Synergistic activation of the insulin gene promoter by the beta-cell enriched transcription factors MafA, Beta2, and Pdx1.

Specific expression of the insulin gene in pancreatic islet beta-cells requires multiple cis-regulatory elements in its promoter. Pdx1, MafA, and Beta2 have been identified as beta-cell enriched transcription factors that bind to these elements. Pdx1 has been shown to bind to A1, A3, A5, and GG2, and Beta2 binds to E1 by forming a heterodimer with the ubiquitous factor E47. MafA was recently identified as a C1-element binding factor. However, interactions between these factors and the promoter have not been characterized in detail. In this report, we show that these transactivators synergistically stimulate insulin promoter activity. Among multiple binding sites for Pdx1, MafA, and Beta2, at least GG2, C1, and E1 elements located in the promoter region between -150 and -100 base pairs are necessary for the synergism. We also found that neither MafB nor c-Maf, close relatives of MafA, showed synergistic activation. These results suggest that co-expression and functional synergism of these beta-cell enriched transactivators, MafA, Pdx1, and Beta2, are critical for establishing the beta-cell-specific and efficient expression of the insulin gene.