. The PDX-1 homeodomain transcription factor is an essential regulator of both early pancreas development and insulin gene expression in adult islet beta cells. In the pancreas, PDX-1 expression is essentially restricted to islet beta cells. The studies outlined in this proposal will focus on two outstanding issues regarding the biological function of PDX-1. First, the applicant will work towards identifying and characterizing the key DAN-binding factors that direct transcription of the pdx-1 gene specifically to beta cells. Transient transfection and transgenic experiments that the applicant has performed have demonstrated that selective expression of the mouse pdx-1 gene is mediated by 5'-flanking control region sequences spanning nuclease hypersensitive site-1 (HSSa; -2560 to -1880 +/- 150 bp). Furthermore, analysis of the promoter region of the human and chicken pdx-1 genes has revealed that the only area of significant sequence similarity with the mouse is found in HSS1. This region could be further divided into three subdomains as a result of sequence conservation and function, which were termed Area I (-2694 to -2561 bp), Area II (-2139 to -1958 bp), and Area III (-1879 to -1799 bp). It is very likely that the sequences conserved between mouse, chicken, and human define the cis-active elements of the pdx-1 gene that are critical for appropriate developmental and adult islet specific expression. Second, the applicant will work towards determining how the action potential of the PDX-1 protein is regulated in beta cells. Their studies have shown that the activity of the PDX-1 activation domain is potentiated by the most important physiological regulator of beta cell function, glucose, and through functional interactions with other beta cell-enriched activators. In addition, that the p300/CBP coactivator was recruted by PDX-1 mediate insulin gene transcription. Understanding how the trans-activation potential of PDX-1 is controlled should provide insight into the mechanisms involved in regulating PDX-1 induced transcription in beta cells under both normal and pathogenic conditions.
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