Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Open Life Sciences

formerly Central European Journal of Biology

Editor-in-Chief: Ratajczak, Mariusz

IMPACT FACTOR 2018: 0.504
5-year IMPACT FACTOR: 0.583

CiteScore 2018: 0.63

SCImago Journal Rank (SJR) 2018: 0.266
Source Normalized Impact per Paper (SNIP) 2018: 0.311

ICV 2017: 154.48

Open Access
See all formats and pricing
More options …
Volume 4, Issue 3


Volume 10 (2015)

Circadian clocks and phosphorylation: Insights from computational modeling

Jean-Christophe Leloup
Published Online: 2009-07-26 | DOI: https://doi.org/10.2478/s11535-009-0025-1


Circadian clocks are based on a molecular mechanism regulated at the transcriptional, translational and post-translational levels. Recent experimental data unravel a complex role of the phosphorylations in these clocks. In mammals, several kinases play differential roles in the regulation of circadian rhythmicity. A dysfunction in the phosphorylation of one clock protein could lead to sleep disorders such as the Familial Advanced Sleep Phase Disorder, FASPS. Moreover, several drugs are targeting kinases of the circadian clocks and can be used in cancer chronotherapy or to treat mood disorders. In Drosophila, recent experimental observations also revealed a complex role of the phosphorylations. Because of its high degree of homology with mammals, the Drosophila system is of particular interest. In the circadian clock of cyanobacteria, an atypical regulatory mechanism is based only on three clock proteins (KaiA, KaiB, KaiC) and ATP and is sufficient to produce robust temperature-compensated circadian oscillations of KaiC phosphorylation. This review will show how computational modeling has become a powerful and useful tool in investigating the regulatory mechanism of circadian clocks, but also how models can give rise to testable predictions or reveal unexpected results.

Keywords: Circadian rhythm; Computational modeling; Phosphorylation; Mammals; Drosophila; Cyanobacteria

  • [1] de Mairan J., Observation botanique, Histoire de l’Academie Royale des Science, 1729, 35–36 (in French) Google Scholar

  • [2] Mackey S.R., Golden S.S., Winding up the cyanobacterial circadian clock, Trends Microbiol., 2007, 15, 381–388 http://dx.doi.org/10.1016/j.tim.2007.08.005CrossrefGoogle Scholar

  • [3] Brunner M., Káldi K., Interlocked feedback loops of the circadian clock of Neurospora crassa, Mol. Microbiol., 2008, 68, 255–262 http://dx.doi.org/10.1111/j.1365-2958.2008.06148.xCrossrefGoogle Scholar

  • [4] Benito J., Zheng H., Ng F.S., Hardin P.E., Transcriptional feedback loop regulation, function, and ontogeny in Drosophila, Cold Spring Harb. Symp. Quant. Biol., 2007, 72, 437–444 http://dx.doi.org/10.1101/sqb.2007.72.009CrossrefGoogle Scholar

  • [5] Más P., Circadian clock function in Arabidopsis thaliana: Time beyond transcription, Trends Cell. Biol., 2008, 18, 273–281 http://dx.doi.org/10.1016/j.tcb.2008.03.005CrossrefGoogle Scholar

  • [6] Hastings M.H., Maywood E.S., Reddy A.B., Two decades of circadian time, J. Neuroendocrinol., 2008, 20, 812–819 http://dx.doi.org/10.1111/j.1365-2826.2008.01715.xCrossrefGoogle Scholar

  • [7] Hardin P.E., Hall J.C., Rosbash M., Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels, Nature, 1990, 343, 536–540 http://dx.doi.org/10.1038/343536a0CrossrefGoogle Scholar

  • [8] Aronson B.D., Johnson K.A., Loros J.J., Dunlap J.C., Negative feedback defining a circadian clock: Autoregulation of the clock gene frequency, Science, 1994, 263, 1578–1584 http://dx.doi.org/10.1126/science.8128244CrossrefGoogle Scholar

  • [9] Kume K., Zylka M.J., Sriram S., Shearman L.P., Weaver D.R., Jin X., et al., mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop, Cell, 1999, 98, 193–205 http://dx.doi.org/10.1016/S0092-8674(00)81014-4CrossrefGoogle Scholar

  • [10] de Paula R.M., Vitalini M.W., Gomer R.H., Bell-Pedersen D., Complexity of the Neurospora crassa circadian clock system: multiple loops and oscillators, Cold Spring Harb. Symp. Quant. Biol., 2007, 72, 345–351 http://dx.doi.org/10.1101/sqb.2007.72.002CrossrefGoogle Scholar

  • [11] Ueda H.R., Hayashi S., Chen W., Sano M., Machida M., Shigeyoshi Y., et al., System-level identification of transcriptional circuits underlying mammalian circadian clocks, Nat. Genet., 2005, 37, 187–192 http://dx.doi.org/10.1038/ng1504CrossrefGoogle Scholar

  • [12] Blau J., PERspective on PER phosphorylation, Genes Dev., 2008, 22, 1737–1740 http://dx.doi.org/10.1101/gad.1696408CrossrefGoogle Scholar

