Abstract
By screening N-ethyl-N-nitrosourea-mutagenized animals for alterations in rhythms of wheel-running activity, we identified a mouse mutation, after hours (Afh). The mutation, a Cys(358)Ser substitution in Fbxl3, an F-box protein with leucine-rich repeats, results in long free-running rhythms of about 27 hours in homozygotes. Circadian transcriptional and translational oscillations are attenuated in Afh mice. The Afh allele significantly affected Per2 expression and delayed the rate of Cry protein degradation in Per2::Luciferase tissue slices. Our in vivo and in vitro studies reveal a central role for Fbxl3 in mammalian circadian timekeeping.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ARNTL Transcription Factors
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Amino Acid Sequence
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Amino Acid Substitution
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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CLOCK Proteins
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COS Cells
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Chlorocebus aethiops
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Circadian Rhythm* / genetics
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Crosses, Genetic
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Cryptochromes
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F-Box Proteins / genetics*
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F-Box Proteins / physiology*
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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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Liver / metabolism
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Lung / metabolism
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C3H
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Molecular Sequence Data
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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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Point Mutation*
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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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F-Box Proteins
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Fbxl3 protein, mouse
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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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Trans-Activators
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Transcription Factors
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CLOCK Proteins
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Clock protein, mouse