Role of cyclic AMP response element-binding protein in cyclic AMP inhibition of NF-kappaB-mediated transcription.
The NF-kappaB family of transcription factors regulates the inducible expression of a variety of genes. Recently, we showed that elevation of intracellular cyclic AMP inhibits NF-kappaB-mediated transcription in human monocytes and endothelial cells without preventing nuclear translocation of NF-kappaB complexes. The present study examined the molecular mechanism of this inhibition. ... We hypothesized that activation of the protein kinase A signaling pathway may inhibit NF-kappaB-mediated transcription by phosphorylating proteins, such as cAMP response element-binding protein (CREB), which compete for limiting amounts of the coactivator CBP. Here, we show that the amino-terminal region (amino acids 1-450) of CBP specifically interacts with the carboxyl-terminal region (amino acids 286-551) of NF-kappaB p65 (RelA) both in vitro and in vivo. Functional studies using human endothelial cells demonstrated that overexpression of CBP rescued cAMP inhibition of NF-kappaB-mediated transcription and transcription mediated by a chimeric protein, GAL4-p65(286-551), which contained the GAL4 DNA binding domain fused to the carboxyl-terminal region of p65 (amino acids 286-551). In contrast, overexpression of CREB inhibited GAL4-p65(286-551)-mediated transcription. These results suggest that activation of the protein kinase A pathway inhibits NF-kappaB transcription by phosphorylating CREB, which competes with p65 for limiting amounts of CBP.
Mesh Terms:
Calcium-Binding Proteins, Cells, Cultured, Cyclic AMP, Cyclic AMP Response Element-Binding Protein, Endothelium, Humans, Membrane Glycoproteins, Monocytes, NF-kappa B, Nerve Tissue Proteins, Promoter Regions, Genetic, Synaptotagmin I, Synaptotagmins, Transcription, Genetic
Calcium-Binding Proteins, Cells, Cultured, Cyclic AMP, Cyclic AMP Response Element-Binding Protein, Endothelium, Humans, Membrane Glycoproteins, Monocytes, NF-kappa B, Nerve Tissue Proteins, Promoter Regions, Genetic, Synaptotagmin I, Synaptotagmins, Transcription, Genetic
J. Immunol.
Date: Dec. 01, 1997
PubMed ID: 9548485
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