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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2001 Nov 29;356(1415):1725–1733. doi: 10.1098/rstb.2001.0935

Cellular signalling and the complexity of biological timing: insights from the ultradian clock of Schizosaccharomyces pombe.

F Kippert 1
PMCID: PMC1088548  PMID: 11710979

Abstract

The molecular bases of circadian clocks are complex and cannot be sufficiently explained by the relatively simple feedback loops, based on transcription and translation, of current models. The existence of additional oscillators has been demonstrated experimentally, but their mechanism(s) have so far resisted elucidation and any universally conserved clock components have yet to be identified. The fission yeast, Schizosaccharomyces pombe, as a simple and well-characterized eukaryote, is a useful model organism in the investigation of many aspects of cell regulation. In fast-growing cells of the yeast an ultradian clock operates, which can serve as a model system to analyse clock complexity. This clock shares strict period homeostasis and efficient entrainment with circadian clocks but, because of its short period of 30 min, mechanisms other than a transcription/translation-based feedback loop must be working. An initial systematic screen involving over 200 deletion mutants has shown that major cellular signalling pathways (calcium/phosphoinositide, mitogen-activated protein kinase and cAMP/protein kinase A) are crucial for the normal functioning of this ultradian clock. A comparative examination of the role of cellular signalling pathways in the S.pombe ultradian clock and in the circadian timekeeping of different eukaryotes may indicate common principles in biological timing processes that are universally conserved amongst eukaryotes.

