Insulin gene transcription is mediated by interactions between the p300 coactivator and PDX-1, BETA2, and E47.
Pancreatic beta-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 beta-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-beta cells, a process inhibited by E1A. In addition, E1A inhibited the level of PDX-1 and BETA2 complex formation in beta 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.
Mesh Terms:
Adenovirus E1A Proteins, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Line, DNA-Binding Proteins, E1A-Associated p300 Protein, Enhancer Elements, Genetic, Gene Expression Regulation, HeLa Cells, Homeodomain Proteins, Humans, Insulin, Islets of Langerhans, Macromolecular Substances, Mastadenovirus, Nuclear Proteins, Rats, TCF Transcription Factors, Trans-Activators, Transcription Factor 7-Like 1 Protein, Transcription Factors, Transcription, Genetic, Transfection
Adenovirus E1A Proteins, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Line, DNA-Binding Proteins, E1A-Associated p300 Protein, Enhancer Elements, Genetic, Gene Expression Regulation, HeLa Cells, Homeodomain Proteins, Humans, Insulin, Islets of Langerhans, Macromolecular Substances, Mastadenovirus, Nuclear Proteins, Rats, TCF Transcription Factors, Trans-Activators, Transcription Factor 7-Like 1 Protein, Transcription Factors, Transcription, Genetic, Transfection
Mol. Cell. Biol.
Date: Jan. 01, 2002
PubMed ID: 11756538
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