Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The circadian clock: pacemaker and tumour suppressor

Nature Reviews Cancer volume 3, pages 350–361 (2003)Cite this article

Key Points

  • The circadian clock is the internal timing machine that can sustain rhythms of about 24 hours in the absence of external cues. The circadian clock is operated by the feedback loops of the circadian genes in the mammalian central pacemaker, as well as in most peripheral tissues.

  • The mammalian central pacemaker is located in the suprachiasmatic nuclei (SCN) of the brain and controls the activity of peripheral clocks through the neuroendocrine and autonomic nervous systems. The circadian clock regulates hundreds of functions in the human body.

  • Disruption of circadian rhythms has been linked to mammalian tumorigenesis and tumour progression, and has been used as an independent prognostic factor of survival time for patients with certain metastatic cancers.

  • Normal and malignant tissues often show asynchronies in cell proliferation and metabolic rhythms. Based on these observations, cancer chronotherapy has been developed to improve the efficacy in cancer treatment and the quality of patients' life.

  • The circadian clock functions in vivo as a tumour suppressor at the systemic, cellular and molecular levels. The central clock is capable of generating 24-hour cell-proliferation rhythms in peripheral tissues through the activity of the neuroendocrine and autonomic nervous systems.

  • Molecular clocks in peripheral tissues control cell-proliferation rhythms by regulating the expression of cell-cycle genes. The core circadian genes are also involved in regulating cell proliferation. The circadian clock in peripheral tissues responds directly to DNA damage and could be important in the control of the cell cycle and apoptosis.

  • The molecular clockworks and cell-cycle clocks in peripheral tissues can be regulated simultaneously by the central clock, through interacting signalling pathways. Further study of the mechanism of the circadian clock in tumour suppression and the DNA-damage response has important implications for cancer therapy.

Abstract

The circadian rhythms are daily oscillations in various biological processes that are regulated by an endogenous clock. Disruption of these rhythms has been associated with cancer in humans. One of the cellular processes that is regulated by circadian rhythm is cell proliferation, which often shows asynchrony between normal and malignant tissues. This asynchrony highlights the importance of the circadian clock in tumour suppression in vivo and is one of the theoretical foundations for cancer chronotherapy. Investigation of the mechanisms by which the circadian clock controls cell proliferation and other cellular functions might lead to new therapeutic targets.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mammalian core circadian gene feedback loops.
Figure 2: Circadian regulation of hormones, urine and the immune system.
Figure 3: The circadian clock controls cell proliferation and apoptosis at the systemic level.
Figure 4: A model for the role of Per2 in tumour suppression.
Figure 5: Signalling pathways linking the circadian clock to cell-cycle regulation in peripheral tissues.

Similar content being viewed by others

References

  1. Pittendrigh, C. S. On temperature independence in the clock system controlling emergence time in Drosophila. Proc. Natl Acad. Sci. USA 40, 1018–1029 (1954).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pittendrigh, C. S. Circadian systems. I. The driving oscillation and its assay in Drosophila pseudoobscura. Proc. Natl Acad. Sci. USA 58, 1762–1767 (1967).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bargielle, T. A., Jackson, F. R. & Young, M. W. Restoration of circadian behavioral rhythms by gene transfer in Drosophila. Nature 312, 752–754 (1984).

    Article  Google Scholar 

  4. Reddy, P. et al. Molecular analysis of the Period locus in Drosophila melanogaster and identification of a transcript involved in biological rhythms. Cell 38, 701–710 (1984).

    Article  CAS  PubMed  Google Scholar 

  5. Young, M. W. & Kay, S. A. Time zones: a comparative genetics of circadian clocks. Nature Rev. Genet. 2, 702–715 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Touitou, Y. & Haus, E. Biologic Rhythms in Clinical and Laboratory Medicine (eds Touitou Y. & Haus, E.) 188–207 (Springer-Verlag, Berlin, 1992).

    Book  Google Scholar 

  7. Mormont, M. C. & Levi, F. Circadian-system alterations during cancer processes: a review. Int. J. Cancer 70, 241–247 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Roenneberg, T. & Lucas, R. J. Light, endocrine systems, and cancer — a view from circadian biologists. Neuroendocrinol. Lett. 23 (Suppl. 2), 82–83 (2002).

    PubMed  Google Scholar 

  9. Schemhammer, E. S. et al. Rotating night shifts and risk of breast cancer in women participating in the nurses' health study. J. Natl Cancer Inst. 93, 1563–1568 (2001). Shows that disruption of circadian rhythm is involved in human cancer development.

    Article  Google Scholar 

  10. Hansen, J. Increased breast cancer risk among women who work predominantly at night. Epidemiology 12, 74–77 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Fu, L., Pellicano, H., Liu, J., Hang, P. & Lee C. C. The circadian gene Period2 plays an important role in tumour suppression and DNA damage response in vivo. Cell 111, 41–50 (2002). First demonstration that loss of function in a mammalian circadian gene results in neoplastic growth and deficiencies in DNA-damage response.

    Article  CAS  PubMed  Google Scholar 

  12. Filipski, E. et al. Host circadian clock as a control point in tumour progression. J. Natl Cancer Inst. 94, 690–697 (2002).

    Article  PubMed  Google Scholar 

  13. Levi, F. From circadian rhythms to cancer chronotherapeutics. Chronobiol. Int. 19, 1–19 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. King, D. P. et al. Positional cloning of the mouse circadian clock gene. Cell 89, 641–653 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ralph, M. R. & Menaker, M. A mutation of the circadian system in gold hamsters. Science 241, 1225–1227 (1998).

