Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Originally published in Science Express on 21 August 2003
Science 10 October 2003:
Vol. 302. no. 5643, pp. 255 - 259
DOI: 10.1126/science.1086271
Prev | Table of Contents | Next

Research Articles

Control Mechanism of the Circadian Clock for Timing of Cell Division in Vivo

Takuya Matsuo,1,2* Shun Yamaguchi,1* Shigeru Mitsui,1 Aki Emi,1 Fukuko Shimoda,1 Hitoshi Okamura1{dagger}

Cell division in many mammalian tissues is associated with specific times of day, but just how the circadian clock controls this timing has not been clear. Here, we show in the regenerating liver (of mice) that the circadian clock controls the expression of cell cycle–related genes that in turn modulate the expression of active Cyclin B1-Cdc2 kinase, a key regulator of mitosis. Among these genes, expression of wee1 was directly regulated by the molecular components of the circadian clockwork. In contrast, the circadian clockwork oscillated independently of the cell cycle in single cells. Thus, the intracellular circadian clockwork can control the cell-division cycle directly and unidirectionally in proliferating cells.

1 Division of Molecular Brain Science, Department of Brain Sciences, Kobe University Graduate School of Medicine, Chuo-ku, Kobe 650–0017, Japan.
2 Department of Physics, Informatics and Biology, Yamaguchi University, Yamaguchi 753–8512, Japan.



* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: okamurah{at}kobe-u.ac.jp

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
A Phylogenetically Conserved DNA Damage Response Resets the Circadian Clock.
J. J. Gamsby, J. J. Loros, and J. C. Dunlap (2009)
J Biol Rhythms 24, 193-202
   Abstract »    PDF »
Clock-Cancer Connection in Non-Hodgkin's Lymphoma: A Genetic Association Study and Pathway Analysis of the Circadian Gene Cryptochrome 2.
A. E. Hoffman, T. Zheng, R. G. Stevens, Y. Ba, Y. Zhang, D. Leaderer, C. Yi, T. R. Holford, and Y. Zhu (2009)
Cancer Res. 69, 3605-3613
   Abstract »    Full Text »    PDF »
Clock Gene Mouse Period2 Overexpression Inhibits Growth of Human Pancreatic Cancer Cells and Has Synergistic Effect with Cisplatin.
A. ODA, Y. KATAYOSE, S. YABUUCHI, K. YAMAMOTO, M. MIZUMA, S. SHIRASOU, T. ONOGAWA, H. OHTSUKA, H. YOSHIDA, H. HAYASHI, et al. (2009)
Anticancer Res 29, 1201-1209
   Abstract »    Full Text »    PDF »
{beta}-Catenin Induces {beta}-TrCP-Mediated PER2 Degradation Altering Circadian Clock Gene Expression in Intestinal Mucosa of ApcMin/+ Mice.
X. Yang, P. A. Wood, C. M. Ansell, M. Ohmori, E.-Y. Oh, Y. Xiong, F. G. Berger, M. M. O. Pena, and W. J.M. Hrushesky (2009)
J. Biochem. 145, 289-297
   Abstract »    Full Text »    PDF »
Expression and Functional Analyses of Circadian Genes in Mouse Oocytes and Preimplantation Embryos: Cry1 Is Involved in the Meiotic Process Independently of Circadian Clock Regulation.
T. Amano, A. Matsushita, Y. Hatanaka, T. Watanabe, K. Oishi, N. Ishida, M. Anzai, T. Mitani, H. Kato, S. Kishigami, et al. (2009)
Biol Reprod 80, 473-483
   Abstract »    Full Text »    PDF »
Loss of cryptochrome reduces cancer risk in p53 mutant mice.
N. Ozturk, J. H. Lee, S. Gaddameedhi, and A. Sancar (2009)
PNAS 106, 2841-2846
   Abstract »    Full Text »    PDF »
Glucocorticoids and the circadian clock.
T. Dickmeis (2009)
J. Endocrinol. 200, 3-22
   Abstract »    Full Text »    PDF »
Period 2 Mutation Accelerates ApcMin/+ Tumorigenesis.
P. A. Wood, X. Yang, A. Taber, E.-Y. Oh, C. Ansell, S. E. Ayers, Z. Al-Assaad, K. Carnevale, F. G. Berger, M. M. O. Pena, et al. (2008)
Mol. Cancer Res. 6, 1786-1793
   Abstract »    Full Text »    PDF »
Implications of circadian clocks for the rhythmic delivery of cancer therapeutics.
