Abstract
Calcium-stimulated nuclear factor of activated T cells (NFAT) transcription activity at the interleukin-2 promoter is negatively regulated by cyclic AMP (cAMP). This effect of cAMP is mediated, in part, by protein kinase A phosphorylation of NFAT. The mechanism of regulation involves the creation of a phosphorylation-dependent binding site for 14-3-3. Decreased NFAT phosphorylation caused by the calcium-stimulated phosphatase calcineurin, or mutation of the PKA phosphorylation sites, disrupted 14-3-3 binding and increased NFAT transcription activity. In contrast, NFAT phosphorylation caused by cAMP increased 14-3-3 binding and reduced NFAT transcription activity. The regulated interaction between NFAT and 14-3-3 provides a mechanism for the integration of calcium and cAMP signaling pathways.
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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14-3-3 Proteins
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Amino Acid Sequence
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Animals
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Binding Sites
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Bucladesine / pharmacology
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Calcineurin / metabolism
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Calcineurin Inhibitors
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Calcium / metabolism*
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Calcium Signaling*
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Cell Line
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Cyclic AMP / metabolism*
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Cyclic AMP-Dependent Protein Kinases / chemistry
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Cyclic AMP-Dependent Protein Kinases / genetics
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Cyclic AMP-Dependent Protein Kinases / metabolism*
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Gene Expression Regulation
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Humans
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Interleukin-2 / genetics
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Ionomycin / pharmacology
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Molecular Sequence Data
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Mutation / genetics
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NFATC Transcription Factors
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Nuclear Localization Signals / genetics
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Nuclear Localization Signals / physiology
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Nuclear Proteins*
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Phosphorylation / drug effects
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Phosphoserine / metabolism
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Proteins / chemistry
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Proteins / metabolism*
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
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Signal Transduction
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / chemistry
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tyrosine 3-Monooxygenase*
Substances
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14-3-3 Proteins
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Calcineurin Inhibitors
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DNA-Binding Proteins
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Interleukin-2
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NFATC Transcription Factors
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Nuclear Localization Signals
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Nuclear Proteins
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Proteins
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Recombinant Fusion Proteins
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Transcription Factors
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Phosphoserine
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Ionomycin
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Bucladesine
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Cyclic AMP
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Tyrosine 3-Monooxygenase
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Cyclic AMP-Dependent Protein Kinases
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Calcineurin
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Calcium