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

Nat Struct Biol. 2003 Mar;10(3):175-81. doi: 10.1038/nsb895.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cells, Cultured
  • Chromatin / metabolism
  • Colforsin / pharmacology
  • Cyclic AMP / metabolism
  • Cyclic AMP / pharmacology
  • Cyclic AMP Response Element-Binding Protein / chemistry
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Histone Deacetylase 1
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Humans
  • Kidney / cytology
  • Kidney / drug effects
  • Kidney / metabolism
  • Macromolecular Substances
  • Mutation
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / physiology
  • Protein Phosphatase 1
  • Serine / metabolism


  • Chromatin
  • Cyclic AMP Response Element-Binding Protein
  • Macromolecular Substances
  • Colforsin
  • Serine
  • Cyclic AMP
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 1
  • HDAC1 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylases