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Gene Review

CLOCK  -  clock circadian regulator

Homo sapiens

Synonyms: BHLHE8, Circadian locomoter output cycles protein kaput, Class E basic helix-loop-helix protein 8, KAT13D, KIAA0334, ...
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Disease relevance of CLOCK

  • With the role of Clock and Bmal1 in fertility becoming clearer, it may be time to pursue the effect of polymorphisms in these genes in relation to the various types of infertility in humans [1].
  • The number of oxygen desaturation episodes exceeding 4% associated with defective delayed Recall of Logical Stories of the Wechsler Memory Scale and with spatial orientation (Clock test) in the habitual snorers' group even after adjusting for age and obesity [2].
  • Lack of association between the 3092 T-->C Clock gene polymorphism and cluster headache [3].
  • One hundred and seven CH patients, diagnosed according to the International Classification of Headache Disorders, 2nd Edition, (ICHD-II) criteria, and 210 healthy age, sex and ethnicity-matched controls were genotyped for the 3092 T-->C Clock gene polymorphism (also known as 3111 T-->C) [3].
  • These results do not support Clock 3111C as a marker for diurnal preference, tau, or delayed sleep phase syndrome in humans [4].

Psychiatry related information on CLOCK


High impact information on CLOCK


Biological context of CLOCK

  • A recent report established a genetic linkage between narcolepsy and the chromosomal region 4p13-q21 that contains the Clock gene [5].
  • We found in the 90% of gestation capuchin monkey fetus expression of the clock genes Bmal-1, Per-2, Cry-2, and Clock in the SCN, adrenal, pituitary, brown fat, and pineal [15].
  • Hypothalamic circadian organization in birds. II. Clock gene expression [16].
  • Furthermore, a study examining the association between Clock gene polymorphisms and insomnia revealed a higher recurrence of initial, middle, and terminal insomnia in patients homozygous for the Clock genotype [17].
  • Here we describe the cloning, sequence, and expression of the circadian Clock and MOP3 cDNAs of the Spalax ehrenbergi superspecies in Israel. Both genes are relatively conserved, although characterized by a significant number of amino acid substitutions [14].

Anatomical context of CLOCK

  • In this study, we indicate the daily expression of clock genes period (Per) 1, 2, 3, Bmal1, and Clock in whole blood cells in 12 healthy male subjects [18].
  • In this article, we develop a mathematical formulation of a new version of the Clock and Wavefront model proposed by Pourquié and co-workers (Dubrulle, J., McGrew, M.J., Pourquié, O., 2001. FGF signalling controls somite boundary position and regulates segmentation clock control of spatiotemporal Hox gene activation. Cell 106, 219-232) [19].
  • Using immunochemistry and biochemical subcellular fractionation, we have shown that Clock localizes to the Z-disk of the myofilaments [20].
  • In this study, we determined some of the factors that regulate Clock expression and subcellular distribution in myocytes [20].
  • The circadian protein Clock localizes to the sarcomeric Z-disk and is a sensor of myofilament cross-bridge activity in cardiac myocytes [20].

Associations of CLOCK with chemical compounds

  • The endogenous circadian machinery involves positive and negative transcriptional feedback loops implicating different genes (particularly period (Per) 1-3, Clock, Bmal1, cryptochrome (Cry) 1-2) [21].
  • In mammals the PAS transcription factors Clock, NPAS2, and BMAL1 regulate gene expression as a function of the day-night cycle [22].
  • Nevertheless, the SCN of Clock(Delta19) + MEL mutant mice cannot maintain liver and muscle rhythmicity through rhythmic outputs, including melatonin secretion, in the absence of functional Clock expression in the tissues [23].
  • We suggest that this reduction in transcriptional activity may be attributed to the Spalax Clock glutamine-rich domain, which is unique in its amino acid composition compared with other studied mammalian species [14].
  • Improved Tumor Control through Circadian Clock Induction by Seliciclib, a Cyclin-Dependent Kinase Inhibitor [24].

Physical interactions of CLOCK

  • Here we report that age alters the 24-h expression profile of Clock and its binding partner Bmal1 in the hamster SCN [25].

Other interactions of CLOCK

  • However, despite multiple putative E-boxes in the MT(1) promoter, transfected Clock and Bmal1 were unable to regulate either basal or Pitx-1-stimulated MT(1) promoter activity [26].
  • Other evidence derives from the relationship of circadian genes, NPAS2 and Clock, to metabolism [27].
  • GIGANTEA Acts in Blue Light Signaling and Has Biochemically Separable Roles in Circadian Clock and Flowering Time Regulation [28].
  • Effects of venlafaxine, an antidepressant acting by selective serotonin and norepinephrine reuptake inhibition with a potency ratio of 5:1, were assessed in a standardized, actual driving test, a battery of psychomotor tests (Critical Flicker/Fusion Frequency, Critical Tracking, Divided Attention), and a 45-minute vigilance test (Mackworth Clock) [29].
  • We compared the expression of period and Clock genes in the head of the linden bug, Pyrrhocoris apterus, kept under diapause promoting short days (SD) and diapause-preventing long days (LD), using an RNase protection assay [30].

Analytical, diagnostic and therapeutic context of CLOCK


  1. Circadian rhythms and reproduction. Boden, M.J., Kennaway, D.J. Reproduction (2006) [Pubmed]
  2. Cognitive function in middle-aged snorers and controls: role of excessive daytime somnolence and sleep-related hypoxic events. Telakivi, T., Kajaste, S., Partinen, M., Koskenvuo, M., Salmi, T., Kaprio, J. Sleep. (1988) [Pubmed]
  3. Lack of association between the 3092 T-->C Clock gene polymorphism and cluster headache. Rainero, I., Rivoiro, C., Gallone, S., Valfrè, W., Ferrero, M., Angilella, G., Rubino, E., De Martino, P., Savi, L., Lo Giudice, R., Pinessi, L. Cephalalgia : an international journal of headache. (2005) [Pubmed]
  4. The 3111 Clock gene polymorphism is not associated with sleep and circadian rhythmicity in phenotypically characterized human subjects. Robilliard, D.L., Archer, S.N., Arendt, J., Lockley, S.W., Hack, L.M., English, J., Leger, D., Smits, M.G., Williams, A., Skene, D.J., Von Schantz, M. Journal of sleep research. (2002) [Pubmed]
  5. Clock gene polymorphisms and narcolepsy in positive and negative HLA-DQB1*0602 patients. Moreira, F., Pedrazzoli, M., Dos Santos Coelho, F.M., Pradella-Hallinan, M., Lopes da Conceição, M.C., Pereira Peregrino, A.J., de Oliveira, E.C., Tufik, S. Brain Res. Mol. Brain Res. (2005) [Pubmed]
  6. Mutation screening of the human Clock gene in circadian rhythm sleep disorders. Iwase, T., Kajimura, N., Uchiyama, M., Ebisawa, T., Yoshimura, K., Kamei, Y., Shibui, K., Kim, K., Kudo, Y., Katoh, M., Watanabe, T., Nakajima, T., Ozeki, Y., Sugishita, M., Hori, T., Ikeda, M., Toyoshima, R., Inoue, Y., Yamada, N., Mishima, K., Nomura, M., Ozaki, N., Okawa, M., Takahashi, K., Yamauchi, T. Psychiatry research. (2002) [Pubmed]
  7. Patterns of cognitive decline in presymptomatic Alzheimer disease: a prospective community study. Chen, P., Ratcliff, G., Belle, S.H., Cauley, J.A., DeKosky, S.T., Ganguli, M. Arch. Gen. Psychiatry (2001) [Pubmed]
  8. The clock drawing test is a poor screen for very mild dementia. Powlishta, K.K., Von Dras, D.D., Stanford, A., Carr, D.B., Tsering, C., Miller, J.P., Morris, J.C. Neurology (2002) [Pubmed]
  9. Development of scoring criteria for the clock drawing task in Alzheimer's disease. Mendez, M.F., Ala, T., Underwood, K.L. Journal of the American Geriatrics Society. (1992) [Pubmed]
  10. A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock. Jin, X., Shearman, L.P., Weaver, D.R., Zylka, M.J., de Vries, G.J., Reppert, S.M. Cell (1999) [Pubmed]
  11. Dec1 and Dec2 are regulators of the mammalian molecular clock. Honma, S., Kawamoto, T., Takagi, Y., Fujimoto, K., Sato, F., Noshiro, M., Kato, Y., Honma, K. Nature (2002) [Pubmed]
  12. Time for chronotherapy? Clock genes dictate sensitivity to cyclophosphamide. Green, C.B. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  13. Toward a detailed computational model for the mammalian circadian clock. Leloup, J.C., Goldbeter, A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  14. Biological clock in total darkness: the Clock/MOP3 circadian system of the blind subterranean mole rat. Avivi, A., Albrecht, U., Oster, H., Joel, A., Beiles, A., Nevo, E. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  15. Maternal melatonin effects on clock gene expression in a nonhuman primate fetus. Torres-Farfan, C., Rocco, V., Monsó, C., Valenzuela, F.J., Campino, C., Germain, A., Torrealba, F., Valenzuela, G.J., Seron-Ferre, M. Endocrinology (2006) [Pubmed]
  16. Hypothalamic circadian organization in birds. II. Clock gene expression. Abraham, U., Albrecht, U., Brandstätter, R. Chronobiol. Int. (2003) [Pubmed]
  17. Genetics of the sleep-wake cycle and its disorders. Hamet, P., Tremblay, J. Metab. Clin. Exp. (2006) [Pubmed]
  18. Daily expression of clock genes in whole blood cells in healthy subjects and a patient with circadian rhythm sleep disorder. Takimoto, M., Hamada, A., Tomoda, A., Ohdo, S., Ohmura, T., Sakato, H., Kawatani, J., Jodoi, T., Nakagawa, H., Terazono, H., Koyanagi, S., Higuchi, S., Kimura, M., Tukikawa, H., Irie, S., Saito, H., Miike, T. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2005) [Pubmed]
  19. A clock and wavefront mechanism for somite formation. Baker, R.E., Schnell, S., Maini, P.K. Dev. Biol. (2006) [Pubmed]
  20. The circadian protein Clock localizes to the sarcomeric Z-disk and is a sensor of myofilament cross-bridge activity in cardiac myocytes. Qi, L., Boateng, S.Y. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  21. Melatonin affects nuclear orphan receptors mRNA in the rat suprachiasmatic nuclei. Agez, L., Laurent, V., P??vet, P., Masson-P??vet, M., Gauer, F. Neuroscience (2007) [Pubmed]
  22. Light pulse-induced heme and iron-associated transcripts in mouse brain: a microarray analysis. Ben-Shlomo, R., Akhtar, R.A., Collins, B.H., Judah, D.J., Davies, R., Kyriacou, C.P. Chronobiol. Int. (2005) [Pubmed]
  23. Functional central rhythmicity and light entrainment, but not liver and muscle rhythmicity, are Clock independent. Kennaway, D.J., Owens, J.A., Voultsios, A., Varcoe, T.J. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2006) [Pubmed]
  24. Improved Tumor Control through Circadian Clock Induction by Seliciclib, a Cyclin-Dependent Kinase Inhibitor. Iurisci, I., Filipski, E., Reinhardt, J., Bach, S., Gianella-Borradori, A., Iacobelli, S., Meijer, L., L??vi, F. Cancer Res. (2006) [Pubmed]
  25. Aging alters circadian and light-induced expression of clock genes in golden hamsters. Kolker, D.E., Fukuyama, H., Huang, D.S., Takahashi, J.S., Horton, T.H., Turek, F.W. J. Biol. Rhythms (2003) [Pubmed]
  26. Regulation of the ovine MT(1) melatonin receptor promoter: Interaction between multiple pituitary transcription factors at different phases of development. Johnston, J.D., Schuster, C., Barrett, P., Hazlerigg, D.G. Mol. Cell. Endocrinol. (2007) [Pubmed]
  27. Sleep: a functional enigma. Greene, R., Siegel, J. Neuromolecular Med. (2004) [Pubmed]
  28. GIGANTEA Acts in Blue Light Signaling and Has Biochemically Separable Roles in Circadian Clock and Flowering Time Regulation. Martin-Tryon, E.L., Kreps, J.A., Harmer, S.L. Plant Physiol. (2007) [Pubmed]
  29. Venlafaxine's effects on healthy volunteers' driving, psychomotor, and vigilance performance during 15-day fixed and incremental dosing regimens. O'Hanlon, J.F., Robbe, H.W., Vermeeren, A., van Leeuwen, C., Danjou, P.E. Journal of clinical psychopharmacology. (1998) [Pubmed]
  30. Photoperiodic regulation of diapause in linden bugs: are period and Clock genes involved? Syrová, Z., Dolezel, D., Saumann, I., Hodková, M. Cell. Mol. Life Sci. (2003) [Pubmed]
  31. Genetic studies in the sleep disorder narcolepsy. Kadotani, H., Faraco, J., Mignot, E. Genome Res. (1998) [Pubmed]
  32. A 7 minute neurocognitive screening battery highly sensitive to Alzheimer's disease. Solomon, P.R., Hirschoff, A., Kelly, B., Relin, M., Brush, M., DeVeaux, R.D., Pendlebury, W.W. Arch. Neurol. (1998) [Pubmed]
  33. Genomic organization of the rat Clock gene and sequence analysis in inbred rat strains. Woon, P.Y., Curtis, A.M., Kaisaki, P.J., Argoud, K., Wallace, K.J., Bihoreau, M.T., FitzGerald, G.A., Gauguier, D. Genomics (2006) [Pubmed]
  34. The Clock Test: a sensitive measure to differentiate normal elderly from those with Alzheimer disease. Tuokko, H., Hadjistavropoulos, T., Miller, J.A., Beattie, B.L. Journal of the American Geriatrics Society. (1992) [Pubmed]
  35. The effects of hormone replacement therapy, lipoprotein cholesterol levels, and other factors on a clock drawing task in older women. Paganini-Hill, A., Henderson, V.W. Journal of the American Geriatrics Society. (1996) [Pubmed]
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