Abstract
One component of the circadian clock in mammals is the Clock-Bmal1 heterodimeric transcription factor. Among its downstream targets, two genes, Cry1 and Cry2, encode inhibitors of the Clock-Bmal1 complex that establish a negative-feedback loop. We found that both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex. This regulation by SCF(Fbxl3) is a prerequisite for the efficient and timely reactivation of Clock-Bmal1 and the consequent expression of Per1 and Per2, two regulators of the circadian clock that display tumor suppressor activity. Silencing of Fbxl3 produced no effect in Cry1-/-;Cry2-/- cells, which shows that Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins.
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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Animals
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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CLOCK Proteins
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cells, Cultured
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Circadian Rhythm* / genetics
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Cryptochromes
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F-Box Proteins / genetics
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F-Box Proteins / metabolism*
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Flavoproteins / genetics
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Flavoproteins / metabolism*
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HeLa Cells
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Humans
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Mice
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NIH 3T3 Cells
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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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Promoter Regions, Genetic
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RNA Interference
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SKP Cullin F-Box Protein Ligases / metabolism*
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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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Transfection
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Ubiquitin / metabolism
Substances
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ARNTL Transcription Factors
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BMAL1 protein, human
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Bmal1 protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
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CRY1 protein, human
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CRY2 protein, human
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Cell Cycle Proteins
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Cry1 protein, mouse
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Cry2 protein, mouse
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Cryptochromes
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F-Box Proteins
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FBXL3 protein, human
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Fbxl3 protein, mouse
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Flavoproteins
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Nuclear Proteins
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PER1 protein, human
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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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Ubiquitin
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CLOCK Proteins
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CLOCK protein, human
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Clock protein, mouse
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SKP Cullin F-Box Protein Ligases