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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,dagger 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 beta -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 beta -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 beta  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 beta  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 beta  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.

dagger 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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