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Mol Cell Biol, May 1998, p. 2957-2964, Vol. 18, No. 5
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
p300 Mediates Transcriptional Stimulation by the
Basic Helix-Loop-Helix Activators of the Insulin Gene
Yi
Qiu,1
Arun
Sharma,1,
and
Roland
Stein1,2,*
Department of Molecular Physiology and
Biophysics1 and
Department of Cell
Biology,2 Vanderbilt Medical Center,
Nashville, Tennessee 37232
Received 30 December 1997/Returned for modification 9 February
1998/Accepted 17 February 1998
Pancreatic
-cell-type-specific and glucose-inducible
transcription of the insulin gene is mediated by the basic
helix-loop-helix factors that bind to and activate expression from an
E-box element within its enhancer. The E-box activator is a heteromeric
complex composed of a
-cell-enriched factor, BETA2/NeuroD, and
ubiquitously distributed proteins encoded by the E2A and HEB
genes. Previously, we demonstrated that the adenovirus type 5 E1A proteins repressed stimulation by the E-box activator in
cells.
In this study, our objective was to determine how E1A repressed
activator function. The results indicate that E1A reduces activation by
binding to and sequestering the p300 cellular coactivator protein.
Thus, we show that expression of p300 in
cells can relieve
inhibition by E1A, as well as potentiate activation by the endogenous
insulin E-box transcription factors. p300 stimulated activation from
GAL4 (amino acids 1 to 147) fusion constructs of either
BETA2/NeuroD or the E2A-encoded E47 protein. The sequences spanning
the activation domains of BETA2/NeuroD (amino acids 156 to 355) and E47
(amino acids 1 to 99 and 325 to 432) were required for this response. The same region of BETA2/NeuroD was shown to be important for binding
to p300 in vitro. The sequences of p300 involved in E47 and
BETA2/NeuroD association resided between amino acids 1 and 1257 and
1945 and 2377, respectively. A mutation in p300 that abolished binding
to BETA2/NeuroD also destroyed the ability of p300 to activate insulin
E-box-directed transcription in
cells. Our results indicate that
physical and functional interactions between p300 and the E-box
activator factors play an important role in insulin gene transcription.
*
Corresponding author. Mailing address: Department of
Molecular Physiology and Biophysics, Vanderbilt Medical Center,
Nashville, TN 37232. Phone: (615) 322-7026. Fax: (615) 322-7236. E-mail: roland.stein{at}mcmail.vanderbilt.edu.

Present address: Joslin Diabetes Center, Boston, MA 02215.
Mol Cell Biol, May 1998, p. 2957-2964, Vol. 18, No. 5
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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