Advanced Search

Journal Navigation

Journal Home

Subscriptions

Archive

Contact Us

Table of Contents

Click here for more information

Sign In to gain access to subscriptions and/or personal tools.
Journal of Biological Rhythms
This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (3)
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Zámborszky, J.
Right arrow Articles by Csikász Nagy, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zámborszky, J.
Right arrow Articles by Csikász Nagy, A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Computational Analysis of Mammalian Cell Division Gated by a Circadian Clock: Quantized Cell Cycles and Cell Size Control

Judit Zámborszky

Materials Structure and Modeling Research Group of the Hungarian Academy of Sciences and Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Budapest, Hungary

Christian I. Hong

Department of Genetics, Dartmouth Medical School, Hanover, New Hampshire

Attila Csikász Nagy

Materials Structure and Modeling Research Group of the Hungarian Academy of Sciences and Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, Budapest, Hungary, csikasz{at}cosbi.eu

Cell cycle and circadian rhythms are conserved from cyanobacteria to humans with robust cyclic features. Recently, molecular links between these two cyclic processes have been discovered. Core clock transcription factors, Bmal1 and Clock (Clk), directly regulate Wee1 kinase, which inhibits entry into the mitosis. We investigate the effect of this connection on the timing of mammalian cell cycle processes with computational modeling tools. We connect a minimal model of circadian rhythms, which consists of transcription—translation feedback loops, with a modified mammalian cell cycle model from Novak and Tyson (2004). As we vary the mass doubling time (MDT) of the cell cycle, stochastic simulations reveal quantized cell cycles when the activity of Wee1 is influenced by clock components. The quantized cell cycles disappear in the absence of coupling or when the strength of this link is reduced. More intriguingly, our simulations indicate that the circadian clock triggers critical size control in the mammalian cell cycle. A periodic brake on the cell cycle progress via Wee1 enforces size control when the MDT is quite different from the circadian period. No size control is observed in the absence of coupling. The issue of size control in the mammalian system is debatable, whereas it is well established in yeast. It is possible that the size control is more readily observed in cell lines that contain circadian rhythms, since not all cell types have a circadian clock. This would be analogous to an ultradian clock intertwined with quantized cell cycles (and possibly cell size control) in yeast. We present the first coupled model between the mammalian cell cycle and circadian rhythms that reveals quantized cell cycles and cell size control influenced by the clock.

Key Words: cell cycle • circadian clock • size control • quantized cycles • mathematical modeling • mammalian • stochastic • simulation

