Role of the CLOCK Protein in the Mammalian Circadian Mechanism

DOI Web Site 155 Citations
  • Nicholas Gekakis
    N. Gekakis, D. Staknis, H. B. Nguyen, C. J. Weitz, Department of Neurobiology, Harvard Medical School, Boston MA 02115, USA.
  • David Staknis
    N. Gekakis, D. Staknis, H. B. Nguyen, C. J. Weitz, Department of Neurobiology, Harvard Medical School, Boston MA 02115, USA.
  • Hubert B. Nguyen
    N. Gekakis, D. Staknis, H. B. Nguyen, C. J. Weitz, Department of Neurobiology, Harvard Medical School, Boston MA 02115, USA.
  • Fred C. Davis
    N. Gekakis, D. Staknis, H. B. Nguyen, C. J. Weitz, Department of Neurobiology, Harvard Medical School, Boston MA 02115, USA.
  • Lisa D. Wilsbacher
    N. Gekakis, D. Staknis, H. B. Nguyen, C. J. Weitz, Department of Neurobiology, Harvard Medical School, Boston MA 02115, USA.
  • David P. King
    N. Gekakis, D. Staknis, H. B. Nguyen, C. J. Weitz, Department of Neurobiology, Harvard Medical School, Boston MA 02115, USA.
  • Joseph S. Takahashi
    N. Gekakis, D. Staknis, H. B. Nguyen, C. J. Weitz, Department of Neurobiology, Harvard Medical School, Boston MA 02115, USA.
  • Charles J. Weitz
    N. Gekakis, D. Staknis, H. B. Nguyen, C. J. Weitz, Department of Neurobiology, Harvard Medical School, Boston MA 02115, USA.

Abstract

<jats:p> The mouse <jats:italic>Clock</jats:italic> 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 <jats:italic>per1</jats:italic> gene and from an identical E-box known to be important for <jats:italic>per</jats:italic> gene expression in <jats:italic>Drosophila.</jats:italic> Mutant CLOCK from the dominant-negative <jats:italic>Clock</jats:italic> allele and BMAL1 formed heterodimers that bound DNA but failed to activate transcription. Thus, CLOCK-BMAL1 heterodimers appear to drive the positive component of <jats:italic>per</jats:italic> transcriptional oscillations, which are thought to underlie circadian rhythmicity. </jats:p>

Journal

  • Science

    Science 280 (5369), 1564-1569, 1998-06-05

    American Association for the Advancement of Science (AAAS)

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