Abstract
We show that, in the mouse, the core mechanism for the master circadian clock consists of interacting positive and negative transcription and translation feedback loops. Analysis of Clock/Clock mutant mice, homozygous Period2(Brdm1) mutants, and Cryptochrome-deficient mice reveals substantially altered Bmal1 rhythms, consistent with a dominant role of PERIOD2 in the positive regulation of the Bmal1 loop. In vitro analysis of CRYPTOCHROME inhibition of CLOCK: BMAL1-mediated transcription shows that the inhibition is through direct protein:protein interactions, independent of the PERIOD and TIMELESS proteins. PERIOD2 is a positive regulator of the Bmal1 loop, and CRYPTOCHROMES are the negative regulators of the Period and Cryptochrome cycles.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ARNTL Transcription Factors
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Animals
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Basic Helix-Loop-Helix Transcription Factors
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Biological Clocks / genetics
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Biological Clocks / physiology*
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CLOCK Proteins
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Cell Cycle Proteins
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Cell Line
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Cell Nucleus / metabolism
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Circadian Rhythm / genetics
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Circadian Rhythm / physiology*
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Cryptochromes
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Dimerization
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Drosophila Proteins*
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Eye Proteins*
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Feedback
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Female
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Flavoproteins / genetics
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Flavoproteins / metabolism*
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Gene Expression Regulation
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In Situ Hybridization
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Models, Biological
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Mutation
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Period Circadian Proteins
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Photoreceptor Cells, Invertebrate*
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Protein Biosynthesis
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RNA / metabolism
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Receptors, G-Protein-Coupled
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Suprachiasmatic Nucleus / metabolism*
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
Substances
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ARNTL Transcription Factors
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Bmal1 protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
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Cell Cycle Proteins
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Cryptochromes
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Drosophila Proteins
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Eye Proteins
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Flavoproteins
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Nuclear Proteins
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Per1 protein, mouse
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Per2 protein, mouse
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Period Circadian Proteins
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Receptors, G-Protein-Coupled
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Trans-Activators
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Transcription Factors
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cry protein, Drosophila
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RNA
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CLOCK Proteins
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Clock protein, mouse