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Molecular and Cellular Biology, March 2000, p. 1596-1603, Vol. 20, No. 5
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.
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
*
Corresponding author. Mailing address: Salk
Institute, La Jolla, CA 92037. Phone: (619) 453-4100. Fax: (619)
552-1546. E-mail: Montminy{at}Salk.edu.
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