  • [13] Etchegaray J.-P., Lee C., Wade P.A., Reppert S.M., Rhythmic histone acetylation underlies transcription in the mammalian circadian clock, Nature, 2003, 421, 177–182 http://dx.doi.org/10.1038/nature01314CrossrefGoogle Scholar

  • [14] Cardone L., Hirayama J., Giordano F., Tamaru T., Palvimo J.J., Sassone-Corsi P., Circadian clock control by SUMOylation of BMAL1, Science, 2005, 309, 1390–1394 http://dx.doi.org/10.1126/science.1110689CrossrefGoogle Scholar

  • [15] Grima B., Lamouroux A., Chelot E., Papin C., Limbourg-Bouchon B., Rouyer F., The F-box protein Slimb controls the levels of clock proteins Period and Timeless, Nature, 2002, 420, 178–182 http://dx.doi.org/10.1038/nature01122CrossrefGoogle Scholar

  • [16] Eide E.J., Woolf M.F., Kang H., Woolf P., Hurst W., Camacho F., et al., Control of mammalian circadian rhythm by CKI-regulated proteasomemediated PER2 degradation, Mol. Cell. Biol., 2005, 25, 2795–2807 http://dx.doi.org/10.1128/MCB.25.7.2795-2807.2005CrossrefGoogle Scholar

  • [17] Toh K.L., Jones C.R., He Y., Eide E.J., Hinz W.A., Virshup D.M., et al., An hPer2 phosphorylation site mutation in familial advanced sleep-phase syndrome, Science, 2001, 291, 1040–1043 http://dx.doi.org/10.1126/science.1057499CrossrefGoogle Scholar

  • [18] Gallego M., Eide E.J., Woolf M.F., Virshup D.M., Forger D.B., An opposite role for tau in circadian rhythms revealed by mathematical modeling, Proc. Natl. Acad. Sci. USA, 2006, 103, 10618–10623 http://dx.doi.org/10.1073/pnas.0604511103CrossrefGoogle Scholar

  • [19] Vanselow K., Vanselow J.T., Westermark P.O., Reischl S., Maier B., Korte T., et al., Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS), Genes Dev., 2006, 20, 2660–2672 http://dx.doi.org/10.1101/gad.397006CrossrefGoogle Scholar

  • [20] Vielhaber E., Eide E., Rivers A., Gao Z.H., Virshup D.M., Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase I epsilon, Mol. Cell. Biol., 2000, 20, 4888–4899 http://dx.doi.org/10.1128/MCB.20.13.4888-4899.2000CrossrefGoogle Scholar

  • [21] Iurisci I., Filipski E., Reinhardt J., Bach S., Gianella-Borradori A., Iacobelli S., et al., Improved tumor control through circadian clock induction by Seliciclib, a cyclin-dependent kinase inhibitor, Cancer Res., 2006, 66, 10720–10728 http://dx.doi.org/10.1158/0008-5472.CAN-06-2086CrossrefGoogle Scholar

  • [22] Yang W.S., Stockwell B.R., Inhibition of casein kinase 1-epsilon induces cancer-cell-selective, PERIOD2-dependent growth arrest, Genome Biol., 2008, 9, R92 http://dx.doi.org/10.1186/gb-2008-9-6-r92Google Scholar

  • [23] Kronauer R.E., A quantitative model for the effects of light on the amplitude and phase of the deep circadian pacemaker based on human data, In: Horne J. (Ed.), Sleep’ 90, Proceedings of the Tenth European Congress on Sleep Research, Pontenagel Press, Bochum, 1990, 306–309 Google Scholar

  • [24] Jewett M.E., Kronauer R.E., Czeisler C.A., Lightinduced suppression of endogenous circadian amplitude in humans, Nature, 1991, 350, 59–62 http://dx.doi.org/10.1038/350059a0CrossrefGoogle Scholar

  • [25] Forger D.B., Jewett M.E., Kronauer R.E., A simpler model of the human circadian pacemaker, J. Biol. Rhythms, 1999, 14, 532–537 http://dx.doi.org/10.1177/074873099129000867CrossrefGoogle Scholar

  • [26] Kalmus H., Wigglesworth L., A. Shock excited systems as models for biological rhythms, Cold Spring Harb. Symp. Quant. Biol., 1960, XXV, 211–216 CrossrefGoogle Scholar

  • [27] Karlsson H.G., Johnsson A., A feedback model for biological rhythms. II. Comparisons with experimental results, especially on the petal rhythm of Kalanchoe, J. Theor. Biol., 1972, 36, 175–194 http://dx.doi.org/10.1016/0022-5193(72)90186-5CrossrefGoogle Scholar

  • [28] Winfree A.T., The Geometry of Biological Time, Springer-Verlag, New York, 1980 Google Scholar

  • [29] Pedersen M., Johnsson A., A study of the singularities in a mathematical model for circadian rhythms, Biosystems, 1994, 33, 193–201 http://dx.doi.org/10.1016/0303-2647(94)90004-3CrossrefGoogle Scholar

  • [30] Roussel M.R., Gonze D., Goldbeter A., Modeling the differential fitness of cyanobacterial strains whose circadian oscillators have different freerunning periods: comparing the mutual inhibition and substrate depletion hypotheses, J. Theor. Biol., 2000, 205, 321–340 http://dx.doi.org/10.1006/jtbi.2000.2072CrossrefGoogle Scholar

  • [31] Gonze D., Roussel M.R., Goldbeter A., A Model for the enhancement of fitness in cyanobacteria based on resonance of a circadian oscillator with the external light-dark cycle, J. Theor. Biol., 2002, 214, 577–597 http://dx.doi.org/10.1006/jtbi.2001.2476CrossrefGoogle Scholar

  • [32] Kunz H., Achermann P., Simulation of circadian rhythm generation in the suprachiasmatic nucleus with locally coupled self-sustained oscillators, J. Theor. Biol., 2003, 224, 63–78 http://dx.doi.org/10.1016/S0022-5193(03)00141-3CrossrefGoogle Scholar

  • [33] Goodwin B.C., Oscillatory behavior in enzymatic control processes, Adv. Enzyme Regul. 1965, 3, 425–438 http://dx.doi.org/10.1016/0065-2571(65)90067-1CrossrefGoogle Scholar

  • [34] Lee K., Loros J.J., Dunlap J.C., Interconnected feedback loops in the Neurospora circadian system, Science, 2000, 289, 107–110 http://dx.doi.org/10.1126/science.289.5476.107CrossrefGoogle Scholar

  • [35] Shearman L.P., Sriram S., Weaver D.R., Maywood E.S., Chaves I., Zheng B., et al., Interacting molecular loops in the mammalian circadian clock, Science, 2000, 288, 1013–1019 http://dx.doi.org/10.1126/science.288.5468.1013CrossrefGoogle Scholar

  • [36] Iwasaki H., Nishiwaki T., Kitayama Y., Nakajima M., Kondo T., KaiA-stimulated KaiC phosphorylation in circadian timing loops in cyanobacteria, Proc. Natl. Acad. Sci. USA, 2002, 99, 15788–15793 http://dx.doi.org/10.1073/pnas.222467299CrossrefGoogle Scholar

  • [37] Eriksson M.E., Millar A.J., The circadian clock. A plant’s best friend in a spinning world, Plant Physiol., 2003, 132, 732–738 http://dx.doi.org/10.1104/pp.103.022343CrossrefGoogle Scholar

  • [38] Iwasaki H., Dunlap J.C., Microbial circadian oscillatory systems in Neurospora and Synechococcus: Models for cellular clocks, Curr. Opin. Microbiol., 2000, 3, 189–196 http://dx.doi.org/10.1016/S1369-5274(00)00074-6CrossrefGoogle Scholar

  • [39] Nakajima M., Imai K., Ito H., Nishiwaki T., Murayama Y., Iwasaki H., et al., Reconstitution of circadian oscillation of cyanobacterial KaiC phosphorylation in vitro, Science, 2005, 308, 414–415 http://dx.doi.org/10.1126/science.1108451CrossrefGoogle Scholar

  • [40] Goldbeter A., A model for circadian oscillations in the Drosophila period protein (PER), Proc. R. Soc. Lond. B., 1995, 261, 319–324 http://dx.doi.org/10.1098/rspb.1995.0153CrossrefGoogle Scholar

  • [41] Leloup J.-C., Goldbeter A., A model for circadian rhythms in Drosophila incorporating the formation of a complex between the PER and TIM proteins, J. Biol. Rhythms, 1998, 13, 70–87 http://dx.doi.org/10.1177/074873098128999934CrossrefGoogle Scholar

  • [42] Leloup J.-C., Gonze D., Goldbeter A., Limit cycle models for circadian rhythms based on transcriptional regulation in Neurospora and Drosophila, J. Biol. Rhythms, 1999, 14, 433–448 http://dx.doi.org/10.1177/074873099129000948CrossrefGoogle Scholar

  • [43] Tyson J.J., Hong C.I., Thron C.D., Novak B., A simple model of circadian rhythms based on dimerization and proteolysis of PER and TIM, Biophys. J., 1999, 77, 2411–2417 http://dx.doi.org/10.1016/S0006-3495(99)77078-5CrossrefGoogle Scholar

  • [44] Smolen P., Baxter D.A., Byrne J.H., Modeling circadian oscillations with interlocking positive and negative feedback loops, J. Neurosci., 2001, 21, 6644–6656 Google Scholar

  • [45] Ueda H.R., Hagiwara M., Kitano H., Robust oscillations within the interlocked feedback model of Drosophila circadian rhythm, J. Theor. Biol., 2001, 210, 401–406 http://dx.doi.org/10.1006/jtbi.2000.2226CrossrefGoogle Scholar

  • [46] Ruoff P., Vinsjevik M., Monnerjahn C., Rensing L., The Goodwin oscillator: On the importance of degradation reactions in the circadian clock, J. Biol. Rhythms, 1999, 14, 469–479 http://dx.doi.org/10.1177/074873099129001037CrossrefGoogle Scholar

