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J. Biol. Chem., Vol. 276, Issue 44, 40721-40726, November 2, 2001
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,,
From the SRCAP (SNF2-related CPB activator protein)
belongs to the SNF2 family of proteins whose members participate in
various aspects of transcriptional regulation, including chromatin
remodeling. It was identified by its ability to bind to
cAMP-responsive-binding protein (CREB)-binding protein (CBP), and it
increases the transactivation function of CBP. The phosphoenolpyruvate
carboxykinase (PEPCK) promoter was used as a model system to explore
the role of SRCAP in the regulation of transcription mediated by
factors that utilize CBP as a coactivator. We show that transcription
of a PEPCK chloramphenicol acetyltransferase (CAT) reporter gene
activated by protein kinase A (PKA) is enhanced 7-fold by SRCAP. In the
absence of PKA this SRCAP-mediated enhancement does not occur,
suggesting that SRCAP functions as a coactivator for PKA-activated
factors such as CREB. Replacing the PEPCK promoter binding site for
CREB with a binding site for Gal4 ( Department of Pharmacological and
Physiological Sciences and the § Department of Molecular
Microbiology and Immunology, Saint Louis University School of
Medicine, Saint Louis, Missouri 63104 and the ¶ Department of
Molecular Physiology and Biophysics, Vanderbilt University School of
Medicine, Nashville, Tennessee 37232
CRE (cAMP-responsive
element) Gal4 PEPCK-CAT reporter gene) blocks the ability of SRCAP to
activate transcription despite the presence of PKA. Expression of a
Gal-CREB chimera restores the ability of PKA to regulate transcription
of the CRE Gal4 PEPCK gene and restored the ability of SRCAP to
stimulate PKA-activated transcription. In addition, SRCAP in the
presence of PKA enhances the ability of the Gal-CREB chimera to
activate transcription of a Gal-CAT reporter gene that contains only
binding sites for Gal4. SRCAP binds to CBP amino acids 280-460, a
region that is important for CBP to function as a coactivator for CREB.
Overexpression of a SRCAP peptide corresponding to this CBP binding
domain acts as a dominant negative inhibitor of CREB-mediated
transcription. Structure-function studies were done to explore the
mechanism(s) by which SRCAP regulates transcription. These studies
indicate that the N-terminal region of SRCAP, which contains five of
the seven regions that comprise the ATPase domain, is not needed for activation of CREB-mediated transcription. SRCAP apparently has several
domains that participate in the activation of transcription.
To whom correspondence should be addressed: Dept. of
Pharmacological and Physiological Sciences, Saint Louis University
School of Medicine, 1402 South Grand, Saint Louis, MO 63104. Tel.: 314-268-5291; Fax: 314-577-8233; E-mail: Chrivia@SLU.edu.
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