beta-cell-specific expression of insulin and PDX-1 genes.

Abstract

␤-cell-restricted expression of the insulin gene relies on the interaction of 5Ј flanking sequence motifs in the promoter region with a number of ubiquitous and islet-specific transcription factors. These interactions determine the temporal expression of the gene and its inducibility by physiological stimuli. Most of the studies on the regulation of insulin gene expression were conducted with rat insulin 1 and 2 and the human genes. They share a number of conserved cis elements in their 5Ј flanking region and are probably regulated by similar trans-acting factors. Among such elements, the E and A boxes appear to be the major determinants of ␤-cell-specific insulin gene expression. The E boxes (E1 and E2), with the consensus CANNTG, bind transcription factors of the basic helix-loop-helix family. The A boxes (A1-A5) containing AT-rich sequences bind factors that belong to the homeodomain-containing protein family. The most conserved A1 and A3 boxes in the insulin promoter bind the pancreatic duodenal homeobox transcription factor (PDX-1), the mammalian homolog of the Xenopus laevis XlHbox8, previously described as insulin promoter factor-1, somatostatin transcription factor-1 (STF-1), islet duodenal homeobox-1 (IDX-1), glucose-sensitive factor (GSF), and insulin upstream factor-1 (IUF-1). Gene disruption experiments in mice showed that PDX-1 is needed for pancreas formation. Thus, tissue-specific expression of the insulin gene appears to depend on a combination of transcription factors, some of which are restricted to the ␤-cell.Because of its central role in metabolic control, tight regulation of insulin production and release is critical. Inducible transcription may depend on the very same sequences in the promoter/enhancer regions that control the cell-type specificity of the insulin gene. In pancreatic ␤-cells, glucose is the major regulator of insulin biosynthesis and secretion. Experiments with rat and human islets, as well as ␤-cell lines, indicated that glucose regulates insulin gene expression by simultaneously stimulating transcription and inhibiting proinsulin mRNA degradation.The glucose-responsiveness of the insulin gene is similarly mediated by cis-acting elements within the 5Ј flanking region relative to the transcription start site. We have previously demonstrated the presence of an islet-specific GSF, whose DNA binding to the A3 motif of the rat I and human insulin promoters is modulated by extracellular glucose. A single mutation in the GSF binding site of the human insulin promoter abolishes the stimulation by high glucose in normal islets. The sequence of the purified protein was shown to correspond to PDX-1. Mapping of GSF/PDX-1 functional domains in normal islet cells showed that its transactivation domain is located within the NH 2 -terminal region of the protein and is also regulated by extracellular glucose levels. Thus, in addition to its essential roles in the development and differentiation of pancreatic islets and in ␤-cell-specific gene expression, PDX-1 protein functions as a mediat...

Tissue MicroArray Analyses of Pancreatic Duodenal Homeobox‐1 in Human Cancers

“…The human PDX-1 gene is also known as insulin promoter factor-1, islet/duodenum homeobox-1, insulin upstream factor-1, and glucose-sensitive factor [20][21][22][23][24]. The pivotal role of PDX-1 in pancreatic development has been demonstrated in transgenic models [25,26].…”

Regulatory Mechanisms of Somatostatin Expression

“…The transcription factor pancreas/duodenum homeobox protein (PDX)1, formerly known as islet/duodenum homeobox (IDX)-1 or somatostatin transactivating factor (STF)-1, is another regulator of somatostatin gene expression. PDX1 triggers insulin gene expression in β-cells [77] and is essential for pancreas development, most probably by determining the maturation and differentiation of common pancreatic precursor cells in the developing gut [78]. In δ-cells, PDX1 is expressed at a low level [79] and activates somatostatin transcription by binding to regulatory elements in the 5 flanking region of the rat somatostatin gene [55,80].…”

Cell‐specific Cytotoxicity of Human Pancreatic Adenocarcinoma Cells Using Rat Insulin Promoter Thymidine Kinase‐directed Gene Therapy

“…The rat insulin promoter (RIP) II has been studied, and results have shown it to be expressed only in pancreatic beta cells. To activate the RIP in vivo as well as in vitro requires several transcription factors, including PDX-1 and ␤-2 [16][17][18][19].…”