    Article  Google Scholar 

  16. Takano, A. et al. Cloning and characterization of rat casein kinase 1ε. FEBS Lett. 477, 106–112 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Hsu, D. S. et al. Putative human blue-light photoreceptors hCRY1 and hCRY2 are flavoproteins. Biochemistry 35, 13871–13877 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. van der Spek, P. J. et al. Cloning, tissue expression, and mapping of a human photolyase homolog with similarity to plant blue-light receptors. Genomics 37, 177–182 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Thresher, R. J. et al. Role of mouse cryptochrome blue-light photoreceptor in circadian photoresponses. Science 282, 1490–1494 (1998.)

    Article  CAS  PubMed  Google Scholar 

  20. Tei, H. et al. Circadian oscillation of a mammalian homologue of the Drosophila period gene. Nature 389, 512–516 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Sun, Z. S. et al. RIGUI, a putative mammalian ortholog of the Drosophila period gene. Cell 90, 1003–1011 (1997). References 20 and 21 describe the identification of mammalian Period1 gene.

    Article  CAS  PubMed  Google Scholar 

  22. Shearman, L. P., Zylka, M. J., Weaver, D. R., Kolakowski, L. F. Jr & Reppert, S. M. Two period homologs: circadian expression and photo regulation in the suprachiasmatic nuclei. Neuron 19, 1261–1269 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Takumi, T. et al. A light-independent oscillatory gene mPer3 in mouse SCN and OVLT. EMBO J. 17, 4753–4759 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Albrecht, U., Sun, Z. S., Eichele, G. & Lee, C. C. A differential response of two putative mammalian circadian regulators, mPer1 and mPer2 to light. Cell 91, 1055–1064 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Hogenesch, J. B., Gu, Y. Z., Jain, S. & Bradfield, C. A. The basic–helix–loop–helix–PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proc. Natl Acad. USA Sci. 95, 5474–5479 (1998).

    Article  CAS  Google Scholar 

  26. Honma, S. et al. Circadian oscillation of BMAL1, a partner of a mammalian clock gene Clock, in rat suprachiasmatic nucleus. Biochem. Biophys. Res. Commun. 250, 83–87 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Reppert, S. M. & Weaver, D. R. Molecular analysis of mammalian circadian rhythms. Ann. Rev. Physiol. 63, 647–676 (2001).

    Article  CAS  Google Scholar 

  28. Reppert, S. M. & Weaver, D. R. Coordination of circadian timing in mammals. Nature 418, 935–941 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Panda, S, Hogenesch, J. B. & Kay, S. A. Circadian rhythms from flies to human. Nature 417, 329–335 (2002). References 27–29 summarize the current understanding of the mammalian circadian clock.

    Article  CAS  PubMed  Google Scholar 

  30. Moore, R. Y. & Eichler, V. B. Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesion in rat. Brain Res. 42, 201–206 (1972).

    Article  CAS  PubMed  Google Scholar 

  31. Stephan, F. K. & Zuker, I. Circadian rhythm in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesion. Proc. Natl Acad. Sci. USA 69, 1583–1586 (1972). References 30 and 31 show that the suprachiasmatic nucleus (SCN) in the brain is the master circadian clock in mammals.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Welsh, D. K., Logothelis, D. E., Meister, M. & Reppert, S. M. Individual neurons dissociated from rat suprachiasmatic nucleus express independently phase circadian firing rhythms. Neuron 14, 697–706 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. Liu, C., Weaver, D. R., Stogatz, S. H. & Reppert, S. M. Cellular construction of a circadian clock: period determination in the suprachiasmatic nucleus. Cell 91, 855–860 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Wright, K. P. Jr & Czeisler, C. A. Absence of circadian phase resetting in response to bright light behind the knee. Science 297, 571 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Lucas, R. et al. Identifying the photoreceptive inputs to the mammalian circadian system using transgenic and retinally degenerate mice. Behav. Brain Res. 125, 97–102 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Freedman, M. S. et al. Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science 284, 502–504 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Lucas, R. J., Freedman, M. S., Munoz, M., Garcia-Fernandez, J. M. & Foster, R. G. Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors. Science 284, 505–507 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Czeisler, C. A. et al. Suppression of melatonin secretion in some blind patients by exposure to bright light. N. Engl. J. Med. 332, 6–11 (1995).

    Article  CAS  PubMed  Google Scholar 

  39. Gooley, J. J., Lu, J., Chou, T. C., Scammell, T. E. & Saper, C. B. Melanopsin in cells of origin of the retinohypothalamic tract. Nature Neurosci. 4, 1165 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Hattar, S, Liao, H. W., Takao, M., Berson, D. M. & Yau, K. W. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 295, 1065–1070 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ruby, N. F. et al. Role of melanopsin in circadian responses to light. Science 298, 2211–2213 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Panda, S. et al. Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science 298, 2213–2216 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Van Gelder, R. N., Wee, R., Lee, J. A. & Tu, D. C. Reduced pupillary light responses in mice lacking cryptochromes. Science 299, 222 (2002).

    Article  Google Scholar 

  44. Bartness, T. J., Song, C. K. & Dernas, G. E. SCN efferents to peripheral tissues: implications for biological rhythms. J. Biol. Rhythms 16, 196–204 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Kalsbeek, A. & Buijs, R. M. Output pathways of the mammalian suprachiasmatic nucleus: coding circadian time by transmitter selection and specific targeting. Cell Tissue Res. 309, 109–118 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Buijs, R. M. et al. Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway. Eur. J. Neurosci. 11, 1535–1544 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. 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 20, 1103–1110 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Morse, D., Cermakian, N., Brancorsini, S., Parvinen, M. & Sassone-Corsi, P. No circadian rhythms in testis: Period1 expression is clock independent and developmentally regulated in the mouse. Mol. Endocrinol. 17, 141–151 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Balsalobre, A., Damiola, F. & Schibler, U. A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93, 929–937 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Sakamoto, K. et al. Multitissue circadian expression of rat period homolog (rPer2) mRNA is governed by the mammalian circadian clock, the suprachiasmatic nucleus in the brain. J. Biol. Chem. 273, 27039–27042 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. Damiola, F. et al. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 14, 2950–2961 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Stokkan, K. A., Yamazaki, S., Tei, H., Sakaki, Y. & Menaker, M. Entrainment of the circadian clock in the liver by feeding. Science 291, 490–493 (2001). References 51 and 52 show that the peripheral clocks can be entrained by non-photo stimuli, such as restricted feeding.

