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Science 5 June 1998:
Vol. 280. no. 5369, pp. 1564 - 1569
DOI: 10.1126/science.280.5369.1564
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Research Articles

Role of the CLOCK Protein in the Mammalian Circadian Mechanism

Nicholas Gekakis, * David Staknis, * Hubert B. Nguyen, Fred C. Davis, Lisa D. Wilsbacher, David P. King, Joseph S. Takahashi, Charles J. Weitz dagger

The mouse Clock gene encodes a bHLH-PAS protein that regulates circadian rhythms and is related to transcription factors that act as heterodimers. Potential partners of CLOCK were isolated in a two-hybrid screen, and one, BMAL1, was coexpressed with CLOCK and PER1 at known circadian clock sites in brain and retina. CLOCK-BMAL1 heterodimers activated transcription from E-box elements, a type of transcription factor-binding site, found adjacent to the mouse per1 gene and from an identical E-box known to be important for per gene expression in Drosophila. Mutant CLOCK from the dominant-negative Clock allele and BMAL1 formed heterodimers that bound DNA but failed to activate transcription. Thus, CLOCK-BMAL1 heterodimers appear to drive the positive component of per transcriptional oscillations, which are thought to underlie circadian rhythmicity.

N. Gekakis, D. Staknis, H. B. Nguyen, C. J. Weitz, Department of Neurobiology, Harvard Medical School, Boston MA 02115, USA.
F. C. Davis, Department of Biology, Northeastern University, Boston MA 02115, USA.
L. D. Wilsbacher, D. P. King, J. S. Takahashi, Department of Neurobiology and Physiology, Howard Hughes Medical Institute and National Science Foundation Center for Biological Timing, Northwestern University, Evanston, IL 60208, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed.

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Inferring combinatorial regulation of transcription in silico.
N. Blüthgen, S. M. Kielbasa, and H. Herzel (2005)
Nucleic Acids Res. 33, 272-279
   Abstract »    Full Text »    PDF »
The role of circadian rhythmicity in reproduction.
D. J. Kennaway (2005)
Hum. Reprod. Update 11, 91-101
   Abstract »    Full Text »    PDF »
The orphan receptor Rev-erb{alpha} gene is a target of the circadian clock pacemaker.
G. Triqueneaux, S. Thenot, T. Kakizawa, M. P Antoch, R. Safi, J. S Takahashi, F. Delaunay, and V. Laudet (2004)
J. Mol. Endocrinol. 33, 585-608
   Abstract »    Full Text »    PDF »
24-Hour Oscillation of Mouse Methionine Aminopeptidase2, a Regulator of Tumor Progression, Is Regulated by Clock Gene Proteins.
H. Nakagawa, S. Koyanagi, T. Takiguchi, Y. Kuramoto, S. Soeda, H. Shimeno, S. Higuchi, and S. Ohdo (2004)
Cancer Res. 64, 8328-8333
   Abstract »    Full Text »    PDF »
Finding New Clock Components: Past and Future.
J. S. Takahashi (2004)
J Biol Rhythms 19, 339-347
   Abstract »    PDF »
Transcription Regulation within the Circadian Clock: The E-box and Beyond.
P. E. Hardin (2004)
J Biol Rhythms 19, 348-360
   Abstract »    PDF »
Effect of feeding on peripheral circadian rhythms and behaviour in mammals.
H. Kobayashi, K. Oishi, S. Hanai, and N. Ishida (2004)
Genes Cells 9, 857-864
   Abstract »    Full Text »    PDF »
Serine phosphorylation of mCRY1 and mCRY2 by mitogen-activated protein kinase.
K. Sanada, Y. Harada, M. Sakai, T. Todo, and Y. Fukada (2004)
Genes Cells 9, 697-708
   Abstract »    Full Text »    PDF »
Circadian and Light-Induced Transcription of Clock Gene Per1 Depends on Histone Acetylation and Deacetylation.
Y. Naruse, K. Oh-hashi, N. Iijima, M. Naruse, H. Yoshioka, and M. Tanaka (2004)
Mol. Cell. Biol. 24, 6278-6287
   Abstract »    Full Text »    PDF »
Inaugural Article: Biography of Joseph S. Takahashi.
M. Marino (2004)
PNAS 101, 5336-5338
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Gene discovery in genetically labeled single dopaminergic neurons of the retina.
S. Gustincich, M. Contini, M. Gariboldi, M. Puopolo, K. Kadota, H. Bono, J. LeMieux, P. Walsh, P. Carninci, Y. Hayashizaki, et al. (2004)
PNAS 101, 5069-5074
   Abstract »    Full Text »    PDF »
Retinal Circadian Clocks and Control of Retinal Physiology.
C. B. Green and J. C. Besharse (2004)
J Biol Rhythms 19, 91-102
   Abstract »    PDF »


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