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J. Biol. Chem., Vol. 278, Issue 44, 43014-43019, October 31, 2003

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

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

From the Vollum Institute L474, Oregon Health and Science University, Portland, Oregon 97239

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.

Received for publication, June 4, 2003 , and in revised form, August 6, 2003.

^* This work was supported by National Institutes of Health Grants DK45423 (to R. H. G.) and GM66563 (to J. E. F. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Vollum Institute L474, Oregon Health and Science University; 3181 SW Sam Jackson Park Rd., Portland, OR 97239. Tel.: 503-494-5078; Fax: 503-494-4353; E-mail: goodmanr{at}ohsu.edu.

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