  • [47] Leloup J.-C., Goldbeter A., Toward a detailed computational model for the mammalian circadian clock, Proc. Natl. Acad. Sci. USA, 2003, 100, 7051–7056 http://dx.doi.org/10.1073/pnas.1132112100CrossrefGoogle Scholar

  • [48] Forger D.B., Peskin C.S., A detailed predictive model of the mammalian circadian clock, Proc. Natl. Acad. Sci. USA, 2003, 100, 14806–14811 http://dx.doi.org/10.1073/pnas.2036281100CrossrefGoogle Scholar

  • [49] Yan J., Wang H., Liu Y., Shao C., Analysis of gene regulatory networks in the Mammalian circadian rhythm, PLoS Comput. Biol., 2008, 4, e1000193 http://dx.doi.org/10.1371/journal.pcbi.1000193CrossrefGoogle Scholar

  • [50] Leloup J.-C., Goldbeter A., Temperature compensation of circadian rhythms: Control of the period in a model for circadian oscillations of the PER protein in Drosophila, Chronobiol. Int., 1997, 14, 511–520 http://dx.doi.org/10.3109/07420529709001472CrossrefGoogle Scholar

  • [51] Hong C.I., Tyson J.J., A proposal for temperature compensation of the circadian rhythm in Drosophila based on dimerization of the per protein, Chronobiol. Int., 1997, 14, 521–529 http://dx.doi.org/10.3109/07420529709001473CrossrefGoogle Scholar

  • [52] Ruoff P., Rensing L., Kommedal R., Mohsenzadeh S., Modeling temperature compensation in chemical and biological oscillators, Chronobiol. Int., 1997, 14, 499–510 http://dx.doi.org/10.3109/07420529709001471CrossrefGoogle Scholar

  • [53] Claude D., Clairambault J., Period shift induction by intermittent stimulation in a Drosophila model of per protein oscillations, Chronobiol. Int., 2000, 17, 1–14 http://dx.doi.org/10.1081/CBI-100101027CrossrefGoogle Scholar

  • [54] Leloup J.-C., Goldbeter A., Modeling the molecular regulatory mechanism of circadian rhythms in Drosophila, BioEssays, 2000, 22, 83–92 http://dx.doi.org/10.1002/(SICI)1521-1878(200001)22:1<84::AID-BIES13>3.0.CO;2-ICrossrefGoogle Scholar

  • [55] Leloup J.-C., Goldbeter A., A molecular explanation for the long-term suppression of circadian rhythms by a single light pulse, Am. J. Physiol. Reg. Int. Comp. Physiol., 2001, 280, R1206–R1212 Google Scholar

  • [56] Bae K., Weaver D.R., Transient, light-induced rhythmicity in mPER-deficient mice, J. Biol. Rhythms, 2007, 22, 85–88 http://dx.doi.org/10.1177/0748730406296718CrossrefGoogle Scholar

  • [57] Hamblen M.J., White N.E., Emery P.T.J., Kaiser K., Hall J.C., Molecular and behavioral analysis of four period mutants in Drosophila melanogaster encompassing extreme short, novel long, and unorthodox arrhythmic types, Genetics, 1998, 149, 165–178 Google Scholar

  • [58] Gallego M., Virshup D.M., Post-translational modifications regulate the ticking of the circadian clock, Nat. Rev. Mol. Cell. Biol., 2007, 8, 139–148 http://dx.doi.org/10.1038/nrm2106CrossrefGoogle Scholar

  • [59] Xu Y., Toh K.L., Jones C.R., Shin J.Y., Fu Y.H., Ptacek L.J., Modeling of a human circadian mutation yields insights into clock regulation by PER2, Cell, 2007, 128, 59–70 http://dx.doi.org/10.1016/j.cell.2006.11.043CrossrefGoogle Scholar

  • [60] Akashi M., Tsuchiya Y., Yoshino T., Nishida E., Control of intracellular dynamics of mammalian period proteins by Casein Kinase I var epsilon (CKIepsilon) and CKIdelta in cultured cells, Mol. Cell. Biol., 2002, 22, 1693–1703 http://dx.doi.org/10.1128/MCB.22.6.1693-1703.2002CrossrefGoogle Scholar

  • [61] Takano A., Isojima Y., Nagai K., Identification of mPer1 phosphorylation sites responsible for the nuclear entry, J. Biol. Chem., 2004, 279, 32578–32585 http://dx.doi.org/10.1074/jbc.M403433200CrossrefGoogle Scholar

  • [62] Iitaka C., Miyazaki K., Akaike T., Ishida N., A role for glycogen synthase kinase-3beta in the mammalian circadian clock, J. Biol. Chem., 2005, 280, 29397–29402 http://dx.doi.org/10.1074/jbc.M503526200CrossrefGoogle Scholar

  • [63] Eide E.J., Vielhaber E.L., Hinz W.A., Virshup D.M., The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein Kinase I epsilon (CKIepsilon), J. Biol. Chem., 2002, 277, 17248–17254 http://dx.doi.org/10.1074/jbc.M111466200CrossrefGoogle Scholar

