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Molecular and Cellular Biology, March 2000, p. 1596-1603, Vol. 20, No. 5
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The Phosphorylation Status of a Cyclic AMP-Responsive Activator Is Modulated via a Chromatin-Dependent Mechanism

Laura F. Michael,1 Hiroshi Asahara,1 Andrew I. Shulman,1 W. Lee Kraus,2 and Marc Montminy1,*

Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037,1 and Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 148532

Received 26 August 1999/Returned for modification 1 November 1999/Accepted 6 December 1999

Cyclic AMP (cAMP) stimulates the expression of numerous genes via the protein kinase A (PKA)-mediated phosphorylation of CREB at Ser133. Ser133 phosphorylation, in turn, promotes recruitment of the coactivator CREB binding protein and its paralog p300, histone acetyltransferases (HATs) that have been proposed to mediate target gene activation, in part, by destabilizing promoter bound nucleosomes and thereby allowing assembly of the transcriptional apparatus. Here we show that although histone deacetylase (HDAC) inhibitors potentiate target gene activation via cAMP, they do not stimulate transcription over the early burst phase, during which CREB phosphorylation and CBP/p300 recruitment are maximal. Rather, HDAC inhibitors augment CREB activity during the late attenuation phase by prolonging CREB phosphorylation on chromosomal but, remarkably, not on extrachromosomal templates. In reconstitution studies, assembly of periodic nucleosomal arrays on a cAMP-responsive promoter template potently inhibited CREB phosphorylation by PKA, and acetylation of these template-bound nucleosomes by p300 partially rescued CREB phosphorylation by PKA. Our results suggest a novel regulatory mechanism by which cellular HATs and HDACs modulate the phosphorylation status of nuclear activators in response to cellular signals.

* Corresponding author. Mailing address: Salk Institute, La Jolla, CA 92037. Phone: (619) 453-4100. Fax: (619) 552-1546. E-mail: Montminy{at}Salk.edu.

Molecular and Cellular Biology, March 2000, p. 1596-1603, Vol. 20, No. 5
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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