Nature Structural Biology10, 175 - 181 (2003)
Published online: 3 February 2003; | doi:10.1038/nsb895
Attenuation of a phosphorylation-dependent activator by an HDAC−PP1 complex
Gianluca Canettieri1, Ianessa Morantte1, Ernesto Guzmán1, Hiroshi Asahara1, 2, Stephan Herzig1, Scott D. Anderson3, John R. Yates III3
& Marc Montminy1
1
Peptide Biology Laboratories, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
2
Present address: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
3
Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Correspondence should be addressed to Marc Montminy montminy@salk.edu
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.
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