  • [64] Harada Y., Sakai M., Kurabayashi N., Hirota T., Fukada Y., SER557-phosphorylated mCRY2 is degraded upon synergistic phosphorylation by GSK-3beta, J. Biol. Chem., 2005, 280, 31714–31721 http://dx.doi.org/10.1074/jbc.M506225200Google Scholar

  • [65] Yin L., Wang J., Klein P.S., Lazar M.A., Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock, Science, 2006, 17, 1002–1005 http://dx.doi.org/10.1126/science.1121613CrossrefGoogle Scholar

  • [66] Sanada K., Harada Y., Sakai M., Todo T., Fukada Y., Serine phosphorylation of mCRY1 and mCRY2 by mitogen-activated protein kinase, Genes Cells, 2004, 9, 697–708 http://dx.doi.org/10.1111/j.1356-9597.2004.00758.xCrossrefGoogle Scholar

  • [67] Sanada K., Okano T., Fukada Y., Mitogen-activated protein kinase phosphorylates and negatively regulates basic helix-loop-helix-PAS transcription factor BMAL1, J. Biol. Chem., 2002, 277, 267–271 http://dx.doi.org/10.1074/jbc.M107850200CrossrefGoogle Scholar

  • [68] Lowrey P.L., Shimomura K., Antoch M.P., Yamazaki S., Zemenides P.D., Ralph M.R., et al., Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau, Science, 2000, 288, 483–492 http://dx.doi.org/10.1126/science.288.5465.483CrossrefGoogle Scholar

  • [69] Meng Q.J., Logunova L., Maywood E.S., Gallego M., Lebiecki J., Brown T.M., et al., Setting clock speed in mammals: the CK1epsilontau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins, Neuron, 2008, 58, 78–88 http://dx.doi.org/10.1016/j.neuron.2008.01.019CrossrefGoogle Scholar

  • [70] Takano A., Uchiyama M., Kajimura N., Mishima K., Inoue Y., Kamei Y., et al., A missense variation in human casein kinase I epsilon gene that induces functional alteration and shows an inverse association with circadian rhythm sleep disorders, Neuropsychopharmacology, 2004, 9, 1901–1909 http://dx.doi.org/10.1038/sj.npp.1300503CrossrefGoogle Scholar

  • [71] Ebisawa T., Circadian rhythms in the CNS and peripheral clock disorders: Human sleep disorders and clock genes, J. Pharmacol. Sci., 2007, 103, 150–154 http://dx.doi.org/10.1254/jphs.FMJ06003X5CrossrefGoogle Scholar

  • [72] Xu Y., Padiath Q.S., Shapiro R.E., Jones C.R., Wu S.C., Saigoh N., et al., Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome, Nature, 2005, 434, 640–644 http://dx.doi.org/10.1038/nature03453CrossrefGoogle Scholar

  • [73] Castro R.M., Barbosa A.A., Pedrazzoli M., Tufik S., Casein kinase I epsilon (CKIvar epsilon) N408 allele is very rare in the Brazilian population and is not involved in susceptibility to circadian rhythm sleep disorders, Behav. Brain Res., 2008, 193, 156–157 http://dx.doi.org/10.1016/j.bbr.2008.05.005CrossrefGoogle Scholar

  • [74] Leloup J.-C., Goldbeter A., Modeling the circadian clock: From molecular mechanism to physiological disorders, BioEssays, 2008, 30, 590–600 http://dx.doi.org/10.1002/bies.20762CrossrefGoogle Scholar

  • [75] Stambolic V., Ruel L., Woodgett J.R., Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells, Curr. Biol., 1996, 6, 1664–1668 http://dx.doi.org/10.1016/S0960-9822(02)70790-2CrossrefGoogle Scholar

  • [76] Iwahana E., Akiyama M., Miyakawa K., Uchida A., Kasahara J., Fukunaga K., et al., Effect of lithium on the circadian rhythms of locomotor activity and glycogen synthase kinase-3 protein expression in the mouse suprachiasmatic nuclei, Eur. J. Neurosci., 2004, 19, 2281–2287 http://dx.doi.org/10.1111/j.0953-816X.2004.03322.xCrossrefGoogle Scholar

  • [77] Yin L., Wang J., Klein P.S., Lazar M.A., Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock, Science, 2006, 17, 1002–1005 http://dx.doi.org/10.1126/science.1121613CrossrefGoogle Scholar

  • [78] Zylka M.J., Shearman L.P., Weaver D.R., Reppert S.M., Three period homologs in mammals: Differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain, Neuron, 1998, 20, 1103–1110 http://dx.doi.org/10.1016/S0896-6273(00)80492-4CrossrefGoogle Scholar

  • [79] Yu W., Hardin P.E., Circadian oscillators of Drosophila and mammals, J. Cell. Sci., 2006, 119, 4793–4795 http://dx.doi.org/10.1242/jcs.03174CrossrefGoogle Scholar

  • [80] Kloss B., Price J.L., Saez L., Blau J., Rothenfluh A., Wesley C.S., et al., The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Iepsilon, Cell, 1998, 94, 97–107 http://dx.doi.org/10.1016/S0092-8674(00)81225-8CrossrefGoogle Scholar

