Deacetylase Activity Is Required for cAMP Activation of a Subset of CREB Target Genes

Daniel M. Fass, Jennifer E F Butler, Richard Goodman

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

Many hormones activate transcription by raising the level of cAMP within cells. In one well studied pathway, cAMP induces protein kinase A to phosphorylate the transcription factor CREB, which binds to a consensus sequence, the cAMP-regulated enhancer, found in many target genes. A generally accepted model suggests that phosphorylated CREB recruits the histone acetyltransferase CBP to activate transcription. In contrast, histone deacetylases have been linked to the cessation of CREB-dependent transcription. Here we tested this model in the regulation of endogenous CREB target genes. We used a constitutively active CREB mutant and microarray analysis to identify target genes in PC12 cells. We then tested the role of histone deacetylase activity in cAMP activation of four of these genes (c-FOS, ICER, NOR-1, and NUR77) by treating cells with the histone deacetylase inhibitor trichostatin A. Consistent with the generally accepted model, trichostatin A enhanced activation of c-FOS and NUR77 by cAMP. Surprisingly, trichostatin A blocked activation of ICER and NOR-1. The block of ICER and NOR-1 activation persisted in the presence of cycloheximide, indicating that the trichostatin A effect did not depend on new protein synthesis. This unexpected role of histone deacetylases in transcriptional activation of certain endogenous CREB target genes was not apparent in transfected reporter genes. Chromatin immunoprecipitation analysis indicated that the differential roles of histone deacetylases in activating or repressing CREB target genes was manifested at the level of preinitiation complex recruitment. These data indicate that histone deacetylases differentially regulate CREB target genes by contributing to either activation or cessation of transcription.

Original languageEnglish (US)
Pages (from-to)43014-43019
Number of pages6
JournalJournal of Biological Chemistry
Volume278
Issue number44
DOIs
StatePublished - Oct 31 2003

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trichostatin A
Histone Deacetylases
Genes
Chemical activation
Transcription
Transcriptional Activation
Histone Acetyltransferases
Histone Deacetylase Inhibitors
Chromatin Immunoprecipitation
PC12 Cells
Consensus Sequence
Cycloheximide
Microarray Analysis
Cyclic AMP-Dependent Protein Kinases
Reporter Genes
Transcription Factors
Microarrays
Hormones
Chromatin
1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole

ASJC Scopus subject areas

  • Biochemistry

Cite this

Deacetylase Activity Is Required for cAMP Activation of a Subset of CREB Target Genes. / Fass, Daniel M.; Butler, Jennifer E F; Goodman, Richard.

In: Journal of Biological Chemistry, Vol. 278, No. 44, 31.10.2003, p. 43014-43019.

Research output: Contribution to journalArticle

Fass, Daniel M. ; Butler, Jennifer E F ; Goodman, Richard. / Deacetylase Activity Is Required for cAMP Activation of a Subset of CREB Target Genes. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 44. pp. 43014-43019.
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