    Article  CAS  PubMed  Google Scholar 

  53. Rutter, J., Reick, M., Wu, L. C. & McKnight, S. L. Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science 293, 510–514 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Rutter, J., Reick, M. & McKnight, S. L. Metabolism and the control of circadian rhythms. Annu. Rev. Biochem. 71, 307–331 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Le Minh, N., Damiola, F., Tronche, F., Schutz, G. & Schibler, U. Glucocorticoid hormones inhibit food-induced phase-shifting of peripheral circadian oscillators. EMBO J. 20, 7128–2136 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kornmann, B., Preitner, N., Rifat, D., Fleuury–Olela, F. & Schibler, U. Analysis of circadian liver gene expression by ADDER, a highly sensitive method for the display of differentially expressed mRNAs. Nucleic Acids Res. 29, E51 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Panda, S. et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109, 307–320 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Duffield, G. E. et al. Circadian programs of transcriptional activation, signaling, and protein turnover revealed by microarray analysis of mammalian cells. Curr. Biol. 12, 551–557 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Akhtar, R. A. et al. Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr. Biol. 12, 540–550 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Kita, Y. et al. Implications of circadian gene expression in kidney, liver and the effects of fasting on pharmacogenomic studies. Pharmacogenetics 12, 55–65 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Storch, K. F. et al. Extensive and divergent circadian gene expression in liver and heart. Nature 417, 78–83 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Jochle, W. Trends in photophysiologic concept. Ann. NY Acad. Sci. 117, 88–104 (1964).

    Article  Google Scholar 

  63. Hamilton, T. Influence of environmental light and melatonin upon mammary tumour induction. Br. J. Surg. 56, 764–766 (1969).

    Article  CAS  PubMed  Google Scholar 

  64. Aubert. C., Janiaud, P. & Lecalvez, J. Effect of pinealectomy and melatoning on mammary tumour growth in Sprague Dawley rats under different conditions of lighting. J. Neural Trans. 47, 121–130 (1980).

    Article  CAS  Google Scholar 

  65. Mhatre, M. C., Shan, P. N. & Juneja, H. S. Effect of varying photoperiods on mammary morphology, DNA synthesis, and hormone profile in female rats. J. Natl Cancer Inst. 72, 1411–1416 (1984).

    CAS  PubMed  Google Scholar 

  66. Shah, P. N., Mhatre, M. C. & Kothari, L. S. Effect of melatonin on mammary carcinogenesis in intact and pinealectomized rats in varying photoperiods. Cancer Res. 44, 3403–3407 (1984).

    CAS  PubMed  Google Scholar 

  67. Van den Heiligenberg, S. et al. The tumour promoting effect of constant light exposure on diethylnitrosamine-induced hepatocarcinogenesis in rats. Life Sci. 64, 2523–2334 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Davis, S., Mirick, D. K. & Stevens, R. G. Night shift work, light at night and risk of breast cancer. J. Natl Cancer Inst. 93, 1513–1515 (2001).

    Article  Google Scholar 

  69. Rafneeon, V., Tulinius, H., Jonasson, J. G. & Hrafnkelsson, J. Risk of breast cancer in female flight attendants: a population-based study (Iceland). Cancer Causes Control 12, 95–101 (2001).

    Article  Google Scholar 

  70. Keith, L. G., Oleszczuk, J. J. & Laguens, M. Circadian rhythm chaos: a new breast cancer marker. Int. J. Fertil. Womens Med. 46, 238–247 (2001).

    CAS  PubMed  Google Scholar 

  71. Li, J. C. & Xu, F. Influence of light-dark shifting on immune system, tumour growth and life span of rats, mice and fruit flies as well as on the concentration of melatonin. Biol. Signals 6, 77–89 (1997).

    Article  PubMed  Google Scholar 

  72. Sephton, S. E., Sapolsky, R. M., Kraemer, H. C. & Spiegel, D. Diurnal cortisol rhythm as a predictor of breast cancer survival. J. Natl Cancer Inst. 92, 994–1000 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Mormont, M. C. et al. Marked 24-h rest/activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status. Clin. Cancer Res. 6, 3038–3045 (2000).

    CAS  PubMed  Google Scholar 

  74. Wood, P. A. & Hrushesky, W. J. M. Circadian rhythms and cancer chemotherapy. Crit. Rev. Eukaryot. Gene Expr. 6, 299–343 (1996). Summary of chronotherapy for human cancer patients.

    Article  CAS  PubMed  Google Scholar 

  75. Bruguerolle, B. Chronopharmacokinetics: current status. Clin. Pharmacokinet. 35, 83–94 (1998).

    Article  CAS  PubMed  Google Scholar 

  76. Hori, K., Zhang, Q. H., Li, H. C., Saito, S. & Sato, Y. Timing of cancer chemotherapy based on circadian variations in tumour tissue blood flow. Int. J. Cancer. 65, 360–364 (1996).

    Article  CAS  PubMed  Google Scholar 

  77. Smaaland, R. et al. DNA sysnthesis in human bone marrow is circadian stage dependent. Blood 77, 2603–2611 (1991).

    Article  CAS  PubMed  Google Scholar 

  78. Bjarnason, G. A. & Jordan, R. Circadian variation of cell proliferation and cell cycle protein expression in man: clinical implications. Prog. Cell Cycle Res. 4,193–206 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Cooper, Z. K. & Schiff, A. Mitotic rhythm in human epidermis. Proc. Soc. Exp. Biol. Med. 39, 323–352 (1938).

    Article  Google Scholar 

  80. Buchi, K. N. et al. Circadian rhythm of cellular proliferation in the human rectal mucosa. Gastroenterol. 101, 410–415 (1991).

    Article  CAS  Google Scholar 

  81. Smaaland, R. Circadian rhythm of cell division. Prog. Cell Cycle Res. 2, 241–266 (1996).

    Article  CAS  PubMed  Google Scholar 

  82. Dublin, W. B., Gregg, R. O. & Broders, A. C. Mitosis in specimens removed during day and night from carcinoma of large intestine. Arch. Pathol. 30, 893–911 (1940).

    Google Scholar 

  83. Hrushesky, W. J. M., Lannin, D. & Haus, E. Evidence from an ontogenetic basis for circadian coordination of cancer proliferation. J. Natl Cancer Inst. 90, 1480–1484 (1998).

    Article  CAS  PubMed  Google Scholar 

  84. Izquierdo, J. N. Increased cell proliferation with persistence of circadian rhythms in hamster cheek pouch neoplasms. Cell Tissue Kinet. 10, 313–322 (1977).

    CAS  PubMed  Google Scholar 

  85. Echave Llanos, J. M. & Nash, R. E. Mitotic circadian rhythm in a fast-growing and a slow-growing hepatoma: mitotic rhythm in hepatomas. J. Natl Cancer Inst. 44, 581–584 (1970).

    CAS  PubMed  Google Scholar 

  86. Klevecz, R. R., Shymko, R. M., Blumenfeld, D. & Braly, P. S. Circadian gating of S phase in human ovarian cancer. Cancer Res. 47, 6267–6271 (1987).

    CAS  PubMed  Google Scholar 

  87. Klevecs, R. R. & Braley, P. S. Circadian and ultradian cytokinetic rhythms of spontaneous human cancer. Ann. NY Acad. Sci. 618, 257–276 (1991).

    Article  Google Scholar 

  88. Tahti, E. Studies of the effect of X-radiation on 24-hour variations in the mitotic activity in human malignant tumours. Acta Pathol. Microbiol. Scand. 117 (Suppl.), 1–61 (1956).

    Google Scholar 

  89. Smaaland, R., Lote, K., Sotteen, R. B. & Laerum, O. O. DNA synthesis and ploidy in non-Hodgkin's lymphomas demonstrate lntrapatient variation depending on circadian stage of cell sampling. Cancer Res. 53, 3129–3138 (1993).

    CAS  PubMed  Google Scholar 

  90. Granda, T. G. & Levi, F. Tumour-based rhythms of anticancer efficacy in experimental models. Chronobiol. Int. 19, 21–41 (2002). Summary of chronotherapy studies using animal models.

    Article  CAS  PubMed  Google Scholar 

  91. Haus, E. et al. Increased tolerance of leukemic mice to arabinosylcytosine with schedule-adjusted to circadian system. Science 177, 80–82 (1972).

    Article  CAS  PubMed  Google Scholar 

  92. Halberg, F. et al. Toward a chronotherapy of neoplasia: tolerance of treatment depends upon host rhythms. Experientia 29, 909–934 (1973).

    Article  CAS  PubMed  Google Scholar 

  93. Boughattas, N. et al. Circadian rhythm in toxicities and tissue uptake of 1. 2-diamminocyclohexane(trans-1)oxalatoplatinum (II) in mice. Cancer Res. 49, 3362–2268 (1989).

    CAS  PubMed  Google Scholar 

  94. Ohdo, S. et al. Cell cycle-dependent chronotoxicity of irinotecan hydrochloride in mice. J. Pharmacol. Exp. Ther. 283, 1383–1388 (1997).

    CAS  PubMed  Google Scholar 

  95. Focan, C. Pharmaco-economic comparative evaluation of combination chronotherapy vs. standard chemotherapy for colorectal cancer. Chronobiol. Int. 19, 289–297 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Rich, T. A., Shelton, C. H., Kirichenko, A. & Straume, M. Chronomodulated chemotherapy and irradiation: an idea whose time has come? Chronobiol. Int. 19, 191–205 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Mormont, M. C. et al. Marker rhythms of circadian system function: a study of patients with metastatic coloretal cancer and good performance status. Chronobiol. Int. 19, 141–155 (2002).

    Article  PubMed  Google Scholar 

  98. Rivard, G. C., Infante-Rivard, C., Dress, M. F., Leclerc, J. M. & Champagne, J. Circadian time-dependent response of childhood lymphoblastic leukemia to chemotherapy: a long-term follow-up study of survival. Chronobiol. Int. 10, 201–204 (1993).

    Article  CAS  PubMed  Google Scholar 

  99. Buijs, R. M. & Kalsbeek, A. Hypothalamic integration of central and peripheral clocks. Nature Rev. Nerosci. 2, 521–526 (2001).

    Article  CAS  Google Scholar 

  100. Costa, L. G. et al. Modulation of DNA synthesis by muscarinic cholinergic receptors. Growth Facors 18, 227–236 (2001).

    Article  CAS  Google Scholar 

  101. Jones, M. A. & Marfurt, C. F. Sympathetic stimulation of corneal epithelial proliferation in wounded and nonwounded rat eyes. Invest. Ophthalmol. Vis. Sci. 37, 2535–2547 (1996).

    CAS  PubMed  Google Scholar 

  102. Suzuki, S. et al. Circadian rhythm of leukocytes and lymphocyte subsets and its possible correlation with the function of autonomic nervous system. Clin. Exp. Immunol. 110, 500–508 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Okamoto, S, Ibaraki, K., Hayashi, S. & Saito, M. Ventromedial hypothalamus suppresses splenic lymphocyte activity through sympathetic innervation. Brain Res. 739, 308–313 (1996).

    Article  CAS  PubMed  Google Scholar 

  104. Maestroni, G. J. et al. Neural and endogenous catecholamines in bone marrow. Circadian association of norepinephrine with hematopoiesis? Exp. Hematol. 26, 1172–1177 (1998).

