ATF3 represses PDX-1 expression in pancreatic ¦Â-cells

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• 作者：Min Kyung Jang ; Hyun Jin Park ; Myeong Ho Jung  ; ;   ; ^{jung0603@pusan.ac.kr}
• 关键词：Pancreatic and duodenal homeobox factor-1 (PDX-1) ; Activating transcription factor 3 (ATF3) ; Promoter ; ATF/CREB responsive element (ATF/CRE) ; Hyperglycemia ; Hyperlipidemia
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2011
• 出版时间：26 August 2011
• 年：2011
• 卷：412
• 期：2
• 页码：385-390
• 全文大小：492 K

文摘

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 ¦Â-cells. Both thapsigargin treatment, an inducer of ER stress, and ATF3 expression decreased PDX-1 expression in pancreatic ¦Â-cells, MIN6N8. Furthermore, they also repressed the activity of ?.5 Kb promoter of mouse PDX-1 gene. Transfection studies with 5?deleted-reporters showed that ATF3 repressed the activity of 0.9 Kb 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 ?03 and ?02. An electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that ATF3 binds directly to the promoter region spanning from ?59 to ?38. Moreover, mutation of the putative ATF/CRE site between ?52 and ?45 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 ¦Â-cells function.