F. Levi, A. Altinok, J. Clairambault, and A. Goldbeter (2008)
Phil Trans R Soc A 366, 3575-3598
   Abstract »    Full Text »    PDF »
S-Phase and M-Phase Timing Are under Independent Circadian Control in the Dinoflagellate Lingulodinium.
S. Dagenais-Bellefeuille, T. Bertomeu, and D. Morse (2008)
J Biol Rhythms 23, 400-408
   Abstract »    PDF »
Nuclear Hormone Receptors for Heme: REV-ERB{alpha} and REV-ERB{beta} Are Ligand-Regulated Components of the Mammalian Clock.
T. P. Burris (2008)
Mol. Endocrinol. 22, 1509-1520
   Abstract »    Full Text »    PDF »
Diurnal Amplitudes of Arterial Pressure and Heart Rate Are Dampened in Clock Mutant Mice and Adrenalectomized Mice.
H. Sei, K. Oishi, S. Chikahisa, K. Kitaoka, E. Takeda, and N. Ishida (2008)
Endocrinology 149, 3576-3580
   Abstract »    Full Text »    PDF »
Bifunctional Role of Rev-erb{alpha} in Adipocyte Differentiation.
J. Wang and M. A. Lazar (2008)
Mol. Cell. Biol. 28, 2213-2220
   Abstract »    Full Text »    PDF »
The Circadian Clock Component BMAL1 Is a Critical Regulator of p21WAF1/CIP1 Expression and Hepatocyte Proliferation.
A. Grechez-Cassiau, B. Rayet, F. Guillaumond, M. Teboul, and F. Delaunay (2008)
J. Biol. Chem. 283, 4535-4542
   Abstract »    Full Text »    PDF »
Computational Analysis of Mammalian Cell Division Gated by a Circadian Clock: Quantized Cell Cycles and Cell Size Control.
J. Zamborszky, C. I. Hong, and A. Csikasz Nagy (2007)
J Biol Rhythms 22, 542-553
   Abstract »    PDF »
Evidence for Circadian Regulation of Activating Transcription Factor 5 But Not Tyrosine Hydroxylase by the Chromaffin Cell Clock.
D. R. Lemos, L. Goodspeed, L. Tonelli, M. P. Antoch, S. R. Ojeda, and H. F. Urbanski (2007)
Endocrinology 148, 5811-5821
   Abstract »    Full Text »    PDF »
Circadian clocks: regulators of endocrine and metabolic rhythms.
M. Hastings, J. S O'Neill, and E. S Maywood (2007)
J. Endocrinol. 195, 187-198
   Abstract »    Full Text »    PDF »
Circadian Transcription Depends on Limiting Amounts of the Transcription Co-activator nejire/CBP.
H.-C. Hung, C. Maurer, S. A. Kay, and F. Weber (2007)
J. Biol. Chem. 282, 31349-31357
   Abstract »    Full Text »    PDF »
Diurnal protein expression in blood revealed by high throughput mass spectrometry proteomics and implications for translational medicine and body time of day.
T. A. Martino, N. Tata, G. A. Bjarnason, M. Straume, and M. J. Sole (2007)
Am J Physiol Regulatory Integrative Comp Physiol 293, R1430-R1437
   Abstract »    Full Text »    PDF »
Tumor Suppression and Circadian Function.
M. Chen-Goodspeed and Cheng Chi Lee (2007)
J Biol Rhythms 22, 291-298
   Abstract »    PDF »
Peripheral Circadian Clocks in the Vasculature.
D. F. Reilly, E. J. Westgate, and G. A. FitzGerald (2007)
Arterioscler. Thromb. Vasc. Biol. 27, 1694-1705
   Abstract »    Full Text »    PDF »
Restriction of DNA Replication to the Reductive Phase of the Metabolic Cycle Protects Genome Integrity.
Z. Chen, E. A. Odstrcil, B. P. Tu, and S. L. McKnight (2007)
Science 316, 1916-1919
   Abstract »    Full Text »    PDF »
SCFFbxl3 Controls the Oscillation of the Circadian Clock by Directing the Degradation of Cryptochrome Proteins.
L. Busino, F. Bassermann, A. Maiolica, C. Lee, P. M. Nolan, S. I. H. Godinho, G. F. Draetta, and M. Pagano (2007)
Science 316, 900-904
   Abstract »    Full Text »    PDF »
Circadian Variations in Clock Gene Expression of Human Bone Marrow CD34+ Cells.
O. Tsinkalovsky, R. Smaaland, B. Rosenlund, R. B. Sothern, A. Hirt, S. Steine, A. Badiee, J. Foss Abrahamsen, H. G. Eiken, and O. D. Laerum (2007)
J Biol Rhythms 22, 140-150
   Abstract »    PDF »
Epigenetic Silencing of the Candidate Tumor Suppressor Gene Per1 in Non-Small Cell Lung Cancer.
S. Gery, N. Komatsu, N. Kawamata, C. W. Miller, J. Desmond, R. K. Virk, A. Marchevsky, R. Mckenna, H. Taguchi, and H. P. Koeffler (2007)
Clin. Cancer Res. 13, 1399-1404
   Abstract »    Full Text »    PDF »
Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation.
B. H. Miller, E. L. McDearmon, S. Panda, K. R. Hayes, J. Zhang, J. L. Andrews, M. P. Antoch, J. R. Walker, K. A. Esser, J. B. Hogenesch, et al. (2007)
PNAS 104, 3342-3347
   Abstract »    Full Text »    PDF »
Genetic and Molecular Analysis of the Central and Peripheral Circadian Clockwork of Mice.
E. S. Maywood, J. S. O'Neill, A. B. Reddy, J. E. Chesham, H. M. Prosser, C. P. Kyriacou, S. I. H. Godinho, P. M. Nolan, and M. H. Hastings (2007)
Cold Spring Harb Symp Quant Biol 72, 85-94
   Abstract »    PDF »
Chromatin Remodeling and Circadian Control: Master Regulator CLOCK Is an Enzyme.
B. Grimaldi, Y. Nakahata, S. Sahar, M. Kaluzova, D. Gauthier, K. Pham, N. Patel, J. Hirayama, and P. Sassone-Corsi (2007)
Cold Spring Harb Symp Quant Biol 72, 105-112
   Abstract »    PDF »
Structure and Function of Animal Cryptochromes.
N. Ozturk, S.-H. Song, S. Ozgur, C. P. Selby, L. Morrison, C. Partch, D. Zhong, and A. Sancar (2007)
Cold Spring Harb Symp Quant Biol 72, 119-131
   Abstract »    PDF »
The Yeast Metabolic Cycle: Insights into the Life of a Eukaryotic Cell.
B. P. Tu and S. L. McKnight (2007)
Cold Spring Harb Symp Quant Biol 72, 339-343
   Abstract »    PDF »
Reversible Protein Phosphorylation Regulates Circadian Rhythms.
D. M. Virshup, E. J. Eide, D. B. Forger, M. Gallego, and E. V. Harnish (2007)
Cold Spring Harb Symp Quant Biol 72, 413-420
   Abstract »    PDF »
The Role of Circadian Regulation in Cancer.
S. Gery and H. P. Koeffler (2007)
Cold Spring Harb Symp Quant Biol 72, 459-464
   Abstract »    PDF »
Cross-talks between Circadian Timing System and Cell Division Cycle Determine Cancer Biology and Therapeutics.
F. Levi, E. Filipski, I. Iurisci, X. M. Li, and P. Innominato (2007)
Cold Spring Harb Symp Quant Biol 72, 465-475
   Abstract »    PDF »
The Clock Proteins, Aging, and Tumorigenesis.
R. V. Kondratov and M. P. Antoch (2007)
Cold Spring Harb Symp Quant Biol 72, 477-482
   Abstract »    PDF »
Suprachiasmatic Nucleus Clock Time in the Mammalian Circadian System.
H. Okamura (2007)
Cold Spring Harb Symp Quant Biol 72, 551-556
   Abstract »    PDF »
Hypothermia modulates circadian clock gene expression in lizard peripheral tissues.
D. Vallone, E. Frigato, C. Vernesi, A. Foa, N. S. Foulkes, and C. Bertolucci (2007)
Am J Physiol Regulatory Integrative Comp Physiol 292, R160-R166
   Abstract »    Full Text »    PDF »
Properties, Entrainment, and Physiological Functions of Mammalian Peripheral Oscillators.
M. Stratmann and U. Schibler (2006)
J Biol Rhythms 21, 494-506
   Abstract »    PDF »
Improved Tumor Control through Circadian Clock Induction by Seliciclib, a Cyclin-Dependent Kinase Inhibitor..
I. Iurisci, E. Filipski, J. Reinhardt, S. Bach, A. Gianella-Borradori, S. Iacobelli, L. Meijer, and F. Levi (2006)
Cancer Res. 66, 10720-10728
   Abstract »    Full Text »    PDF »
The Neurospora Checkpoint Kinase 2: A Regulatory Link Between the Circadian and Cell Cycles.
A. M. Pregueiro, Q. Liu, C. L. Baker, J. C. Dunlap, and J. J. Loros (2006)
Science 313, 644-649
   Abstract »    Full Text »    PDF »
Circadian clock coordinates cancer cell cycle progression, thymidylate synthase, and 5-fluorouracil therapeutic index..
P. A. Wood, J. Du-Quiton, S. You, and W. J.M. Hrushesky (2006)
Mol. Cancer Ther. 5, 2023-2033
   Abstract »    Full Text »    PDF »
An opposite role for tau in circadian rhythms revealed by mathematical modeling.
M. Gallego, E. J. Eide, M. F. Woolf, D. M. Virshup, and D. B. Forger (2006)
PNAS 103, 10618-10623
   Abstract »    Full Text »    PDF »
Does mPER2 protein oscillate without its coding mRNA cycling?: post-transcriptional regulation by cell clock.
Y. Fujimoto, K. Yagita, and H. Okamura (2006)
Genes Cells 11, 525-530
   Abstract »    Full Text »    PDF »
Proinflammatory Cytokine Production in Liver Regeneration Is Myd88-Dependent, but Independent of Cd14, Tlr2, and Tlr4.
J. S. Campbell, K. J. Riehle, J. T. Brooling, R. L. Bauer, C. Mitchell, and N. Fausto (2006)
J. Immunol. 176, 2522-2528
   Abstract »    Full Text »    PDF »
Circadian pharmacology of L-alanosine (SDX-102) in mice..
X.-M. Li, S. Kanekal, D. Crepin, C. Guettier, J. Carriere, G. Elliott, and F. Levi (2006)
Mol. Cancer Ther. 5, 337-346
   Abstract »    Full Text »    PDF »
The circadian clock within the heart: potential influence on myocardial gene expression, metabolism, and function.
M. E. Young (2006)
Am J Physiol Heart Circ Physiol 290, H1-H16
   Abstract »    Full Text »    PDF »
Logic of the Yeast Metabolic Cycle: Temporal Compartmentalization of Cellular Processes.
B. P. Tu, A. Kudlicki, M. Rowicka, and S. L. McKnight (2005)
Science 310, 1152-1158
   Abstract »    Full Text »    PDF »
Bioinformatic Analysis of Circadian Gene Oscillation in Mouse Aorta.
R. D. Rudic, P. McNamara, D. Reilly, T. Grosser, A.-M. Curtis, T. S. Price, S. Panda, J. B. Hogenesch, and G. A. FitzGerald (2005)
Circulation 112, 2716-2724
   Abstract »    Full Text »    PDF »
Transcription profiling of C/EBP targets identifies Per2 as a gene implicated in myeloid leukemia.
S. Gery, A. F. Gombart, W. S. Yi, C. Koeffler, W.-K. Hofmann, and H. P. Koeffler (2005)
Blood 106, 2827-2836
   Abstract »    Full Text »    PDF »
Cryptochrome, Circadian Cycle, Cell Cycle Checkpoints, and Cancer.
M. A. Gauger and A. Sancar (2005)
Cancer Res. 65, 6828-6834
   Abstract »    Full Text »    PDF »
Gene Ontology Mapping as an Unbiased Method for Identifying Molecular Pathways and Processes Affected by Toxicant Exposure: Application to Acute Effects Caused by the Rodent Non-Genotoxic Carcinogen Diethylhexylphthalate.
R. A. Currie, V. Bombail, J. D. Oliver, D. J. Moore, F. L. Lim, V. Gwilliam, I. Kimber, K. Chipman, J. G. Moggs, and G. Orphanides (2005)
Toxicol. Sci. 86, 453-469
   Abstract »    Full Text »    PDF »
Common pathways in circadian and cell cycle clocks: Light-dependent activation of Fos/AP-1 in zebrafish controls CRY-1a and WEE-1.
J. Hirayama, L. Cardone, M. Doi, and P. Sassone-Corsi (2005)
PNAS 102, 10194-10199
   Abstract »    Full Text »    PDF »
Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers.
