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Attenuation of a phosphorylation-dependent activator by an HDAC–PP1 complex

Nature Structural & Molecular Biology volume 10, pages 175–181 (2003)Cite this article

Abstract

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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Figure 1: CREB associates with active class I HDACs.
Figure 2: HDAC1 is recruited to a cAMP-responsive promoter during pre-stimulus and attenuation phases.
Figure 3: HDAC1 disrupts Ser133 phosphorylation of CREB in response to cAMP.
Figure 4: HDAC1 associates with PP1C.
Figure 5: HDAC1 disrupts CREB phosphorylation via an association with PP1.

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Acknowledgements

We thank M. Downes, W. Xu and R. Evans for the gift of HDAC expression plasmids and 3H-labeled histones. This work was supported by funds from the National Institutes of Health. G.C. was supported by a fellowship granted by Istituto Pasteur-Fondazione Cenci, Bolognetti, Italy. S.H. was supported by a grant from the DFG.

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Author notes

  1. Scott D. Anderson & John R. Yates III

    Present address: Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

  2. Hiroshi Asahara

    Present address: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, 92037, USA

Authors and Affiliations

  1. Peptide Biology Laboratories, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, 92037, California, USA

    Gianluca Canettieri, Ianessa Morantte, Ernesto Guzmán, Hiroshi Asahara, Stephan Herzig & Marc Montminy

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Canettieri, G., Morantte, I., Guzmán, E. et al. Attenuation of a phosphorylation-dependent activator by an HDAC–PP1 complex. Nat Struct Mol Biol 10, 175–181 (2003). https://doi.org/10.1038/nsb895

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