  • [81] Price J.L., Blau J., Rothenfluh A., Abodeely M., Kloss B., Young M.W., double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation, Cell, 1998, 94, 83–95 http://dx.doi.org/10.1016/S0092-8674(00)81224-6CrossrefGoogle Scholar

  • [82] Martinek S., Inonog S., Manoukian A.S., Young M.W., A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock, Cell, 2001, 105, 769–779 http://dx.doi.org/10.1016/S0092-8674(01)00383-XCrossrefGoogle Scholar

  • [83] Nawathean P., Rosbash M., The doubletime and CKII kinases collaborate to potentiate Drosophila PER transcriptional repressor activity, Mol. Cell., 2004, 13, 213–223 http://dx.doi.org/10.1016/S1097-2765(03)00503-3CrossrefGoogle Scholar

  • [84] Preuss F., Fan J.Y., Kalive M., Bao S., Schuenemann E., Bjes E.S., et al., Drosophila doubletime mutations which either shorten or lengthen the period of circadian rhythms decrease the protein kinase activity of Casein kinase I, Mol. Cell. Biol., 2004, 24, 886–898 http://dx.doi.org/10.1128/MCB.24.2.886-898.2004CrossrefGoogle Scholar

  • [85] Kivimäe S., Saez L., Young M.W., Activating PER repressor through a DBT-directed phosphorylation switch, PLoS. Biol., 2008, 6, e183 http://dx.doi.org/10.1371/journal.pbio.0060183CrossrefGoogle Scholar

  • [86] Sekine T., Yamaguchi T., Hamano K., Young M.W., Shimoda M., Saez L., Casein kinase I does not rescue double-time function in Drosophila despite evolutionarily conserved roles in the circadian clock, J. Biol. Rhythms, 2008, 23, 3–15 http://dx.doi.org/10.1177/0748730407311652CrossrefGoogle Scholar

  • [87] Xie Z., Kulasiri D., Modelling of circadian rhythms in Drosophila incorporating the interlocked PER/TIM and VRI/PDP1 feedback loops, J. Theor. Biol., 2006, 245, 290–304 http://dx.doi.org/10.1016/j.jtbi.2006.10.028CrossrefGoogle Scholar

  • [88] Leise T.L., Moin E.E., A mathematical model of the Drosophila circadian clock with emphasis on posttranslational mechanisms, J. Theor. Biol., 2007, 248, 48–63 http://dx.doi.org/10.1016/j.jtbi.2007.04.013CrossrefGoogle Scholar

  • [89] Tomita J., Nakajima M., Kondo T., Iwasaki H., No transcription-translation feedback in circadian rhythm of KaiC phosphorylation, Science, 2005, 307, 251–254 http://dx.doi.org/10.1126/science.1102540CrossrefGoogle Scholar

  • [90] Xu Y., Mori T., Pattanayek R., Pattanayek S., Egli M., Johnson C.H., Identification of key phosphorylation sites in the circadian clock protein KaiC by crystallographic and mutagenetic analyses, Proc. Natl. Acad. Sci. USA, 2004, 101, 13933–13938 http://dx.doi.org/10.1073/pnas.0404768101CrossrefGoogle Scholar

  • [91] Nishiwaki T., Iwasaki H., Ishiura M., Kondo T., Nucleotide binding and autophosphorylation of the clock protein KaiC as a circadian timing process of cyanobacteria, Proc. Natl. Acad. Sci. USA, 2000, 97, 495–499 http://dx.doi.org/10.1073/pnas.97.1.495CrossrefGoogle Scholar

  • [92] Mori T., Saveliev S.V., Xu Y., Stafford W.F., Cox M.M., Inman R.B., et al., Circadian clock protein KaiC forms ATP-dependent hexameric rings and binds DNA, Proc. Natl. Acad. Sci. USA, 2002, 99, 17203–17208 http://dx.doi.org/10.1073/pnas.262578499CrossrefGoogle Scholar

  • [93] Hayashi F., Iwase R., Uzumaki T., Ishiura M., Hexamerization by the N-terminal domain and intersubunit phosphorylation by the C-terminal domain of cyanobacterial circadian clock protein KaiC, Biochem. Biophys. Res. Commun., 2006, 348, 864–872 http://dx.doi.org/10.1016/j.bbrc.2006.07.143CrossrefGoogle Scholar

  • [94] Nishiwaki T., Iwasaki H., Ishiura M., Kondo T., Nucleotide binding and autophosphorylation of the clock protein KaiC as a circadian timing process of cyanobacteria, Proc. Natl. Acad. Sci. USA, 2000, 97, 495–499 http://dx.doi.org/10.1073/pnas.97.1.495CrossrefGoogle Scholar

  • [95] Xu Y., Mori T., Johnson C.H., Cyanobacterial circadian clockwork: Roles of KaiA, KaiB and the kaiBC promoter in regulating KaiC, EMBO J., 2003, 22, 2117–2126 http://dx.doi.org/10.1093/emboj/cdg168CrossrefGoogle Scholar

