Inhibitory effect of Pax4 on the human insulin and islet amyloid polypeptide (IAPP) promoters

Campbell, Susan L.; Cragg, Helen; Elrick, Lucy J.; Macfarlane, Wendy M.; Shennan, K. I. J.; Docherty, Kevin

doi:10.1016/s0014-5793(99)01584-7

Cited by 35 publications

(20 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The transcription factor PDX-1 is a primary regulator of insulin expression along with MafA, E47/␤2, and cAMP-associated regulation (43). C/EBP␤ and PAX4 negatively regulate the insulin promoter (44,45) and an inhibitory sequence (Ϫ279 to Ϫ258) referred to as the negative regulatory element lies within the glucose sensing Z element (Ϫ243 to Ϫ292) on the human insulin promoter (32,33). Interestingly, the negative regulatory element acts as a potent glucose-responsive transcriptional enhancer in primary cultured islet cells and as a transcriptional repressor in immortalized ␤-cells, non-␤-cells, and in fibroblasts (32).…”

Section: Function In Smad3mentioning

confidence: 99%

Transforming Growth Factor-β/Smad3 Signaling Regulates Insulin Gene Transcription and Pancreatic Islet β-Cell Function

Lin

Lee

Yadav

et al. 2009

Journal of Biological Chemistry

150

155

View full text Add to dashboard Cite

Pancreatic islet ␤-cell dysfunction is a signature feature of Type 2 diabetes pathogenesis. Consequently, knowledge of signals that regulate ␤-cell function is of immense clinical relevance. Transforming growth factor (TGF)-␤ signaling plays a critical role in pancreatic development although the role of this pathway in the adult pancreas is obscure. Here, we define an important role of the TGF-␤ pathway in regulation of insulin gene transcription and ␤-cell function. We identify insulin as a TGF-␤ target gene and show that the TGF-␤ signaling effector Smad3 occupies the insulin gene promoter and represses insulin gene transcription. In contrast, Smad3 small interfering RNAs relieve insulin transcriptional repression and enhance insulin levels. Transduction of adenoviral Smad3 into primary human and non-human primate islets suppresses insulin content, whereas, dominant-negative Smad3 enhances insulin levels. Consistent with this, Smad3-deficient mice exhibit moderate hyperinsulinemia and mild hypoglycemia. Moreover, Smad3 deficiency results in improved glucose tolerance and enhanced glucose-stimulated insulin secretion in vivo. In ex vivo perifusion assays, Smad3-deficient islets exhibit improved glucosestimulated insulin release. Interestingly, Smad3-deficient islets harbor an activated insulin-receptor signaling pathway and TGF-␤ signaling regulates expression of genes involved in ␤-cell function. Together, these studies emphasize TGF-␤/Smad3 signaling as an important regulator of insulin gene transcription and ␤-cell function and suggest that components of the TGF-␤ signaling pathway may be dysregulated in diabetes.

show abstract

Section: Function In Smad3mentioning

confidence: 99%

Transforming Growth Factor-β/Smad3 Signaling Regulates Insulin Gene Transcription and Pancreatic Islet β-Cell Function

Lin

Lee

Yadav

et al. 2009

Journal of Biological Chemistry

150

155

View full text Add to dashboard Cite

show abstract

“…Therefore, identifying potential targets of Pax4 is a necessary step toward learning how this transcription factor controls early endocrine development in the pancreas. Previous studies have shown that, in certain cellular contexts, Pax4 directly represses the expression of various islet genes, including glucagon, Arx, islet amyloid polypeptide (IAPP), and insulin (Campbell et al, 1999;Fujitani, et al, 1999;Kaulosova, et al, 1999;Smith, et al, 1999;Petersen, et al, 2000;Ritz-Laser et al, 2002;Collombat et al, 2005). Consequently, it has been proposed that, in developing endocrine cells of the pancreas, Pax4 functions primarily as a transcriptional repressor (Fujitani et al, 1999;Smith et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

ghrelinis a novel target of Pax4 in endocrine progenitors of the pancreas and duodenum

Wang

Elghazi

Martin

et al. 2007

Developmental Dynamics

View full text Add to dashboard Cite

Pax4-deficient mice have a severe gastrointestinal endocrine deficiency: they lack most pancreatic cells that produce insulin or somatostatin and various duodenal endocrine cell types. Remarkably, Pax4-deficient mice also have an overabundance of ghrelin-expressing cells in the pancreas and duodenum. Detailed analysis of the Pax4 nullizygous pancreas determined that the mutant islets are largely composed of a distinctive endocrine cell type that expresses ghrelin, glucagon, islet amyloid polypeptide (IAPP), and low levels of Pdx1. Lineage-tracing analysis revealed that most of these unique endocrine cells directly arose from Pax4-deficient progenitors. Previous in vitro work reported that Pax4 is a transcriptional repressor of islet amyloid polypeptide (IAPP) and glucagon. In this study, we expanded those results by showing that Pax4 is also a repressor of gherlin. Together, our data further support the notion that Pax4 activity is necessary to establish appropriate patterns of gene expression in endocrine progenitors of the digestive tract. Developmental Dynamics 237:51-61, 2008.

show abstract

“…Insulin secretion is regulated by a variety of transcription factors in pancreatic beta cells (12), such as Pax4 (13), Nkx6.1 (14,15), Maf (16,17), Foxa (18), Pdx1 (19,20), and LIM-homeodomain transcription factor Isl-1 (7), most of which are required for pancreatic development and cell functions (21)(22)(23)(24)(25). A genetic study of a morbidly obese human population suggests that Isl-1 is associated with type 2 diabetes (26).…”

mentioning

confidence: 99%

LIM-homeodomain Transcription Factor Isl-1 Mediates the Effect of Leptin on Insulin Secretion in Mice

Chen

Cui

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Leptin and Isl-1 have functions to regulate the insulin secretion, but the interaction between Leptin and Isl-1 remains unknown. Results: Isl-1 mediates the signaling pathway of leptin affecting insulin secretion. Conclusion: Isl-1 and STAT3 are the keynote proteins linking the leptin and insulin signaling networks. Significance: These findings are crucial for understanding the mechanisms of insulin secretion and metabolism.

show abstract

Inhibitory effect of Pax4 on the human insulin and islet amyloid polypeptide (IAPP) promoters

Cited by 35 publications

References 26 publications

Transforming Growth Factor-β/Smad3 Signaling Regulates Insulin Gene Transcription and Pancreatic Islet β-Cell Function

Transforming Growth Factor-β/Smad3 Signaling Regulates Insulin Gene Transcription and Pancreatic Islet β-Cell Function

ghrelinis a novel target of Pax4 in endocrine progenitors of the pancreas and duodenum

LIM-homeodomain Transcription Factor Isl-1 Mediates the Effect of Leptin on Insulin Secretion in Mice

Contact Info

Product

Resources

About