    CAS  PubMed  Google Scholar 

  105. Kiba, T. The role of the autonomic nervous system in liver regeneration and apoptosis — recent developments. Digestion 66, 79–88 (2002).

    Article  PubMed  Google Scholar 

  106. Lavoie, C. et al. β1/β2-adrenergic receptor heterodimerization regulates β2-adrenergic receptor internalization and ERK signaling efficacy. J. Biol. Chem. 277, 35402–35410 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Moverara, S., Lindberg, M. K., Faergemann, J., Gustafsson, J. A. & Ohlsson, C. Estrogen receptor alpha, but not estrogen recepotr beta, is involved in the regulation of the hair follicle cycling as well as the thickness of epidermis in male mice. J. Invest. Dermatol. 119, 1053–1058 (2002).

    Article  Google Scholar 

  108. Song, R. X. & Santen, R. J. Apoptotic action of estrogen. Apoptosis 8, 55–60 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Clarke, R., Dickson, R. B. & Lippman, M. E. Hormonal aspects of breast cancer. Crit. Rev. Oncol. Hematol. 12, 1–23 (1992).

    Article  CAS  PubMed  Google Scholar 

  110. Yamamoto, T. et al. Inhibition of murine osteosarcoma cell proliferation by glucocorticoid. Anticancer 22, 4151–4156 (2002).

    CAS  Google Scholar 

  111. Latta, K., Krieg, R. J., Carbajo-Perez, E., Carbajo, S. & Chan, J. C. Effects of deflazacort and cortisone on cellular proliferation in the rat thymus. Life Sci. 71, 1951–1960 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Abo, T. & Kawamura, T. Immunomodulation by the autonomic nervous system: therapeutic approach for cancer, collagen disease, and inflammatory bowel disease. Therap. Apheresis 6, 348–357 (2002).

    Article  Google Scholar 

  113. Haus, E. & Smolensky, M. H. Biologic rhythms in the immue system. Chronobiol. Int. 16, 581–622 (1999).

    Article  CAS  PubMed  Google Scholar 

  114. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumour escape. Nature Immunol. 3, 991–998 (2002).

    Article  CAS  Google Scholar 

  115. Roberts, J. E. Light and immunomodulation. Ann. NY Acad. Sci. 917, 435–445 (2000).

    Article  CAS  PubMed  Google Scholar 

  116. Ohdo, S., Koyanagi, S., Suyama, H., Higuchi, S. & Aramaki, H. Changing the dosing schedule minimizes the disruptive effects of interferon on clock function. Nature Med. 7, 356–360 (2001).

    Article  CAS  PubMed  Google Scholar 

  117. Miller, D. B. & O'Callaghan, J. P. Neuroendocrine aspects of the response to stress. Metabolism 51, 5–10 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Besedovsky, H., Rey, A. D., Sorkin, E. & Dinarello, C. A. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science 233, 652–654 (1986).

    Article  CAS  PubMed  Google Scholar 

  119. Bjarnason, G. A., Jordan, R. C. & Sothern, R. B. Circadian variation in the expression of cell-cycle proteins in human oral epithelium. Am. J. Pathol. 154, 613–622 (1999). Shows that the expression of cell-cycle regulators follows circadian oscillating patterns in normal human tissues.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Bjarnason, G. A. et al. Circadian expression of clock genes in human oral mucosa and skin: association with specific cell-cycle phases. Am. J. Pathol. 158, 1793–1801 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Gao, Z. H., Seeling, J. M., Hill, V., Yochum, A. & Virshup, D. M. Casein kinase I phosphorylates and destabilizes the beta-catenin degradation complex. Proc. Natl Acad. Sci. USA 99, 1182–1187 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lee, E., Salic, A. & Kirschner, M. W. Physiological regulation of β-catenin stability by Tcf3 and CK1epsilon. J. Cell Biol. 154, 983–993 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Schwarz-Romond, T. et al. The ankyrin repeat protein diversin recruits casein kinase I epsilon to the beta-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling. Genes Dev. 16, 2073–2084 (2002). Shows that the circadian regulator CKIε directly regulates the Wnt-signalling pathway by controlling β-catenin signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Van de Wetering, M., de Lau, W. & Clevers, H. Wnt signaling and lymphocyte development. Cell 109, S13–S19 (2002).

    Article  CAS  PubMed  Google Scholar 

  125. Morin, P. J. β-Catenin signaling and cancer. Bioessays 21, 1021–1030 (1999).

    Article  CAS  PubMed  Google Scholar 

  126. Crawford, H. C. et al. The PEA3 subfamily of Ets transcription factors synergizes with beta-catenin–LEF-1 to activate matrilysin transcription in intestinal tumours. Mol. Cell. Biol. 21, 1370–1383 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Mann, B. et al. Target genes of beta-catenin–T-cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas. Proc. Natl Acad. Sci. USA 96, 1603–1608 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Tetsu, O. & McCormick, F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422–426 (1999).

    Article  CAS  PubMed  Google Scholar 

  129. Ahmed, Y., Hayashi, S., Levine, A. & Wieschaus, E. Regulation of armadillo by a Drosophila APC inhibits neuronal apoptosis during retinal development. Cell 93, 1171–1182 (1998).

    Article  CAS  PubMed  Google Scholar 

  130. Gat, U., DasGupta, R., Degenstein, L. & Fuchs, E. De novo hair follicle morphogenesis and hair tumours in mice expressing a truncated beta-catenin in skin. Cell 95, 605–614 (1998).

    Article  CAS  PubMed  Google Scholar 

  131. 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 105, 769–779 (2001).

    Article  CAS  PubMed  Google Scholar 

  132. Pelengaris, S., Khan, M. & Evan, G. I. Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109, 321–334 (2002).

    Article  CAS  PubMed  Google Scholar 

  133. Breckenridge, D. C. & Shore, G. C. Regulation of apoptosis by E1A and Myc oncoproteins. Crit. Rev. Eukaryot. Gene Expr. 10, 273–280 (2000).

    Article  CAS  PubMed  Google Scholar 

  134. Blyth, K. et al. Synergy between a human c-myc transgene and p53 null genotype in murine thymic lymphomas: contrasting effects of homozygous and heterozygous p53 loss. Oncogene 10, 1717–1723 (1995).

    CAS  PubMed  Google Scholar 

  135. Elson, A., Deng, C., Campos-Torres, J., Donehower, L. A. & Leder, P. The MMTV/c-myc transgene and p53 null alleles collaborate to induce T-cell lymphomas, but not mammary carcinomas in transgenic mice. Oncogene 11, 181–190 (1995).

    CAS  PubMed  Google Scholar 

  136. Kawara, S. et al. Low-dose ultraviolet B rays alter the mRNA expression of the circadian clock genes in cultured human keratinocytes. J. Invest. Dermatol. 119, 1220–1223 (2002).

    Article  CAS  PubMed  Google Scholar 

  137. Sugano, S., Andronis, C., Green, R. M., Wang, Z. Y. & Tobin, E. M. Protein kinase CK2 interacts with and phosphorylates the Arabidopsis circadian clock-associated 1 protein. Proc. Natl Acad. Sci. USA 95, 11020–11025 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Sugano, S., Andronis, C., Ong, M. S., Green, R. M. & Tobin, E. M. The protein kinase CK2 is involved in regulation of circadian rhythms in Arabidopsis. Proc. Natl Acad. Sci. USA 96, 12362–12366 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Yang, Y., Cheng, P. & Liu, Y. Regulation of the Neurospora circadian clock by casein kinase II. Genes Dev. 16, 994–1006 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Lin, J. M. et al. A role for casein kinase 2alpha in the Drosophila circadian clock. Nature 420, 816–820 (2002). Shows that casein kinase 2 is involved in Drosophila circadian-clock control.

    Article  CAS  PubMed  Google Scholar 

  141. Pulverer, B. J. et al. Site-specific modulation of c-Myc cotransformation by residues phosphorylated in vivo. Oncogene 9, 59–70 (1994).

    CAS  PubMed  Google Scholar 

  142. Channavajhala, P. & Seldin, D. C. Functional interaction of protein kinase CK2 and c-Myc in lymphomagenesis. Oncogene 21, 5280–5288 (2002).

    Article  CAS  PubMed  Google Scholar 

  143. Landesman-Bollag, E. et al. Protein kinase CK2: signaling and tumourigenesis in the mammary gland. Mol. Cell. Biochem. 227, 153–165 (2001).

    Article  CAS  PubMed  Google Scholar 

  144. Keller, D. M. et al. A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1. Mol. Cell 7, 283–292 (2001).

    Article  CAS  PubMed  Google Scholar 

  145. Field, M. D. et al. Analysis of clock proteins in mouse SCN demonstrates phylogenetic divergence of the circadian clockwork and resetting mechanisms. Neuron 25, 437–447 (2000).

    Article  CAS  PubMed  Google Scholar 

  146. Shigeyoshi, Y. et al. Light-induced resetting of a mammalian circadian clock is associated with rapid induction of the mPer1 transcript. Cell 91, 1043–1053 (1997). Shows that light-induced Per1 expression is associated with phase resetting in the mammalian central clock.

    Article  CAS  PubMed  Google Scholar 

  147. Takeuchi, J., Shannon, W., Aronin, N. & Schwartz, W. J. Compositional changes of AP-1 DNA-binding proteins are regulated by light in a mammalian circadian clock. Neuron 11, 825–836 (1993).

    Article  CAS  PubMed  Google Scholar 

  148. Obrietan, K., Impey, S. & Storm, D. R. Light and circadian rhythmicity regulate MAP kinase activation in the suprachiasmatic nuclei. Nature Neurosci. 1, 693–700 (1998).

    Article  CAS  PubMed  Google Scholar 

  149. Ding, J. M., Faiman, L. E., Hurst, W. J., Kuriashkina, L. R. & Gillette, M. U. Resetting the biological clock: mediation of nocturnal CREB phosphorylation via light, glutamate, and nitric oxide. J. Neurosci. 17, 667–675 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Weber, E. T., Gannon, R. L., Michel, A. M., Gillette, M. U. & Rea, M. A. Nitric oxide synthase inhibitor blocks light-induced phase shifts of the circadian activity rhythm, but not c-fos expression in the suprachiasmatic nucleus of the Syrian hamster. Brain Res. 692, 137–142 (1995).

    Article  CAS  PubMed  Google Scholar 

  151. Ginty, D. D. et al. Regulation of CREB phosphorylation in the suprachiasmatic nucleus by light and a circadian clock. Science 260, 238–241 (1993).

    Article  CAS  PubMed  Google Scholar 

  152. Hurst, W. J., Mitchell, J. W. & Gillette, M. U. Synchronization and phase-resetting by glutamate of an immortalized SCN cell line. Biochem. Biophys. Res. Commun. 298, 133–143 (2002).

    Article  CAS  PubMed  Google Scholar 

  153. Balsalobre, A. et al. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 289, 2344–2347 (2000). Shows that the mammalian peripheral clocks are controlled by hormonal signals throughout the 24-hour period.

    Article  CAS  PubMed  Google Scholar 

  154. McNamara, P. et al. Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock. Cell 105, 877–889 (2001).

    Article  CAS  PubMed  Google Scholar 

  155. Yamamoto, K. R. Steroid receptor regulated transcription of specific genes and gene networks. Ann. Rev. Genet. 19, 209–252 (1985).

    Article  CAS  PubMed  Google Scholar 

  156. Hida, A. et al. The human and mouse Period1 genes: five well-conserved E-box additively contribute to the enhancement of mPer1 transcription. Genomics 65, 224–233 (2000).

    Article  CAS  PubMed  Google Scholar 

  157. Akashi, M. & Nishida, E. Involvement of the MAP kinase cascade in resetting of the mammalian circadian clock. Genes Dev. 14, 645–649 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Balsalobre, A., Marcacci, L. & Schibler, U. Multiple signaling pathways elicit circadian gene expression in cultured Rat-1 fibroblasts. Curr. Biol. 10, 1291–1294 (2000). References 157 and 158 show that mammalian peripheral clocks are regulated by multiple signalling pathways.

    Article  CAS  PubMed  Google Scholar 

  159. Williams, J. A., Su, H., Bernards, A., Field J. & Sehgal, A. A circadian ouput mediated by NF1 and the Ras/MAPK pathway. Science 293, 2251–2256 (2001).

    Article  CAS  PubMed  Google Scholar 

  160. Ko, G. Y.-P., Ko, M. L. & Dryer, S. E. Circadian regulation of cGMP-gated cationic channels of chick retinal cones: Erk MAP kinase and Ca2+/calmodulin–dependent protein kinase II. Neuron 29, 255–266 (2001).

    Article  CAS  PubMed  Google Scholar 

  161. Johnson, G. L. & Lapadat, R. Mitogene-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298, 1911–1912 (2002).

    Article  CAS  PubMed  Google Scholar 

  162. Stork, P. J. & Schmitt, J. M. Crosstalk between cAMP and MAP kinase signaling in regulation of cell proliferation. Trends Cell Biol. 12, 258–266 (2002).

    Article  CAS  PubMed  Google Scholar 

  163. Vaudry, D., Stork, P. J., Lazarovici, P. & Eiden, L. E. Signaling pathways for PC12 cell differentiation: making the right connections. Science 296, 1648–1649 (2002).

    Article  CAS  PubMed  Google Scholar 

  164. Neves, S. R., Ram, P. T. & Ivengar, R. G protein pathways. Science 296, 1636–1639 (2002).

    Article  CAS  PubMed  Google Scholar 

  165. Brunton, V. G. et al. The protrusive phase and full development of integrin-dependent adhesions in colon epithelial cells require FAK- and ERK-mediated actin spike formation: deregulation in cancer cells. Neoplasia 3, 215–226 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Fribourg, A. F., Knudsen, K. E., Strobeck, M. W., Lindhorst, C. M. & Knudsen, E. S. Differential requirements for Ras and the retinoblastoma tumour suppressor protein in the androgen dependence of prostatic adenocarcinoma cells. Cell Growth Differ. 11, 361–372 (2000).

    CAS  PubMed  Google Scholar 

  167. Aguirre Ghiso, J. A. et al. Deregulation of the signaling pathways controlling urokinase production. Its relationship with the invasive phenotype. Eur. J. Biochem. 263, 295–304 (1999).

    Article  CAS  PubMed  Google Scholar 

  168. De Bono, J. S. & Rowinsky, E. K. Therapeutics targeting signal transduction for patients with colorectal carcinoma. Br. Med. Bull. 64, 227–254 (2002).

    Article  CAS  PubMed  Google Scholar 

  169. Shaulian, E. & Karin, M. AP-1 as a regulator of cell life and death. Nature Cell Biol. 4, E131–E136 (2002).

    Article  CAS  PubMed  Google Scholar 

  170. Brown, J. R. et al. Fos family members induce cell cycle entry by activating cyclin D1. Mol. Cell. Biol. 18, 5609–5619 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Schreiber, M. et al. Control of cell cycle progression by c-Jun is p53 dependent. 13, 607–619 (1999).

  172. Shaulian, E. et al. The mammalian UV response: c-Jun induction is required for exit from p53-imposed growth arrest. Cell 103, 897–907 (2000).

    Article  CAS  PubMed  Google Scholar 

  173. Passegue, E. & Wagner, E. F. JunB suppresses cell proliferation by transcriptional activation of p16 (INK4a) expression. EMBO J. 19, 2969–2979 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Honrado, G. I. et al. The circadian system of c-fos deficient mice. J. Comp. Physiol. 178, 563–570 (1996).

    Article  CAS  Google Scholar 

  175. Wang, J. et al. Retinoid-induced G1 arrest and differentiation activation are associated with a switch to cyclin-dependent kinase-activating kinase hypophosphorylation of retinoic acid receptor alpha. J. Biol. Chem. 277, 43369–43376 (2002).

    Article  CAS  PubMed  Google Scholar 

  176. Toyota, M. et al. Peroxisome proliferator-activated receptor gamma reduces the growth rate of pancreatic cancer cells through the reduction of cyclin D1. Life Sci. 70, 1565–1575 (2002).

    Article  CAS  PubMed  Google Scholar 

  177. Spinella, M. J. et al. Retinoic acid promotes ubiquitination and proteolysis of cyclin D1 during induced tumour cell differentiation. J. Biol. Chem. 274, 22013–2208 (1999).

    Article  CAS  PubMed  Google Scholar 

  178. Lin, R. J., Sternsdrof, T., Tini, M. & Evans, R, M. Transcriptional regulation in acute promyelocytic leukemia. Oncogene 20, 7204–7215 (2001).

    Article  CAS  PubMed  Google Scholar 

  179. Ayroldi, E. et al. Glucocorticoid-induced leucine zipper inhibits the Raf-extracellular signal-regulated kinase pathway by binding to Raf-1. Mol. Cell. Biol. 22, 7929–7941 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Herrlich, P. Cross-talk between glucocorticoid receptor and AP-1. Oncogene 20, 2465–2475 (2001).

    Article  CAS  PubMed  Google Scholar 

  181. Liu, J. L., Papachristor, D. N. & Patel, Y. C. Glucocorticoids activate somatostatin gene transcription through co-operative interaction with the cyclic AMP signaling pathway. Biochem. J. 301, 863–869 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Qiu, J. et al. Rapid activation of ERK1/2 mitogen-activated protein kinase by corticosterone in PC12 cells. Biochem. Biophys. Res. Commun. 287, 1017–1021 (2001).

