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Abstract
Pancreatic duodenal homeobox factor-1, PDX-1, is required for pancreas development, islet cell differentiation, and the maintenance of beta cell function. Selective expression in the pancreas appears to be principally regulated by Area II, one of four conserved regulatory sequence domains found within the 5'-flanking region of the pdx-1 gene. Detailed mutagenesis studies have identified potential sites of interaction for both positive- and negative-acting factors within the conserved sequence blocks of Area II. The islet beta cell-enriched RIPE3b1 transcription factor, the activator of insulin C1 element-driven expression, was shown here to also stimulate Area II by binding to sequence blocks 4 and 5 (termed B4/5). Accordingly, B4/5 DNA-binding protein's molecular mass (i.e. 46 kDa), binding specificity, and islet beta cell-enriched distribution were identical to RIPE3b1. Area II-mediated activation was also unaffected upon replacing B4/5 with the insulin C1/RIPE3b1 binding site. In addition, the chromatin immunoprecipitation assay showed that the Area II region of the endogenous pdx-1 gene was precipitated by an antiserum that recognizes the large Maf protein that comprises the RIPE3b1 transcription factor. These results strongly suggest that RIPE3b1/Maf has an important role in generating and maintaining physiologically functional beta cells.
Highlights
Selective expression in the pancreas appears to be principally regulated by Area II, one of four conserved regulatory sequence domains found within the 5-flanking region of the pdx-1 gene
Targeting of the pancreatic duodenal homeobox factor-11 gene in mice has established that expression in a common progenitor cell population is essential for the development of both the endocrine and exocrine compartments of the pancreas
We show that the B4/5 activator of Area II is RIPE3b1/Maf, a 46-kDa islet  cell-enriched protein(s) essential for both cell type-specific [30, 31] and glucose-inducible [32, 33] transcription of the insulin gene
Summary
Targeting of the pancreatic duodenal homeobox factor-1 (pdx-1) gene in mice has established that expression in a common progenitor cell population is essential for the development of both the endocrine and exocrine compartments of the pancreas. Mutations in pdx-1 cause pancreatic agenesis [2, 3] and a form of maturity onset diabetes of the young in humans [14, 15] These data have established an essential role for PDX-1 in islet  cell development and function. A pdx-1 gene fragment spanning Areas I and II directed transgene expression to islet  cells in vivo (termed PstBst, Ϫ2917/Ϫ1918 bp [18, 23]), only Area II, and not Areas I [22] or III [18], functioned independently in these in vivo assays These data strongly suggest that Area II represents the core of the mammalian pdx-1 transcription control region. The ability of Pax and Foxa to bind within Area II of the endogenous pdx-1 gene strongly supports a direct role in mediating transcription in  cells [22]
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