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      Role of the CLOCK protein in the mammalian circadian mechanism.

      Science (New York, N.Y.)

      Transcriptional Activation, ARNTL Transcription Factors, Animals, Basic Helix-Loop-Helix Transcription Factors, Biological Clocks, CLOCK Proteins, Cell Cycle Proteins, Circadian Rhythm, genetics, physiology, Cloning, Molecular, Cricetinae, DNA, metabolism, Dimerization, Feedback, Gene Expression, Helix-Loop-Helix Motifs, Male, Mesocricetus, Mice, Mutation, Nuclear Proteins, Period Circadian Proteins, Promoter Regions, Genetic, Retina, Suprachiasmatic Nucleus, Trans-Activators, Transcription Factors

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          Abstract

          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.

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          9616112

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