References

  • Bjarnason GA, Jordan RC, Wood PA, Li Q., Lincoln DW, Sothern RB, Hrushesky WJ, and Ben-David Y. (2001) Circadian expression of clock genes in human oral mucosa and skin: association with specific cell-cycle phases . Am J Pathol 158: 1793-1801 .[Abstract/Free Full Text]
  • Chen KC, Calzone L., Csikasz-Nagy A., Cross FR, Novak B., and Tyson JJ (2004) Integrative analysis of cell cycle control in budding yeast . Mol Biol Cell 15: 3841-3862 .[Abstract/Free Full Text]
  • Chen YG, Mantalaris A., Bourne P., Keng P., and Wu JH (2000) Expression of mPer1 and mPer2, two mammalian clock genes, in murine bone marrow . Biochem Biophys Res Commun 276: 724-728 .[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Chow Jph, Siu WY, Ho Htb, Ma Kht, Ho CC, and Poon Ryc (2003) Differential contribution of inhibitory phosphorylation of CDC2 and CDK2 for unperturbed cell cycle control and DNA integrity checkpoints . J Biol Chem 278: 40815-40828 .[Abstract/Free Full Text]
  • Conlon I. and Raff M. (2003) Differences in the way a mammalian cell and yeast cells coordinate cell growth and cell-cycle progression . J Biol 2: 7 .[CrossRef][Medline] [Order article via Infotrieve]
  • Conlon IJ, Dunn GA, Mudge AW, and Raff MC (2001) Extracellular control of cell size . Nat Cell Biol 3: 918-921 .[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Cross FR and Siggia ED (2005) Mode locking the cell cycle . Phys Rev E Stat Nonlin Soft Matter Phys 72: 021910 .[Medline] [Order article via Infotrieve]
  • Csikasz-Nagy A., Battogtokh D., Chen KC, Novak B., and Tyson JJ (2006) Analysis of a generic model of eukaryotic cell-cycle regulation . Biophys J 90: 4361-4379 .[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Dolznig H., Grebien F., Sauer T., Beug H., and Mullner EW (2004) Evidence for a size-sensing mechanism in animal cells . Nat Cell Biol 6: 899-905 .[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Dunlap JC (1999) Molecular bases for circadian clocks . Cell 96: 271-290 .[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Edmunds LN Jr (1974a) Circadian clock control of the cell developmental cycle in synchronized cultures of Euglena. In Mechanisms of Regulation of Plant Growth, RL Bieleski, AR Ferguson, and MM Cresswell, eds, pp 287-297, The Royal Society of New Zealand, Wellington .
  • Edmunds LN Jr (1974b) Phasing effects of light on cell division in exponentially increasing cultures of Tetrahymena grown at low temperatures . Exp Cell Res 83: 367-379 .[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Ermentrout B. (2002) Simulating, Analyzing, and Animating Dynamical Systems, SIAM, Philadelphia .
  • Forger DB and Peskin CS (2005) Stochastic simulation of the mammalian circadian clock . Proc Natl Acad Sci U S A 102: 321-324 .[Abstract/Free Full Text]
  • Fu L., Pelicano H., Liu J., Huang P., and Lee C. (2002) The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo . Cell 111: 41-50 .[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Gardner SN (2002) Cell cycle phase-specific chemotherapy: computational methods for guiding treatment . Cell Cycle 1: 369-374 .[Medline] [Order article via Infotrieve]
  • Gery S., Komatsu N., Baldjyan L., Yu A., Koo D., and Koeffler HP (2006) The circadian gene per1 plays an important role in cell growth and DNA damage control in human cancer cells . Mol Cell 22: 375-382 .[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Gonze D., Halloy J., and Goldbeter A. (2002) Robustness of circadian rhythms with respect to molecular noise . Proc Natl Acad Sci U S A 99: 673-678 .[Abstract/Free Full Text]
  • Grebien F., Dolznig H., Beug H., and Mullner EW (2005) Cell size control: new evidence for a general mechanism . Cell Cycle 4: 418-421 .[Web of Science][Medline] [Order article via Infotrieve]
  • Hardin PE (2004) Transcription regulation within the circadian clock: the E-box and beyond . J Biol Rhythms 19: 348-360 .[Abstract/Free Full Text]
  • Hong CI, Conrad E., and Tyson JJ (2007) A proposal for robust temperature compensation of circadian rhythms . Proc Natl Acad Sci U S A 104: 1195-1200 .[Abstract/Free Full Text]
  • Johnston GC, Ehrhardt CW, Lorincz A., and Carter Bla (1979) Regulation of cell size in the yeast Saccharomyces cerevisiae . J Bacteriol 137: 1-5 .[Abstract/Free Full Text]
  • Kastan MB and Bartek J. (2004) Cell-cycle checkpoints and cancer . Nature 432: 316-323 .[CrossRef][Medline] [Order article via Infotrieve]
  • Killander D. and Zetterberg A. (1965) A quantitative cytochemical investigation of the relationship between cell mass and initiation of DNA synthesis in mouse fibroblast in vitro . Exp Cell Res 40: 12-20 .[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Klevecz RR (1976) Quantized generation time in mammalian cells as an expression of the cellular clock . Proc Natl Acad Sci U S A 73: 4012-4016 .[Abstract/Free Full Text]
  • Klevecz RR, Bolen J., Forrest G., and Murray DB (2004) A genomewide oscillation in transcription gates DNA replication and cell cycle . Proc Natl Acad Sci U S A 101: 1200-1205 .[Abstract/Free Full Text]
  • Lloyd D. and Kippert F. (1987) A temperature-compensated ultradian clock explains temperature-dependent quantal cell cycle times . Symp Soc Exp Biol 41: 135-155 .[Medline] [Order article via Infotrieve]
  • Lloyd D. and Volkov EI (1990) Quantized cell cycle times: interaction between a relaxation oscillator and ultradian clock pulses . Biosystems 23: 305-310 .[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Matsuo T., Yamaguchi S., Mitsui S., Emi A., Shimoda F., and Okamura H. (2003) Control mechanism of the circadian clock for timing of cell division in vivo . Science 302: 255-259 .[Abstract/Free Full Text]
  • Mori T., Binder B., and Johnson CH (1996) Circadian gating of cell division in cyanobacteria growing with average doubling times of less than 24 hours . Proc Natl Acad Sci U S A 93: 10183-10188 .[Abstract/Free Full Text]
  • Mormont MC and Levi F. (2003) Cancer chronotherapy: principles, applications, and perspectives . Cancer 97: 155-169 .[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Morohashi M., Winn AE, Borisuk MT, Bolouri H., Doyle J., and Kitano H. (2002) Robustness as a measure of plausibility in models of biochemical networks . J Theor Biol 216: 19-30 .[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Nagoshi E., Saini C., Bauer C., Laroche T., Naef F., and Schibler U. (2004) Circadian gene expression in individual fibroblasts: cell-autonomous and self-sustained oscillators pass time to daughter cells . Cell 119: 693-705 .[Web of Science][Medline] [Order article via Infotrieve]
  • Novak B. and Tyson JJ (2004) A model for restriction point control of the mammalian cell cycle . J Theor Biol 230: 563-579 .[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Nurse P. (1990) Universal control mechanism regulating onset of M-phase . Nature 344: 503-508 .[CrossRef][Medline] [Order article via Infotrieve]
  • Nurse P. (2000) A long twentieth century of the cell cycle and beyond . Cell 100: 71-78 .[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Okamura H. (2004) Clock genes in cell clocks: roles, actions, and mysteries . J Biol Rhythms 19: 388-399 .[Abstract/Free Full Text]
  • Pregueiro AM, Liu Q., Baker CL, Dunlap JC, and Loros JJ (2006) The Neurospora checkpoint kinase 2: a regulatory link between the circadian and cell cycles . Science 313: 644-649 .[Abstract/Free Full Text]
  • Rupes I. (2002) Checking cell size in yeast . Trends Genet 18: 479-485 .[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Sherr CJ (1996) Cancer cell cycles . Science 274: 1672-1677 .[Abstract/Free Full Text]
  • Steuer R. (2004) Effects of stochasticity in models of the cell cycle: from quantized cycle times to noise-induced oscillations . J Theor Biol 228: 293-301 .[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Sveiczer A., Csikasz-Nagy A., Gyorffy B., Tyson JJ, and Novak B. (2000) Modeling the fission yeast cell cycle: quantized cycle times in wee1- cdc25Delta mutant cells . Proc Natl Acad Sci U S A 97: 7865-7870 .[Abstract/Free Full Text]
  • Sveiczer A., Novak B., and Mitchison JM (1996) The size control of fission yeast revisited . J Cell Sci 109: 2947-2957 .[Abstract]
  • Sveiczer A., Novak B., and Mitchison JM (1999) Mitotic control in the absence of cdc25 mitotic inducer in fission yeast . J Cell Sci 112: 1085-1092 .[Abstract]
  • Sveiczer A., Novak B., and Mitchison JM (2004) Size control in growing yeast and mammalian cells . Theoretical Biology and Medical Modelling 1: 12 .[CrossRef]
  • Sweeney BM and Hastings J. (1958) Rhythmic cell division in populations of Gonyaulax polyedra . J Protozool 5: 217-224 .
  • Tsuchiya Y., Akashi M., and Nishida E. (2003) Temperature compensation and temperature resetting of circadian rhythms in mammalian cultured fibroblasts . Genes Cells 8: 713-720 .[Abstract]
  • Tyson JJ (1985) The coordination of cell growth and division— intentional or incidental? Bioessays 2: 72-77 .[CrossRef][Web of Science]
  • Tyson JJ, Hong CI, Thron CD, and Novak B. (1999) A simple model of circadian rhythms based on dimerization and proteolysis of PER and TIM . Biophys J 77: 2411-2417 .[Web of Science][Medline] [Order article via Infotrieve]
  • van Kampen NG (1981) Stochastic Processes in Physics and Chemistry, North-Holland Publishing Company, Amsterdam .
  • Vanselow K., Vanselow JT, Westermark PO, Reischl S., Maier B., Korte T., Herrmann A., Herzel H., Schlosser A., and Kramer A. (2006) Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS) . Genes Dev 20: 2660-2672 .[Abstract/Free Full Text]
  • Wells W. (2002) Does size matter? J Cell Biol 158: 1156-1159 .[Abstract/Free Full Text]
  • Welsh DK, Yoo SH, Liu AC, Takahashi JS, and Kay SA (2004) Bioluminescence imaging of individual fibroblasts reveals persistent, independently phased circadian rhythms of clock gene expression . Curr Biol 14: 2289-2295 .[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Yamaguchi S., Isejima H., Matsuo T., Okura R., Yagita K., Kobayashi M., and Okamura H. (2003) Synchronization of cellular clocks in the suprachiasmatic nucleus . Science 302: 1408-1412 .[Abstract/Free Full Text]
  • Zetterberg A. and Larsson O. (1995) Cell cycle progression and growth in mammalian cells: kinetic aspects of transition events. In Cell Cycle Control, C Hutchison and DM Glover, eds, pp 206-227, Oxford University Press, Oxford, UK .

Journal of Biological Rhythms, Vol. 22, No. 6, 542-553 (2007)
DOI: 10.1177/0748730407307225
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 Brief BioinformHome page
A. Csikasz-Nagy
Computational systems biology of the cell cycle
Brief Bioinform, July 1, 2009; 10(4): 424 - 434.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (3)
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Zámborszky, J.
Right arrow Articles by Csikász Nagy, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zámborszky, J.
Right arrow Articles by Csikász Nagy, A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?