S.-T. Chen, K.-B. Choo, M.-F. Hou, K.-T. Yeh, S.-J. Kuo, and J.-G. Chang (2005)
Carcinogenesis 26, 1241-1246
   Abstract »    Full Text »    PDF »
Gene expression patterns define key transcriptional events in cell-cycle regulation by cAMP and protein kinase A.
A. C. Zambon, L. Zhang, S. Minovitsky, J. R. Kanter, S. Prabhakar, N. Salomonis, K. Vranizan, I. Dubchak, B. R. Conklin, and P. A. Insel (2005)
PNAS 102, 8561-8566
   Abstract »    Full Text »    PDF »
Circadian G2 Arrest as Related to Circadian Gating of Cell Population Growth in Euglena.
A. Bolige, S.-y. Hagiwara, Y. Zhang, and K. Goto (2005)
Plant Cell Physiol. 46, 931-936
   Abstract »    Full Text »    PDF »
Mouse Period1 (mPER1) Acts as a Circadian Adaptor to Entrain the Oscillator to Environmental Light/Dark Cycles by Regulating mPER2 Protein.
S. Masubuchi, N. Kataoka, P. Sassone-Corsi, and H. Okamura (2005)
J. Neurosci. 25, 4719-4724
   Abstract »    Full Text »    PDF »
Circadian profiling of the transcriptome in immortalized rat SCN cells.
G. J. Menger, K. Lu, T. Thomas, V. M. Cassone, and D. J. Earnest (2005)
Physiol Genomics 21, 370-381
   Abstract »    Full Text »    PDF »
Coupling of Human Circadian and Cell Cycles by the Timeless Protein.
K. Unsal-Kacmaz, T. E. Mullen, W. K. Kaufmann, and A. Sancar (2005)
Mol. Cell. Biol. 25, 3109-3116
   Abstract »    Full Text »    PDF »
Effects of Light and Food Schedules on Liver and Tumor Molecular Clocks in Mice.
E. Filipski, P. F. Innominato, M. Wu, X.-M. Li, S. Iacobelli, L.-J. Xian, and F. Levi (2005)
J Natl Cancer Inst 97, 507-517
   Abstract »    Full Text »    PDF »
The Thymus Is Similar to the Testis in Its Pattern of Circadian Clock Gene Expression.
J. D. Alvarez and A. Sehgal (2005)
J Biol Rhythms 20, 111-121
   Abstract »    PDF »
Elevated Serum Cytokines Correlated with Altered Behavior, Serum Cortisol Rhythm, and Dampened 24-Hour Rest-Activity Patterns in Patients with Metastatic Colorectal Cancer.
T. Rich, P. F. Innominato, J. Boerner, M. C. Mormont, S. Iacobelli, B. Baron, C. Jasmin, and F. Levi (2005)
Clin. Cancer Res. 11, 1757-1764
   Abstract »    Full Text »    PDF »
Genome-wide Expression Analysis Reveals 100 Adrenal Gland-dependent Circadian Genes in the Mouse Liver.
K. Oishi, N. Amagai, H. Shirai, K. Kadota, N. Ohkura, and N. Ishida (2005)
DNA Res 12, 191-202
   Abstract »    Full Text »    PDF »
Effects of Chronic Jet Lag on Tumor Progression in Mice.
E. Filipski, F. Delaunay, V. M. King, M.-W. Wu, B. Claustrat, A. Grechez-Cassiau, C. Guettier, M. H. Hastings, and L. Francis (2004)
Cancer Res. 64, 7879-7885
   Abstract »    Full Text »    PDF »
Finding New Clock Components: Past and Future.
J. S. Takahashi (2004)
J Biol Rhythms 19, 339-347
   Abstract »    PDF »
Clock Genes in Cell Clocks: Roles, Actions, and Mysteries.
H. Okamura (2004)
J Biol Rhythms 19, 388-399
   Abstract »    PDF »
An ultradian clock shapes genome expression in yeast.
M. W. Young (2004)
PNAS 101, 1118-1119
   Full Text »    PDF »
The Transcriptional Repressor STRA13 Regulates a Subset of Peripheral Circadian Outputs.
A. Grechez-Cassiau, S. Panda, S. Lacoche, M. Teboul, S. Azmi, V. Laudet, J. B. Hogenesch, R. Taneja, and F. Delaunay (2004)
J. Biol. Chem. 279, 1141-1150
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)