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Selected References

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  1. Akashi M., Nishida E. Involvement of the MAP kinase cascade in resetting of the mammalian circadian clock. Genes Dev. 2000 Mar 15;14(6):645–649. [PMC free article] [PubMed] [Google Scholar]
  2. Alberini C. M. Genes to remember. J Exp Biol. 1999 Nov;202(Pt 21):2887–2891. doi: 10.1242/jeb.202.21.2887. [DOI] [PubMed] [Google Scholar]
  3. Balsalobre A., Marcacci L., Schibler U. Multiple signaling pathways elicit circadian gene expression in cultured Rat-1 fibroblasts. Curr Biol. 2000 Oct 19;10(20):1291–1294. doi: 10.1016/s0960-9822(00)00758-2. [DOI] [PubMed] [Google Scholar]
  4. Bell-Pedersen D., Crosthwaite S. K., Lakin-Thomas P. L., Merrow M., Økland M. The Neurospora circadian clock: simple or complex? Philos Trans R Soc Lond B Biol Sci. 2001 Nov 29;356(1415):1697–1709. doi: 10.1098/rstb.2001.0968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Belvin M. P., Zhou H., Yin J. C. The Drosophila dCREB2 gene affects the circadian clock. Neuron. 1999 Apr;22(4):777–787. doi: 10.1016/s0896-6273(00)80736-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Berridge M. J., Downes C. P., Hanley M. R. Neural and developmental actions of lithium: a unifying hypothesis. Cell. 1989 Nov 3;59(3):411–419. doi: 10.1016/0092-8674(89)90026-3. [DOI] [PubMed] [Google Scholar]
  7. Berridge M. J., Lipp P., Bootman M. D. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol. 2000 Oct;1(1):11–21. doi: 10.1038/35036035. [DOI] [PubMed] [Google Scholar]
  8. Bonnet C., Perret E., Dumont X., Picard A., Caput D., Lenaers G. Identification and transcription control of fission yeast genes repressed by an ammonium starvation growth arrest. Yeast. 2000 Jan 15;16(1):23–33. doi: 10.1002/(SICI)1097-0061(20000115)16:1<23::AID-YEA503>3.0.CO;2-A. [DOI] [PubMed] [Google Scholar]
  9. Buck V., Quinn J., Soto Pino T., Martin H., Saldanha J., Makino K., Morgan B. A., Millar J. B. Peroxide sensors for the fission yeast stress-activated mitogen-activated protein kinase pathway. Mol Biol Cell. 2001 Feb;12(2):407–419. doi: 10.1091/mbc.12.2.407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Colwell C. S. Circadian modulation of calcium levels in cells in the suprachiasmatic nucleus. Eur J Neurosci. 2000 Feb;12(2):571–576. doi: 10.1046/j.1460-9568.2000.00939.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. De Cesare D., Sassone-Corsi P. Transcriptional regulation by cyclic AMP-responsive factors. Prog Nucleic Acid Res Mol Biol. 2000;64:343–369. doi: 10.1016/s0079-6603(00)64009-6. [DOI] [PubMed] [Google Scholar]
  12. Dunlap J. C. Molecular bases for circadian clocks. Cell. 1999 Jan 22;96(2):271–290. doi: 10.1016/s0092-8674(00)80566-8. [DOI] [PubMed] [Google Scholar]
  13. Edmunds L. N., Jr, Carré I. A., Tamponnet C., Tong J. The role of ions and second messengers in circadian clock function. Chronobiol Int. 1992 Jun;9(3):180–200. doi: 10.3109/07420529209064529. [DOI] [PubMed] [Google Scholar]
  14. Gillette M. U., Tischkau S. A. Suprachiasmatic nucleus: the brain's circadian clock. Recent Prog Horm Res. 1999;54:33–59. [PubMed] [Google Scholar]
  15. Gu Y. Z., Hogenesch J. B., Bradfield C. A. The PAS superfamily: sensors of environmental and developmental signals. Annu Rev Pharmacol Toxicol. 2000;40:519–561. doi: 10.1146/annurev.pharmtox.40.1.519. [DOI] [PubMed] [Google Scholar]
  16. Johnson C. H., Knight M. R., Kondo T., Masson P., Sedbrook J., Haley A., Trewavas A. Circadian oscillations of cytosolic and chloroplastic free calcium in plants. Science. 1995 Sep 29;269(5232):1863–1865. doi: 10.1126/science.7569925. [DOI] [PubMed] [Google Scholar]
  17. Khalsa S. B., Michel S., Block G. D. The effects of lithium on a neuronal in vitro circadian pacemaker. Chronobiol Int. 1993 Oct;10(5):321–330. doi: 10.3109/07420529309064486. [DOI] [PubMed] [Google Scholar]
  18. Kippert F., Hunt P. Ultradian clocks in eukaryotic microbes: from behavioural observation to functional genomics. Bioessays. 2000 Jan;22(1):16–22. doi: 10.1002/(SICI)1521-1878(200001)22:1<16::AID-BIES5>3.0.CO;2-1. [DOI] [PubMed] [Google Scholar]
  19. Kippert F. The ultradian clocks of eukaryotic microbes: timekeeping devices displaying a homeostasis of the period. Chronobiol Int. 1997 Sep;14(5):469–479. doi: 10.3109/07420529709001469. [DOI] [PubMed] [Google Scholar]
  20. Klemfuss H. Rhythms and the pharmacology of lithium. Pharmacol Ther. 1992;56(1):53–78. doi: 10.1016/0163-7258(92)90037-z. [DOI] [PubMed] [Google Scholar]
  21. Lakin-Thomas P. L. Circadian rhythms: new functions for old clock genes. Trends Genet. 2000 Mar;16(3):135–142. doi: 10.1016/s0168-9525(99)01945-9. [DOI] [PubMed] [Google Scholar]
  22. Lakin-Thomas P. L., Gooch V. D., Ramsdale M. Rhythms of differentiation and diacylglycerol in Neurospora. Philos Trans R Soc Lond B Biol Sci. 2001 Nov 29;356(1415):1711–1715. doi: 10.1098/rstb.2001.0966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Levine J. D., Casey C. I., Kalderon D. D., Jackson F. R. Altered circadian pacemaker functions and cyclic AMP rhythms in the Drosophila learning mutant dunce. Neuron. 1994 Oct;13(4):967–974. doi: 10.1016/0896-6273(94)90262-3. [DOI] [PubMed] [Google Scholar]
  24. Majercak J., Kalderon D., Edery I. Drosophila melanogaster deficient in protein kinase A manifests behavior-specific arrhythmia but normal clock function. Mol Cell Biol. 1997 Oct;17(10):5915–5922. doi: 10.1128/mcb.17.10.5915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. McWatters H. G., Roden L. C., Staiger D. Picking out parallels: plant circadian clocks in context. Philos Trans R Soc Lond B Biol Sci. 2001 Nov 29;356(1415):1735–1743. doi: 10.1098/rstb.2001.0936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Morgan L. W., Feldman J. F., Bell-Pedersen D. Genetic interactions between clock mutations in Neurospora crassa: can they help us to understand complexity? Philos Trans R Soc Lond B Biol Sci. 2001 Nov 29;356(1415):1717–1724. doi: 10.1098/rstb.2001.0967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Obrietan K., Impey S., Smith D., Athos J., Storm D. R. Circadian regulation of cAMP response element-mediated gene expression in the suprachiasmatic nuclei. J Biol Chem. 1999 Jun 18;274(25):17748–17756. doi: 10.1074/jbc.274.25.17748. [DOI] [PubMed] [Google Scholar]
  28. Obrietan K., Impey S., Storm D. R. Light and circadian rhythmicity regulate MAP kinase activation in the suprachiasmatic nuclei. Nat Neurosci. 1998 Dec;1(8):693–700. doi: 10.1038/3695. [DOI] [PubMed] [Google Scholar]
  29. 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 Jul 10;94(1):83–95. doi: 10.1016/s0092-8674(00)81224-6. [DOI] [PubMed] [Google Scholar]
  30. Prosser R. A., Gillette M. U. Cyclic changes in cAMP concentration and phosphodiesterase activity in a mammalian circadian clock studied in vitro. Brain Res. 1991 Dec 24;568(1-2):185–192. doi: 10.1016/0006-8993(91)91396-i. [DOI] [PubMed] [Google Scholar]
  31. Roenneberg T., Merrow M. Circadian systems and metabolism. J Biol Rhythms. 1999 Dec;14(6):449–459. doi: 10.1177/074873099129001019. [DOI] [PubMed] [Google Scholar]
  32. Roenneberg T., Merrow M. Circadian systems: different levels of complexity. Philos Trans R Soc Lond B Biol Sci. 2001 Nov 29;356(1415):1687–1696. doi: 10.1098/rstb.2001.0969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rosato E., Kyriacou C. P. Flies, clocks and evolution. Philos Trans R Soc Lond B Biol Sci. 2001 Nov 29;356(1415):1769–1778. doi: 10.1098/rstb.2001.0961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Ruoff P., Behzadi A., Hauglid M., Vinsjevik M., Havås H. pH homeostasis of the circadian sporulation rhythm in clock mutants of Neurospora crassa. Chronobiol Int. 2000 Nov;17(6):733–750. doi: 10.1081/cbi-100102109. [DOI] [PubMed] [Google Scholar]
  35. Sanada K., Hayashi Y., Harada Y., Okano T., Fukada Y. Role of circadian activation of mitogen-activated protein kinase in chick pineal clock oscillation. J Neurosci. 2000 Feb 1;20(3):986–991. doi: 10.1523/JNEUROSCI.20-03-00986.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sargent M. L., Kaltenborn S. H. Effects of medium composition and carbon dioxide on circadian conidiation in neurospora. Plant Physiol. 1972 Jul;50(1):171–175. doi: 10.1104/pp.50.1.171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Tischkau S. A., Gallman E. A., Buchanan G. F., Gillette M. U. Differential cAMP gating of glutamatergic signaling regulates long-term state changes in the suprachiasmatic circadian clock. J Neurosci. 2000 Oct 15;20(20):7830–7837. doi: 10.1523/JNEUROSCI.20-20-07830.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Trewavas A. J., Malhó R. Ca2+ signalling in plant cells: the big network! Curr Opin Plant Biol. 1998 Oct;1(5):428–433. doi: 10.1016/s1369-5266(98)80268-9. [DOI] [PubMed] [Google Scholar]
  39. Wilkinson M. G., Millar J. B. Control of the eukaryotic cell cycle by MAP kinase signaling pathways. FASEB J. 2000 Nov;14(14):2147–2157. doi: 10.1096/fj.00-0102rev. [DOI] [PubMed] [Google Scholar]
  40. Williams R. S., Harwood A. J. Lithium therapy and signal transduction. Trends Pharmacol Sci. 2000 Feb;21(2):61–64. doi: 10.1016/s0165-6147(99)01428-5. [DOI] [PubMed] [Google Scholar]
  41. Woolum J. C. A re-examination of the role of the nucleus in generating the circadian rhythm in Acetabularia. J Biol Rhythms. 1991 Summer;6(2):129–136. doi: 10.1177/074873049100600203. [DOI] [PubMed] [Google Scholar]
  42. Zilian O., Frei E., Burke R., Brentrup D., Gutjahr T., Bryant P. J., Noll M. double-time is identical to discs overgrown, which is required for cell survival, proliferation and growth arrest in Drosophila imaginal discs. Development. 1999 Dec;126(23):5409–5420. doi: 10.1242/dev.126.23.5409. [DOI] [PubMed] [Google Scholar]

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