  • [96] Kitayama Y., Iwasaki H., Nishiwaki T., Kondo T., KaiB functions as an attenuator of KaiC phosphorylation in the cyanobacterial circadian clock system, EMBO J., 2003, 22, 2127–2134 http://dx.doi.org/10.1093/emboj/cdg212CrossrefGoogle Scholar

  • [97] Pattanayek R., Williams D.R., Pattanayek S., Xu Y., Mori T., Johnson C.H., et al., Analysis of KaiA-KaiC protein interactions in the cyano-bacterial circadian clock using hybrid structural methods, EMBO J., 2006, 25, 2017–2028 http://dx.doi.org/10.1038/sj.emboj.7601086CrossrefGoogle Scholar

  • [98] Kageyama H., Kondo T., Iwasaki H., Circadian formation of clock protein complexes by KaiA, KaiB, KaiC and SasA in cyanobacteria, J. Biol. Chem., 2003, 278, 2388–2395 http://dx.doi.org/10.1074/jbc.M208899200CrossrefGoogle Scholar

  • [99] Kageyama H., Nishiwaki T., Nakajima M., Iwasaki H., Oyama T., Kondo T., Cyanobacterial circadian pacemaker: Kai protein complex dynamics in the KaiC phosphorylation cycle in vitro, Mol. Cell., 2006, 23, 161–171 http://dx.doi.org/10.1016/j.molcel.2006.05.039CrossrefGoogle Scholar

  • [100] Ishiura M., Kutsuna S., Aoki S., Iwasaki H., Andersson C.R., Tanabe A., et al., Expression of a gene cluster kaiABC as a circadian feedback process in cyanobacteria, Science, 1998, 281, 1519–1523 http://dx.doi.org/10.1126/science.281.5382.1519CrossrefGoogle Scholar

  • [101] Kitayama Y., Nishiwaki T., Terauchi K., Kondo T., Dual KaiC-based oscillations constitute the circadian system of cyanobacteria, Genes Dev., 2008, 22, 1513–1521 http://dx.doi.org/10.1101/gad.1661808CrossrefGoogle Scholar

  • [102] Emberly E., Wingreen N.S., Hourglass model for a protein-based circadian oscillator, Phys. Rev. Lett., 2006, 96, 038303 http://dx.doi.org/10.1103/PhysRevLett.96.038303CrossrefGoogle Scholar

  • [103] Mehra A., Hong C.I., Shi M., Loros J.J., Dunlap J.C., Ruoff P., Circadian rhythmicity by autocatalysis, PLoS. Comput. Biol., 2006, 2, e96 http://dx.doi.org/10.1371/journal.pcbi.0020096CrossrefGoogle Scholar

  • [104] Takigawa-Imamura H., Mochizuki A., Predicting regulation of the phosphorylation cycle of KaiC clock protein using mathematical analysis, J. Biol. Rhythms, 2006, 21, 405–416 http://dx.doi.org/10.1177/0748730406291329CrossrefGoogle Scholar

  • [105] Kurosawa G., Aihara K., Iwasa Y., A model for circadian rhythm of cyanobacteria, which maintains oscillation without gene expression, Biophys. J., 2006, 91, 2015–2023 http://dx.doi.org/10.1529/biophysj.105.076554CrossrefGoogle Scholar

  • [106] Mori T., Williams D.R., Byrne M.O., Qin X., Egli M., McHaourab H.S., et al., Elucidating the ticking of an in vitro circadian clockwork, PLoS Biol., 2007, 5, e93 http://dx.doi.org/10.1371/journal.pbio.0050093CrossrefGoogle Scholar

  • [107] Yoda M., Eguchi K., Terada T.P., Sasai M., Monomer-shuffling and allosteric transition in KaiC circadian oscillation, PLoS ONE, 2007, 2, e408 http://dx.doi.org/10.1371/journal.pone.0000408CrossrefGoogle Scholar

  • [108] van Zon J.S., Lubensky D.K., Altena P.R., Rein Ten Wolde P., An allosteric model of circadian KaiC phosphorylation, Proc. Natl. Acad. Sci. USA, 2007, 104, 7420–7425 http://dx.doi.org/10.1073/pnas.0608665104CrossrefGoogle Scholar

  • [109] Rust M.J., Markson J.S., Lane W.S., Fisher D.S., O’shea E.K., Ordered phosphorylation governs oscillation of a three-protein circadian clock, Science, 2007, 318, 809–812 http://dx.doi.org/10.1126/science.1148596CrossrefGoogle Scholar

  • [110] Brunner M., Simons M.J., Merrow M., Lego clocks: Building a clock from parts, Genes Dev., 2008, 22, 1422–1426 http://dx.doi.org/10.1101/gad.1686608CrossrefGoogle Scholar

  • [111] Yoshida T., Murayama Y., Ito H., Kageyama H., Kondo T., Nonparametric entrainment of the in vitro circadian phosphorylation rhythm of cyanobacterial KaiC by temperature cycle, Proc. Natl. Acad. Sci. USA, 2009, 106, 1648–53 http://dx.doi.org/10.1073/pnas.0806741106CrossrefGoogle Scholar

  • [112] Johnson C.H., Mori T., Xu Y., A cyanobacterial circadian clockwork, Curr. Biol., 2008, 18, R816–R825 http://dx.doi.org/10.1016/j.cub.2008.07.012CrossrefGoogle Scholar

  • [113] Gallego M., Kang H., Virshup D.M., Protein phosphatase 1 regulates the stability of the circadian protein PER2, Biochem. J., 2006, 399, 169–175 http://dx.doi.org/10.1042/BJ20060678CrossrefGoogle Scholar

  • [114] Fang Y., Sathyanarayanan S., Sehgal A., Posttranslational regulation of the Drosophila circadian clock requires protein phosphatase 1 (PP1), Genes Dev., 2007, 21, 1506–1518 http://dx.doi.org/10.1101/gad.1541607CrossrefGoogle Scholar

  • [115] Sathyanarayanan S., Zheng X., Xiao R., Sehgal A., Posttranslational regulation of Drosophila PERIOD protein by protein phosphatase 2A, Cell, 2004, 116, 603–615 http://dx.doi.org/10.1016/S0092-8674(04)00128-XGoogle Scholar

  • [116] Schafmeier T., Haase A., Kaldi K., Scholz J., Fuchs M., Brunner M., Transcriptional feedback of Neurospora circadian clock gene by phosphorylation-dependent inactivation of its transcription factor, Cell, 2005, 122, 235–246 http://dx.doi.org/10.1016/j.cell.2005.05.032CrossrefGoogle Scholar

  • [117] Partch C.L., Shields K.F., Thompson C.L., Selby C.P., Sancar A., Posttranslational regulation of the mammalian circadian clock by cryptochrome and protein phosphatase 5, Proc. Natl. Acad. Sci. USA, 2006, 103, 10467–10472 http://dx.doi.org/10.1073/pnas.0604138103CrossrefGoogle Scholar

  • [118] Gietzen K.F., Virshup D.M., Identification of inhibitory autophosphorylation sites in casein kinase Iå, J. Biol. Chem., 1999, 274, 32063–32070 http://dx.doi.org/10.1074/jbc.274.45.32063CrossrefGoogle Scholar

  • [119] Doi M., Hirayama J., Sassone-Corsi P., Circadian regulator CLOCK is a histone acetyltransferase, Cell, 2006, 125, 497–508 http://dx.doi.org/10.1016/j.cell.2006.03.033CrossrefGoogle Scholar

  • [120] Hirayama J., Sahar S., Grimaldi B., Tamaru T., Takamatsu K., Nakahata Y., Sassone-Corsi P., CLOCK-mediated acetylation of BMAL1 controls circadian function, Nature, 2007, 450, 1086–1090 http://dx.doi.org/10.1038/nature06394CrossrefGoogle Scholar

  • [121] Asher G., Gatfield D., Stratmann M., Reinke H., Dibner C., Kreppel F., et al., SIRT1 regulates circadian clock gene expression through PER2 deacetylation, Cell, 2008, 134, 317–328 http://dx.doi.org/10.1016/j.cell.2008.06.050CrossrefGoogle Scholar

  • [122] Nakahata Y., Kaluzova M., Grimaldi B., Sahar S., Hirayama J., Chen D., et al., The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control, Cell, 2008, 134, 329–340 http://dx.doi.org/10.1016/j.cell.2008.07.002CrossrefGoogle Scholar

  • [123] Smolen P., Hardin P.E., Lo B.S., Baxter D.A., Byrne J.H., Simulation of Drosophila circadian oscillations, mutations, and light responses by a model with VRI, PDP-1, and CLK, Biophys. J., 2004, 86, 2786–2802 http://dx.doi.org/10.1016/S0006-3495(04)74332-5CrossrefGoogle Scholar

  • [124] Leloup J.-C., Goldbeter A., Modeling the mammalian circadian clock: Sensitivity analysis and multiplicity of oscillatory mechanisms, J. Theor. Biol., 2004, 230, 541–562 http://dx.doi.org/10.1016/j.jtbi.2004.04.040CrossrefGoogle Scholar

  • [125] Locke J.C., Westermark P.O., Kramer A., Herzel H., Global parameter search reveals design principles of the mammalian circadian clock, BMC Syst. Biol., 2008, 2, 22 http://dx.doi.org/10.1186/1752-0509-2-22CrossrefGoogle Scholar

About the article

Published Online: 2009-07-26

Published in Print: 2009-09-01

Citation Information: Open Life Sciences, Volume 4, Issue 3, Pages 290–303, ISSN (Online) 2391-5412, DOI: https://doi.org/10.2478/s11535-009-0025-1.

Export Citation

© 2009 Versita Warsaw. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. BY-NC-ND 3.0

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Kazuhiro Maeda and Hiroyuki Kurata
BMC Systems Biology, 2014, Volume 8, Number Suppl 5, Page S1
Sebastián Risau-Gusman and Pablo M. Gleiser
Journal of Theoretical Biology, 2012, Volume 307, Page 53
Kazuhiro Maeda and Hiroyuki Kurata
Journal of Theoretical Biology, 2011, Volume 272, Number 1, Page 174

Comments (0)

Please log in or register to comment.
Log in