The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Interestingly, the spawning profile was found unaffected.”
From The Still Dark Side of the Moon: Molecular Mechanisms of Lunar-Controlled Rhythms and Clocks (2020) · cites this paper as [36]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
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
Cited by
Sorted by citations
Molecular components of the mammalian circadian clock
Ko, C. H., & Takahashi, J. S. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl207 · Cited by 1,725
The genetics of mammalian circadian order and disorder: implications for physiology and disease
Takahashi, J. S., Hong, H.-K., Ko, C. H., & McDearmon, E. L. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2430 · Cited by 1,611
Molecular mechanisms and physiological importance of circadian rhythms
Patke, A., Young, M. W., & Axelrod, S. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0179-2 · Cited by 1,388
SIRT1 regulates circadian clock gene expression through PER2 deacetylation
Asher, G., Gatfield, D., Stratmann, M., Reinke, H., Dibner, C., Kreppel, F., Mostoslavsky, R., Alt, F. W., & Schibler, U. (2008) · Cell · doi:10.1016/j.cell.2008.06.050 · Cited by 1,376
Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer
Frescas, D., & Pagano, M. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2396 · Cited by 903
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
