcription Factors CRY1 protein, human Cryptochromes Drosophila Proteins Eye Proteins Flavoproteins Receptors, G-Protein-Coupled Transcription Factors cry protein, Drosophila Protein Kinases Casein Kinases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Eide Erik J
Department of Oncological Sciences, Huntsman Cancer Institute Center for Children, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
Vielhaber Erica L
Hinz William A
Virshup David M
References (32)
32 references, click to expand
  1. Analysis of clock proteins in mouse SCN demonstrates phylogenetic divergence of the circadian clockwork and resetting mechanisms.
    Neuron. 2000 Feb;25(2):437-47 PMID: 10719897
  2. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau.
    Science. 2000 Apr 21;288(5465):483-92 PMID: 10775102
  3. Phosphorylation and destabilization of human period I clock protein by human casein kinase I epsilon.
    Neuroreport. 2000 Apr 7;11(5):951-5 PMID: 10790862
  4. Interacting molecular loops in the mammalian circadian clock.
    Science. 2000 May 12;288(5468):1013-9 PMID: 10807566
  5. Dimerization and nuclear entry of mPER proteins in mammalian cells.
    Genes Dev. 2000 Jun 1;14(11):1353-63 PMID: 10837028
  6. Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase I epsilon.
    Mol Cell Biol. 2000 Jul;20(13):4888-99 PMID: 10848614
  7. Cloning and characterization of rat casein kinase 1epsilon.
    FEBS Lett. 2000 Jul 14;477(1-2):106-12 PMID: 10899319
  8. Two novel doubletime mutants alter circadian properties and eliminate the delay between RNA and protein in Drosophila.
    J Neurosci. 2000 Oct 15;20(20):7547-55 PMID: 11027213
  9. Short-period mutations of per affect a double-time-dependent step in the Drosophila circadian clock.
    Curr Biol. 2000 Nov 2;10(21):1399-402 PMID: 11084344
  10. Genetics of the mammalian circadian system: Photic entrainment, circadian pacemaker mechanisms, and posttranslational regulation.
    Annu Rev Genet. 2000;34:533-562 PMID: 11092838
  11. Molecular analysis of mammalian circadian rhythms.
    Annu Rev Physiol. 2001;63:647-76 PMID: 11181971
  12. Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2.
    FEBS Lett. 2001 Feb 2;489(2-3):159-65 PMID: 11165242
  13. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome.
    Science. 2001 Feb 9;291(5506):1040-3 PMID: 11232563
  14. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells.
    Nature. 2001 May 24;411(6836):494-8 PMID: 11373684
  15. Constitutive expression and delayed light response of casein kinase Iepsilon and Idelta mRNAs in the mouse suprachiasmatic nucleus.
    J Neurosci Res. 2001 Jun 15;64(6):612-6 PMID: 11398185
  16. Phosphorylation of period is influenced by cycling physical associations of double-time, period, and timeless in the Drosophila clock.
    Neuron. 2001 Jun;30(3):699-706 PMID: 11430804
  17. Casein kinase I: another cog in the circadian clockworks.
    Chronobiol Int. 2001 May;18(3):389-98 PMID: 11475410
  18. Stopping time: the genetics of fly and mouse circadian clocks.
    Annu Rev Neurosci. 2001;24:1091-119 PMID: 11520929
  19. Nuclear entry mechanism of rat PER2 (rPER2): role of rPER2 in nuclear localization of CRY protein.
    Mol Cell Biol. 2001 Oct;21(19):6651-9 PMID: 11533252
  20. Nuclear export of mammalian PERIOD proteins.
    J Biol Chem. 2001 Dec 7;276(49):45921-7 PMID: 11591712
  21. Mitogen-activated protein kinase phosphorylates and negatively regulates basic helix-loop-helix-PAS transcription factor BMAL1.
    J Biol Chem. 2002 Jan 4;277(1):267-71 PMID: 11687575
  22. Posttranslational mechanisms regulate the mammalian circadian clock.
    Cell. 2001 Dec 28;107(7):855-67 PMID: 11779462
  23. The regulation of transcription by phosphorylation.
    Cell. 1992 Aug 7;70(3):375-87 PMID: 1643656
  24. Isolation and characterization of human casein kinase I epsilon (CKI), a novel member of the CKI gene family.
    J Biol Chem. 1995 Jun 23;270(25):14875-83 PMID: 7797465
  25. Transcriptional control by protein phosphorylation: signal transmission from the cell surface to the nucleus.
    Curr Biol. 1995 Jul 1;5(7):747-57 PMID: 7583121
  26. Autoinhibition of casein kinase I epsilon (CKI epsilon) is relieved by protein phosphatases and limited proteolysis.
    J Biol Chem. 1998 Jan 16;273(3):1357-64 PMID: 9430669
  27. double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation.
    Cell. 1998 Jul 10;94(1):83-95 PMID: 9674430
  28. The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Iepsilon.
    Cell. 1998 Jul 10;94(1):97-107 PMID: 9674431
  29. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop.
    Cell. 1999 Jul 23;98(2):193-205 PMID: 10428031
  30. Casein kinase I transduces Wnt signals.
    Nature. 1999 Sep 23;401(6751):345-50 PMID: 10517632
  31. Light-independent role of CRY1 and CRY2 in the mammalian circadian clock.
    Science. 1999 Oct 22;286(5440):768-71 PMID: 10531061
  32. Casein kinase iepsilon in the wnt pathway: regulation of beta-catenin function.
    Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12548-52 PMID: 10535959
Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M111466200
Published
2002-05-10
Epub
2002-00-01
Pages
17248-54
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC1513548
Subset
IM
Grants
NCI NIH HHS · P30 CA042014 · United States
NCI NIH HHS · P30CA42014 · United States
NIGMS NIH HHS · R01 GM060387-04 · United States
NCI NIH HHS · R01CA71074 · United States
External Links
PubMed source DOI: 10.1074/jbc.M111466200 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2