The transcription factor pancreatic and duodenal homeobox factor 1 (PDX-1) is expressed in pancreatic progenitor cells. In exocrine pancreas, PDX-1 is down-regulated during late development, while re-up-regulation of PDX-1 has been reported in pancreatic cancer and pancreatitis. To determine whether sustained expression of PDX-1 could affect pancreas development, PDX-1 was constitutively expressed in all pancreatic lineages by transgenic approaches. The transgenic pancreas was markedly small with the replacement of acinar cells by duct-like structures, accompanied by activated Stat3. Genetic ablation of Stat3 in the transgenic pancreas profoundly suppressed the metaplastic phenotype. These results provide a mechanism of pancreatic metaplasia by which persistent PDX-1 expression cell-autonomously induces acinar-to-ductal transition through Stat3 activation.Supplemental material is available at http://www.genesdev.org.

Abstract. Pancreatic and duodenal homeobox factor-1 (PDX-1) plays a crucial role in pancreas development, β-cell differentiation, and maintenance of mature β-cell function. PDX-1 expression is maintained in pancreatic precursor cells during pancreas development but becomes restricted to β-cells in mature pancreas. In mature β-cells, PDX-1 transactivates the insulin and other genes involved in glucose sensing and metabolism such as GLUT2 and glucokinase. MafA is a recently isolated β-cell-specific transcription factor which functions as a potent activator of insulin gene transcription. Furthermore, these transcription factors play an important role in induction of insulin-producing cells in various non-β-cells and thus could be therapeutic targets for diabetes. On the other hand, under diabetic conditions, expression and/or activities of PDX-1 and MafA in β-cells are reduced, which leads to suppression of insulin biosynthesis and secretion. It is likely that alteration of such transcription factors explains, at least in part, the molecular mechanism for β-cell glucose toxicity found in diabetes.

Gastric cancer is an inflammation-related malignancy related to long-standing acute and chronic inflammation caused by infection with the human bacterial pathogen Helicobacter pylori. Inflammation can result in genomic instability. However, there are considerable data that H. pylori itself can also produce genomic instability both directly and through epigenetic pathways. Overall, the mechanisms of H. pylori-induced host genomic instabilities remain poorly understood. We used microarray screening of H. pylori-infected human gastric biopsy specimens to identify candidate genes involved in H. pylori-induced host genomic instabilities. We found upregulation of ATM expression in vivo in gastric mucosal cells infected with H. pylori. Using gastric cancer cell lines, we confirmed that the H. pylori-related activation of ATM was due to the accumulation of DNA double-strand breaks (DSBs). DSBs were observed following infection with both cag pathogenicity island (PAI)-positive and -negative strains, but the effect was more robust with cag PAI-positive strains. These results are consistent with the fact that infections with both cag PAI-positive and -negative strains are associated with gastric carcinogenesis, but the risk is higher in individuals infected with cag PAI-positive strains.

Abstract. reactive oxygen species (ros) are induced under diabetic conditions and are likely associated with the development of type 2 diabetes. it is also known that ros production is facilitated in the presence of copper ion through the Fenton reaction. The aim of this study was to examine the involvement of copper ion in the pathogenesis of type 2 diabetes and to evaluate the potential usefulness of a copper chelating agent for the treatment of type 2 diabetes. First, both serum copper ion and ROS levels in diabetic C57BL/KsJ-db/db mice were significantly higher compared to those in nondiabetic mice. second, we treated diabetic db/db mice with a copper chelating agent tetrathiomolybdate and examined the effects on the development of type 2 diabetes. As the results, both serum copper ion and ROS levels were significantly decreased by the treatment, which were equivalent to those in non-diabetic mice. consequently, the treatment with a copper chelating agent reduced insulin resistance and ameliorated glucose intolerance in diabetic db/db mice. in addition, serum triglyceride levels were also decreased by the treatment. in conclusion, our present results suggest that copper ion is involved in the development of type 2 diabetes and thereby a potential therapeutic target for diabetes.

OBJECTIVEIslet β-cells loose their ability to synthesize insulin under diabetic conditions, which is at least partially due to the decreased activity of insulin transcription factors such as MafA. Although an in vitro study showed that reactive oxygen species (ROS) decrease MafA expression, the underlying mechanism still remains unclear. In this study, we examined the effects of c-Jun, which is known to be upregulated by ROS, on the expression of MafA under diabetic conditions.RESEARCH DESIGN AND METHODSTo examine the protein levels of MafA and c-Jun, we performed histological analysis and Western blotting using diabetic db/db mice. In addition, to evaluate the possible effects of c-Jun on MafA expression, we performed adenoviral overexpression of c-Jun in the MIN6 β-cell line and freshly isolated islets.RESULTSMafA expression was markedly decreased in the islets of db/db mice, while in contrast c-Jun expression was increased. Costaining of these factors in the islets of db/db mice clearly showed that MafA and insulin levels are decreased in c-Jun–positive cells. Consistent with these results, overexpression of c-Jun significantly decreased MafA expression, accompanied by suppression of insulin expression. Importantly, MafA overexpression restored the insulin promoter activity and protein levels that were suppressed by c-Jun. These results indicate that the decreased insulin biosynthesis induced by c-Jun is principally mediated by the suppression of MafA activity.CONCLUSIONSIt is likely that the augmented expression of c-Jun in diabetic islets decreases MafA expression and thereby reduces insulin biosynthesis, which is often observed in type 2 diabetes.