title: ATF3 represses PDX-1 expression in pancreatic β-cells.
abstract: The downregulation of PDX-1 expression plays an important role in development of type 2 diabetes. However, the negative regulator of PDX-1 expression is not well known. In this study, we analyzed the mouse PDX-1 promoter to characterize the effects of ATF3 on PDX-1 expression in pancreatic β-cells. Both thapsigargin treatment, an inducer of ER stress, and ATF3 expression decreased PDX-1 expression in pancreatic β-cells, MIN6N8. Furthermore, they also repressed the activity of -4.5 Kb promoter of mouse PDX-1 gene. Transfection studies with 5' deleted-reporters showed that ATF3 repressed the activity of 0.9Kb PDX-1 promoter, whereas it did not affect the activity of 0.7 Kb PDX-1 promoter, suggesting that ATF3 responsive element is located between the -903 and -702. An electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that ATF3 binds directly to the promoter region spanning from -759 to -738. Moreover, mutation of the putative ATF/CRE site between -752 and -745 abrogated ATF3-mediated transrepression of the PDX-1 promoter. PDX-1 was decreased in MIN6N8 cells treated with high glucose or high palmitate, whereas ATF3 was increased, indicating that ATF3 plays a role in hyperglycemia or hyperlipidemia-mediated downregulation of PDX-1 expression. Collectively, these results demonstrate that ATF3 represses PDX-1 expression via binding to an ATF3-responsive element in its promoter, which plays an important role in suppression of pancreatic β-cells function.
authors.affiliation: Pusan National University, School of Korean Medicine, #30 Beom-eo ri, Mulguem-eup, Yangsan-si, Gyeongnam 609-735, South Korea.
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Jang
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Park
authors.forename: Myeong Ho
authors.initials: MH
authors.lastname: Jung
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics; D006949:Hyperlipidemias / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein