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J. Biol. Chem., Vol. 280, Issue 15, 15103-15110, April 15, 2005

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Glutamine Rich and Basic Region/Leucine Zipper (bZIP) Domains Stabilize cAMP-response Element-binding Protein (CREB) Binding to Chromatin^*

Bernhard M. Mayr, Ernesto Guzman, and Marc Montminy

From the Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037

We have examined the dynamics of cAMP-response element-binding protein (CREB) binding to chromatin in live cells using fluorescence recovery after photobleaching (FRAP). CREB was found to bind to target sites with a residence time of 100 s, and exposure to a cAMP agonist had no effect on these kinetics. In addition to the basic region/leucine zipper (bZIP) domain, a glutamine-rich trans-activation domain in CREB called Q2 also appeared to be critical for promoter occupancy. Indeed, mutations in Q2 that reduced residence time by FRAP assay disrupted target gene activation via CREB in cells exposed to a cAMP agonist. Notably, insertion of the glutamine-rich B trans-activation domain of SP1 into a mutant CREB polypeptide lacking Q2 stabilized CREB occupancy and rescued target gene activation. These results suggest a novel mechanism by which the family of glutamine-rich activators promotes cellular gene expression.

Received for publication, December 16, 2004 , and in revised form, February 3, 2005.

^* This work was supported in part by National Institutes of Health Grant RO1 GM 037828. 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.

The on-line version of this article (available at www.jbc.org) contains a summary of FRAP assays for wild-type and mutant YFP-CREB polypeptides in the form of supplemental Table I.

Special Fellow of the Leukemia and Lymphoma Society. Present address: Nikolaus-Fiebiger Center for Molecular Medicine, Experimental Medicine II, Glueckstr. 6, 91054 Erlangen, Germany.

To whom correspondence should be addressed. Tel.: 858-453-4100; Fax: 858-552-1546; E-mail: montminy{at}salk.edu.

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