Attenuation of a phosphorylation-dependent activator by an HDAC-PP1 complex.
The second messenger cAMP stimulates transcription with burst-attenuation kinetics that mirror the PKA-dependent phosphorylation and subsequent protein phosphatase 1 (PP1)-mediated dephosphorylation of the cAMP responsive element binding protein (CREB) at Ser133. Phosphorylation of Ser133 promotes recruitment of the co-activator histone acetylase (HAT) paralogs CBP and P300, which in turn stimulate ... acetylation of promoter-bound histones during the burst phase. Remarkably, histone deacetylase (HDAC) inhibitors seem to potentiate CREB activity by prolonging Ser133 phosphorylation in response to cAMP stimulus, suggesting a potential role for HDAC complexes in silencing CREB activity. Here we show that HDAC1 associates with and blocks Ser133 phosphorylation of CREB during pre-stimulus and attenuation phases of the cAMP response. HDAC1 promotes Ser133 dephosphorylation via a stable interaction with PP1, which we detected in co-immunoprecipitation and co-purification studies. These results illustrate a novel mechanism by which signaling and chromatin-modifying activities act coordinately to repress the activity of a phosphorylation-dependent activator.
Mesh Terms:
Cells, Cultured, Chromatin, Cyclic AMP, Cyclic AMP Response Element-Binding Protein, Forskolin, Histone Deacetylase 1, Histone Deacetylases, Humans, Kidney, Macromolecular Substances, Mutation, Phosphoprotein Phosphatases, Phosphorylation, Promoter Regions, Genetic, Protein Phosphatase 1, Serine
Cells, Cultured, Chromatin, Cyclic AMP, Cyclic AMP Response Element-Binding Protein, Forskolin, Histone Deacetylase 1, Histone Deacetylases, Humans, Kidney, Macromolecular Substances, Mutation, Phosphoprotein Phosphatases, Phosphorylation, Promoter Regions, Genetic, Protein Phosphatase 1, Serine
Nat. Struct. Biol.
Date: Mar. 01, 2003
PubMed ID: 12567184
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