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Molecular and Cellular Biology, January 2002, p. 412-420, Vol. 22, No. 2
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.2.412-420.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Insulin Gene Transcription Is Mediated by Interactions between the p300 Coactivator and PDX-1, BETA2, and E47

Yi Qiu,1,{dagger} Min Guo,1 Suming Huang,2,{dagger} and Roland Stein1*

Department of Molecular Physiology and Biophysics,1 Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 372152

Received 31 August 2001/ Accepted 10 October 2001

Pancreatic ß-cell-type-specific expression of the insulin gene requires both ubiquitous and cell-enriched activators, which are organized within the enhancer region into a network of protein-protein and protein-DNA interactions to promote transcriptional synergy. Protein-protein-mediated communication between DNA-bound activators and the RNA polymerase II transcriptional machinery is inhibited by the adenovirus E1A protein as a result of E1A’s binding to the p300 coactivator. E1A disrupts signaling between the non-DNA-binding p300 protein and the basic helix-loop-helix DNA-binding factors of insulin’s E-element activator (i.e., the islet-enriched BETA2 and generally distributed E47 proteins), as well as a distinct but unidentified enhancer factor. In the present report, we show that E1A binding to p300 prevents activation by insulin’s ß-cell-enriched PDX-1 activator. p300 interacts directly with the N-terminal region of the PDX-1 homeodomain protein, which contains conserved amino acid sequences essential for activation. The unique combination of PDX-1, BETA2, E47, and p300 was shown to promote synergistic activation from a transfected insulin enhancer-driven reporter construct in non-ß cells, a process inhibited by E1A. In addition, E1A inhibited the level of PDX-1 and BETA2 complex formation in ß cells. These results indicate that E1A inhibits insulin gene transcription by preventing communication between the p300 coactivator and key DNA-bound activators, like PDX-1 and BETA2:E47.

* Corresponding author. Mailing address: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37215. Phone: (615) 322-7026. Fax: (615) 322-7236. E-mail: roland.stein{at}mcmail.vanderbilt.edu.

{dagger} Present address: The Picower Institute for Medical Research, Manhasset, NY 11030.

Molecular and Cellular Biology, January 2002, p. 412-420, Vol. 22, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.2.412-420.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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