    Article  CAS  PubMed  Google Scholar 

  183. Rider, L. G., Hirasawa, N., Santini, F. & Beaven, M. A. Activation of the mitogen-activated protein kinase cascade is suppressed by low concentrations of dexamethasone in mast cells. J. Immunol. 157, 2374–2380 (1996).

    CAS  PubMed  Google Scholar 

  184. Gonzalez, M. V. et al. Glucocorticoids antagonize AP-1 by inhibiting the activation/phosphorylation of JNK without affecting its subcellular distribution. J. Cell Biol. 150, 1199–1208 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Cidlowski, J. A. et al. The biochemistry and molecular biology of glucocorticoid-induced apoptosis in the immune system. Recent Prog. Horm. Res. 51, 457–490 (1996).

    CAS  PubMed  Google Scholar 

  186. Eastman-Reks, S. B. & Vedeckis, W. V. Glucocorticoid inhibition of c-Myc, c-Myb and c-Ki-ras expression in a mouse lymphoma cell line. Cancer Res. 46, 2457–2462 (1986).

    CAS  PubMed  Google Scholar 

  187. Rhee, K., Bresnahan, W., Hirai, A., Hirai, M. & Thompson, E. A. c-Myc and cyclin D3 (CcnD3) genes are independent targets for glucocorticoid inhibition of lymphoid cell proliferation. Cancer Res. 55, 4188–4195 (1995).

    CAS  PubMed  Google Scholar 

  188. Silver, R. et al. A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomoter rhythms. Nature 382, 810–813 (1996).

    Article  CAS  PubMed  Google Scholar 

  189. Lehman, M. N. et al. Circadian rhythmicity restored by neural transplant. Immunocytochemical characterization of the graft and its integration with host brain. J. Neurosci. 7, 1626–1638 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Meyer-Bernstein, E. L. et al. Effects of supreachiasmatic transplants on circadian rhythms of neuroendocrine function in golden hamsters. Endocrinology 140, 207–218 (1999).

    Article  CAS  PubMed  Google Scholar 

  191. Van Esseveldt, K. E., Lehman, M. N. & Boer, G. J. The supreachiasmatic nucleus and the circadian time-keeping stsem revisited. Brain Res. Brain Res. Rev. 33, 34–77 (2000).

    Article  CAS  PubMed  Google Scholar 

  192. Kalsbeek, A., Buijs, R. M., Van Heerikhuize, J. J., Arts, M. & Van Der Woude, T. P. Vasopressin-containing neurons of the supreachiasmatic nuclei inhibit corticosterone release. Brain Res. 580, 62–67 (1992).

    Article  CAS  PubMed  Google Scholar 

  193. Preitner, N. et al. The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110, 251–260 (2002).

    Article  CAS  PubMed  Google Scholar 

  194. Etchegaray, J., Lee, C., Wade, P. & Reppert, S. M. Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421, 177–182 (2002).

    Article  PubMed  CAS  Google Scholar 

  195. Moore–Ede, M., Sulzman, F. & Fuller, C. The Clocks That Time Us: Physiology of Circadian Timing System 448 (Harvard Univ. Press, Cambridge, Massachusetts, 1982).

    Google Scholar 

  196. Liu, C. et al. Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron 19, 91–102 (1997).

    Article  CAS  PubMed  Google Scholar 

  197. Toh, K. L. et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291, 1040–1043 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, 77030, Texas, USA

    Loning Fu & Cheng Chi Lee

Authors
  1. Loning Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cheng Chi Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cheng Chi Lee.

Related links

Related links

DATABASES

Cancer.gov

acute lymphoblastic leukaemia

breast cancer

colorectal cancer

osteosarcoma

pancreatic cancer

LocusLink

β-catenin

Bcl-xL

Bmal1

Ccna1

Ccna2

Ccnd1

CKIε

Cry1

Cry2

cyclin D3

Fos

Fra1

Gadd45α

Gsk3β

Jun

JunB

MAPK

Mdm2

Myc

Per1

Per2

Per3

PKC

Ras

Trp53

FURTHER INFORMATION

A time to heal – chronotherapy tunes in to body's rhythms

Biological clocks

Biotiming tutorial

From circadian rhythm to cancer therapy

Glossary

SUPRACHIASMATIC NUCLEI

(SCN). The mammalian master circadian clock. The SCN are small bilateral structures located next to the third ventricle and just above the optic chiasm in mammalian brain. Each SCN nucleus contains about 10,000 neurons that are synchronized to generate coordinated circadian outputs in vivo.

PHASE SHIFT

The displacement of waveform in time. When a waveform is displaced by a complete wavelength, it is described as having a phase shift of 360 degrees. When a waveform is displaced by a half a wavelength, it is described as having a phase shift of 180 degrees.

MELANOPSIN-EXPRESSING RETINAL GANGLION CELLS

A small subset of retinal ganglion cells that are intrinsically photosensitive and express the opsin-like protein melanopsin. These neurons project directly to the suprachiasmatic nucleus of the mammalian central circadian clock, as well as to the intergeniculate leaflet and the olivary pretectal nucleus in the brain. Mice that are deficient in melanopsin show attenuated responses to light stimuli.

PINEALECTOMY

Ablation of the pineal gland. The pineal gland is a cone-shape gland that is located at the posterior end of the third ventricle in the brain. The pineal gland produces melatonin, a hormone that is important for regulating circadian rhythmicity in humans. The level of melatonin rises at night and falls during the day.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fu, L., Lee, C. The circadian clock: pacemaker and tumour suppressor. Nat Rev Cancer 3, 350–361 (2003). https://doi.org/10.1038/nrc1072

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1072

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing