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Control of Mammalian Circadian Rhythm by CKIε-Regulated Proteasome-Mediated PER2 Degradation
Open accessAbstract
The mammalian circadian regulatory proteins PER1 and PER2 undergo a daily cycle of accumulation followed by phosphorylation and degradation. Although phosphorylation-regulated proteolysis of these inhibitors is postulated to be essential for the function of the clock, inhibition of this process has not yet been shown to alter mammalian circadian rhythm. We have developed a cell-based model of PER2 degradation. Murine PER2 (mPER2) hyperphosphorylation induced by the cell-permeable protein phosphatase inhibitor calyculin A is rapidly followed by ubiquitination and degradation by the 26S proteasome. Proteasome-mediated degradation is critically important in the circadian clock, as proteasome inhibitors cause a significant lengthening of the circadian period in Rat-1 cells. CKIepsilon (casein kinase Iepsilon) has been postulated to prime PER2 for degradation. Supporting this idea, CKIepsilon inhibition also causes a significant lengthening of circadian period in synchronized Rat-1 cells. CKIepsilon inhibition also slows the degradation of PER2 in cells. CKIepsilon-mediated phosphorylation of PER2 recruits the ubiquitin ligase adapter protein beta-TrCP to a specific site, and dominant negative beta-TrCP blocks phosphorylation-dependent degradation of mPER2. These results provide a biochemical mechanism and functional relevance for the observed phosphorylation-degradation cycle of mammalian PER2. Cell culture-based biochemical assays combined with measurement of cell-based rhythm complement genetic studies to elucidate basic mechanisms controlling the mammalian clock.
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Cites
Coordination of circadian timing in mammals
Reppert, S. M., & Weaver, D. R. (2002) · Nature · doi:10.1038/nature00965 · Cited by 4,379
Mechanisms Underlying Ubiquitination
Pickart, C. M. (2001) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.70.1.503 · Cited by 3,184
Preitner, N., Damiola, F., Luis-Lopez-Molina, Zakany, J., Duboule, D., Albrecht, U., & Schibler, U. (2002) · Cell · doi:10.1016/s0092-8674(02)00825-5 · Cited by 2,198
A Serum Shock Induces Circadian Gene Expression in Mammalian Tissue Culture Cells
Balsalobre, A., Damiola, F., & Schibler, U. (1998) · Cell · doi:10.1016/s0092-8674(00)81199-x · Cited by 2,001
Resetting central and peripheral circadian oscillators in transgenic rats
Yamazaki, S., Numano, R., Abe, M., Hida, A., Takahashi, R.-I., Ueda, M., Block, G. D., Sakaki, Y., Menaker, M., & Tei, H. (2000) · Science · doi:10.1126/science.288.5466.682 · Cited by 1,907
An h Per2 Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome
Toh, K. L., Jones, C. R., He, Y., Eide, E. J., Hinz, W. A., Virshup, D. M., Ptáček, L. J., & Fu, Y.-H. (2001) · Science · doi:10.1126/science.1057499 · Cited by 1,460
Self-citationPosttranslational Mechanisms Regulate the Mammalian Circadian Clock
Lee, C., Etchegaray, J., Cagampang, F. R. A., Loudon, A. S. I., & Reppert, S. M. (2001) · Cell · doi:10.1016/s0092-8674(01)00610-9 · Cited by 1,174
Ubiquitin-dependent c-Jun degradation in vivo is mediated by the δ domain
Treier, M., Staszewski, L. M., & Bohmann, D. (1994) · Cell · doi:10.1016/s0092-8674(94)90502-9 · Cited by 919
Positional Syntenic Cloning and Functional Characterization of the Mammalian Circadian Mutation tau
Lowrey, P. L., Shimomura, K., Antoch, M. P., Yamazaki, S., Zemenides, P. D., Ralph, M. R., Menaker, M., & Takahashi, J. S. (2000) · Science · doi:10.1126/science.288.5465.483 · Cited by 860
double-time Is a Novel Drosophila Clock Gene that Regulates PERIOD Protein Accumulation
Price, J. L., Blau, J., Rothenfluh, A., Abodeely, M., Kloss, B., & Young, M. W. (1998) · Cell · doi:10.1016/s0092-8674(00)81224-6 · Cited by 839
The Drosophila Clock Gene double-time Encodes a Protein Closely Related to Human Casein Kinase Iε
Kloss, B., Price, J. L., Sáez, L., Blau, J., Rothenfluh, A., Wesley, C. S., & Young, M. W. (1998) · Cell · doi:10.1016/s0092-8674(00)81225-8 · Cited by 682
Margottin-Goguet, F., Bour, S. P., Durand, H., Selig, L., Bénichou, S., Richard, V., Thomas, D., Strebel, K., & Bénarous, R. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80056-8 · Cited by 670
Hart, M. J., Concordet, J., Lassot, I., Albert, I., Santos, R., Durand, H., Perret, C., Rubinfeld, B., Margottin-Goguet, F., Bénarous, R., et al. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80091-8 · Cited by 670
Identification of the receptor component of the IκBα–ubiquitin ligase
Yaron, A., Hatzubai, A., Davis, M., Lavon, I., Amit, S., Manning, A. M., Andersen, J., Mann, M., Mercurio, F., & Ben‐Neriah, Y. (1998) · Nature · doi:10.1038/25159 · Cited by 654
The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases
Jackson, P. K., Eldridge, A. G., Freed, E., Furstenthal, L., Hsu, J. Y., Kaiser, B. K., & Reimann, J. D. R. (2000) · Trends in Cell Biology · doi:10.1016/s0962-8924(00)01834-1 · Cited by 635
Structure of a β-TrCP1-Skp1-β-Catenin Complex
Wu, G., Xu, G., Schulman, B. A., Jeffrey, P. D., Harper, J. W., & Pavletich, N. P. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00234-x · Cited by 612
A Role for the Segment Polarity Gene shaggy/GSK-3 in the Drosophila Circadian Clock
Martinek, S., Inonog, S., Manoukian, A. S., & Young, M. W. (2001) · Cell · doi:10.1016/s0092-8674(01)00383-x · Cited by 512
Multiple signaling pathways elicit circadian gene expression in cultured Rat-1 fibroblasts
Balsalobre, A., Marcacci, L., & Schibler, U. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00758-2 · Cited by 485
M-phase kinases induce phospho-dependent ubiquitination of somatic Wee1 by SCF β-TrCP
Watanabe, N., Arai, H., Nishihara, Y., Taniguchi, M., Watanabe, N., Hunter, T., & Osada, H. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307700101 · Cited by 472
Light and circadian rhythmicity regulate MAP kinase activation in the suprachiasmatic nuclei
Obrietan, K. H., Impey, S., & Storm, D. R. (1998) · Nature Neuroscience · doi:10.1038/3695 · Cited by 369
Role for Slimb in the degradation of Drosophila Period protein phosphorylated by Doubletime
Ko, H. W., Jiang, J., & Edery, I. (2002) · Nature · doi:10.1038/nature01272 · Cited by 328
Nuclear Entry of the Circadian Regulator mPER1 Is Controlled by Mammalian Casein Kinase I ɛ
Vielhaber, E. L., Eide, E. J., Rivers, A. M., Gao, Z.-H., & Virshup, D. M. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.13.4888-4899.2000 · Cited by 308
Self-citationThe Circadian Regulatory Proteins BMAL1 and Cryptochromes Are Substrates of Casein Kinase Iε
Eide, E. J., Vielhaber, E. L., Hinz, W. A., & Virshup, D. M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111466200 · Cited by 302
Self-citationAkashi, M., Tsuchiya, Y., Yoshino, T., & Nishida, E. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.6.1693-1703.2002 · Cited by 298
Lowrey, P. L., & Takahashi, J. S. (2000) · Annual Review of Genetics · doi:10.1146/annurev.genet.34.1.533 · Cited by 296
The F-box protein Slimb controls the levels of clock proteins Period and Timeless
Grima, B., Lamouroux, A., Chélot, E., Papin, C., Limbourg‐Bouchon, B., & Rouyer, F. (2002) · Nature · doi:10.1038/nature01122 · Cited by 285
A role for CK2 in the Drosophila circadian oscillator
Akten, B., Jauch, E., Genova, G., Kim, E. Y., Edery, I., Raabe, T., & Jackson, F. R. (2003) · Nature Neuroscience · doi:10.1038/nn1007 · Cited by 280
Yagita, K., Tamanini, F., Yasuda, M., Hoeijmakers, J. H. J., van der Horst, G. T. J., & Okamura, H. (2002) · The EMBO Journal · doi:10.1093/emboj/21.6.1301 · Cited by 273
Posttranslational Regulation of Drosophila PERIOD Protein by Protein Phosphatase 2A
Sathyanarayanan, S., Zheng, X., Xiao, R., & Sehgal, A. (2004) · Cell · doi:10.1016/s0092-8674(04)00128-x · Cited by 271
A Role for the Proteasome in the Light Response of the Timeless Clock Protein
Naidoo, N. N., Song, W., Hunter-Ensor, M., & Sehgal, A. (1999) · Science · doi:10.1126/science.285.5434.1737 · Cited by 269
Involvement of the MAP kinase cascade in resetting of the mammalian circadian clockPreprint
Akashi, M., & Nishida, E. (2000) · Genes & Development · doi:10.1101/gad.14.6.645 · Cited by 269
Regulators of Serine / Threonine Protein Phosphatases at the Dawn of a Clinical Era?
Honkanen, R. E., & Golden, T. A. (2002) · Current Medicinal Chemistry · doi:10.2174/0929867023368836 · Cited by 261
ATF4 Degradation Relies on a Phosphorylation-Dependent Interaction with the SCFβTrCPUbiquitin Ligase
Lassot, I., Ségéral, E., Berlioz‐Torrent, C., Durand, H., Groussin, L., Hai, T., Bénarous, R., & Margottin-Goguet, F. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.6.2192-2202.2001 · Cited by 254
Liu, Y., Loros, J., & Dunlap, J. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.1.234 · Cited by 210
Price, J. L., Dembinska, M. E., Young, M. W., & Rosbash, M. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb00075.x · Cited by 210
He, Q., Cheng, P., Yang, Y., He, Q., Yu, H., & Liu, Y. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg425 · Cited by 177
Izumo, M., Johnson, C. H., & Yamazaki, S. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2536313100 · Cited by 159
Human casein kinase Iδ phosphorylation of human circadian clock proteins period 1 and 2
Camacho, F., Cilio, M., Guo, Y., Virshup, D. M., Patel, K., Khorkova, O., Styren, S. D., Morse, B., Yao, Z., & Keesler, G. A. (2001) · FEBS Letters · doi:10.1016/s0014-5793(00)02434-0 · Cited by 157
Self-citationButcher, G. Q., Dziema, H., Collamore, M., Burgoon, P. W., & Obrietan, K. H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203301200 · Cited by 152
E-box function in a period gene repressed by light
Vallone, D., Gondi, S. B., Whitmore, D., & Foulkes, N. S. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0305436101 · Cited by 149
Crystal Structure of a Conformation-selective Casein Kinase-1 Inhibitor
Mashhoon, N., DeMaggio, A. J., Tereshko, V. A., Bergmeier, S. C., Egli, M., Hoekstra, M. F., & Kuret, J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001713200 · Cited by 149
Regulation of the Neurospora circadian clock by casein kinase IIPreprint
Yang, Y., Cheng, P., & Liu, Y. (2002) · Genes & Development · doi:10.1101/gad.965102 · Cited by 144
Phosphorylation and destabilization of human period I clock protein by human casein kinase Iε
Keesler, G. A., Camacho, F., Guo, Y. X., Virshup, D. M., Mondadori, C., & Yao, Z. (2000) · Neuroreport · doi:10.1097/00001756-200004070-00011 · Cited by 136
Self-citationGFP fluorescence reports Period 1 circadian gene regulation in the mammalian biological clock
Kuhlman, S. J., Quintero, J. E., & McMahon, D. G. (2000) · Neuroreport · doi:10.1097/00001756-200005150-00024 · Cited by 132
Kim, D., Kang, J., Yang, S., Chung, K.-S., Song, P., & Park, C. (2002) · The Plant Cell · doi:10.1105/tpc.005306 · Cited by 127
Identification of Inhibitory Autophosphorylation Sites in Casein Kinase I ε
Gietzen, K. F., & Virshup, D. M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.45.32063 · Cited by 126
Self-citationRegulation of Casein Kinase Iϵ Activity by Wnt Signaling
Swiatek, W., Tsai, I.-C., Klimowski, L., Pepler, A., Barnette, J. E., Yost, H. J., & Virshup, D. M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m304682200 · Cited by 106
Self-citationYang, Y., Cheng, P., He, Q., Wang, L., & Liu, Y. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.17.6221-6228.2003 · Cited by 100
CASEIN KINASE I: ANOTHER COG IN THE CIRCADIAN CLOCKWORKS
Eide, E. J., & Virshup, D. M. (2001) · Chronobiology International · doi:10.1081/cbi-100103963 · Cited by 94
Self-citationMechanism of Regulation of Casein Kinase I Activity by Group I Metabotropic Glutamate Receptors
Liu, F., Virshup, D. M., Nairn, A. C., & Greengard, P. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204499200 · Cited by 88
Self-citationPreuss, F., Fan, J.-Y., Kalive, M., Bao, S., Schuenemann, E., Bjes, E. S., & Price, J. L. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.24.2.886-898.2004 · Cited by 85
Miyazaki, K., Nagase, T., Mesaki, M., Narukawa, J., Ohara, O., & Ishida, N. (2004) · Biochemical Journal · doi:10.1042/bj20031308 · Cited by 61
Negative Control of Circadian Clock Regulator E4BP4 by Casein Kinase Iϵ-Mediated Phosphorylation
Doi, M., Okano, T., Yujnovsky, I., Sassone‐Corsi, P., & Fukada, Y. (2004) · Current Biology · doi:10.1016/j.cub.2004.05.043 · Cited by 43
Identification of Casein Kinase I Substrates by in Vitro Expression Cloning Screening
Gao, Z.-H., Metherall, J. E., & Virshup, D. M. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2168 · Cited by 28
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Takahashi, J. S., Hong, H.-K., Ko, C. H., & McDearmon, E. L. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2430 · Cited by 1,611
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Metadata
- Authors
- Eide, E. J., Woolf, M. F., Kang, H., Woolf, P., Hurst, W., Camacho, F., Vielhaber, E. L., Giovanni, A., & Virshup, D. M.
- Affiliations
- Huntsman Cancer Institute (US)
- University of Michigan (US)
- Aventis Pharmaceuticals, Bridgewater, New Jersey
- University of Utah (US)
- Corresponding author
- Virshup, David M.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2005-04-01
- Volume
- 25
- Issue
- 7
- Pages
- 2795-2807
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1061645
- OpenAlex
- W1990361088
- Cited by
- 495
- References
- 54
- Citations by year
- 2026: 10 · 2025: 24 · 2024: 14 · 2023: 16 · 2022: 26 · 2021: 22 · 2020: 33 · 2019: 25 · 2018: 21 · 2017: 22 · 2016: 23 · 2015: 24 · 2014: 24 · 2013: 23 · 2012: 20
- FWCI
- 10.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Huntsman Cancer Foundation
- National Institutes of Health
- National Cancer Institute (P04CA42104)
- National Institute of General Medical Sciences (R01 GM60387, R01GM060387)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Light effects on plants
- Keywords
- circadian clock, casein kinase I epsilon, proteasome-mediated proteolysis, ubiquitination, calyculin A, Rat-1 cells
- MeSH terms
- Animals, Cell Line, Circadian Rhythm, Gene Expression Regulation, Humans, Nuclear Proteins, Phosphorylation, Protein Binding, Transcription Factors, Cell Cycle Proteins, Ubiquitin-Protein Ligases, beta-Transducin Repeat-Containing Proteins, Proteasome Endopeptidase Complex, Casein Kinase 1 epsilon, Mice, Rats, Period Circadian Proteins
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