Abstract
Circadian clock genes are expressed in the suprachiasmatic nucleus and in peripheral tissues to regulate cyclically physiological processes. Synchronization of peripheral oscillators is thought to involve humoral signals, but the mechanisms by which these are mediated and integrated are poorly understood. We report a hormone-dependent interaction of the nuclear receptors, RAR alpha and RXR alpha, with CLOCK and MOP4. These interactions negatively regulate CLOCK/MOP4:BMAL1-mediated transcriptional activation of clock gene expression in vascular cells. MOP4 exhibits a robust rhythm in the vasculature, and retinoic acid can phase shift Per2 mRNA rhythmicity in vivo and in serum-induced smooth muscle cells in vitro, providing a molecular mechanism for hormonal control of clock gene expression. We propose that circadian or periodic availability of nuclear hormones may play a critical role in resetting a peripheral vascular clock.
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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3T3 Cells
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Animals
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Basic Helix-Loop-Helix Transcription Factors
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Biological Clocks / drug effects
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Blood Vessels / metabolism*
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CLOCK Proteins
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Cell Cycle Proteins
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Circadian Rhythm* / drug effects
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Dexamethasone / pharmacology
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Genes, Reporter
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Glucocorticoids / pharmacology
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Humans
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Immunoblotting
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Ligands
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Mice
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Mice, Inbred BALB C
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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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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Protein Binding
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Protein Structure, Tertiary
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Receptors, Retinoic Acid / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Regulatory Sequences, Nucleic Acid
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Retinoic Acid Receptor alpha
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Retinoid X Receptors
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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
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Two-Hybrid System Techniques
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Cell Cycle Proteins
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Glucocorticoids
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Ligands
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NPAS2 protein, human
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Nerve Tissue Proteins
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Npas2 protein, mouse
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Nuclear Proteins
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PER2 protein, human
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Per2 protein, mouse
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Period Circadian Proteins
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RARA protein, human
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Rara protein, mouse
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Receptors, Retinoic Acid
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Recombinant Fusion Proteins
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Retinoic Acid Receptor alpha
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Retinoid X Receptors
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Trans-Activators
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Transcription Factors
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Dexamethasone
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CLOCK Proteins
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CLOCK protein, human
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Clock protein, mouse