Abstract
Cyclic AMP-induced phosphorylation of the transcription factor CREB elicits expression of genes mediating diverse biological functions. In lymphoid organs, the neurotransmitter norepinephrine stimulates beta(2)-adrenergic receptors on B lymphocytes to promote CREB-dependent expression of genes like the B cell Oct 2 coactivator (OCA-B). Although CREB phosphorylation recruits cofactors such as CBP/p300 to stimulate transcription, bona fide endogenous inhibitors of CREB-coactivator or CREB-DNA interactions have not emerged. Here, we identified RGS13, a member of the Regulator of G protein Signaling (RGS) protein family, as a nuclear factor that suppresses CREB-mediated gene expression. cAMP or Ca(2+) signaling promoted RGS13 accumulation in the nucleus, where it formed a complex with phosphorylated CREB and CBP/p300. RGS13 reduced the apparent affinity of pCREB for both the CRE and CBP. B lymphocytes from Rgs13(-/-) mice had more beta(2)-agonist-induced OCA-B expression. Thus, RGS13 inhibits CREB-dependent transcription of target genes through disruption of complexes formed at the promoter.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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B-Lymphocytes / cytology
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B-Lymphocytes / metabolism
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CREB-Binding Protein / genetics
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CREB-Binding Protein / metabolism
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Cell Line
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Cell Nucleus / metabolism*
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / metabolism*
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Cyclic AMP-Dependent Protein Kinases / metabolism
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GTP-Binding Protein alpha Subunits, Gs / genetics
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GTP-Binding Protein alpha Subunits, Gs / metabolism
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Gene Expression Regulation*
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Humans
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Mice
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Mice, Knockout
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Promoter Regions, Genetic
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RGS Proteins / genetics
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RGS Proteins / metabolism*
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RNA Interference
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Signal Transduction / physiology
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Transcription, Genetic
Substances
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Cyclic AMP Response Element-Binding Protein
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Nuclear Proteins
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RGS Proteins
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RGS13 protein, human
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Recombinant Fusion Proteins
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Repressor Proteins
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CREB-Binding Protein
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Cyclic AMP-Dependent Protein Kinases
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GTP-Binding Protein alpha Subunits, Gs