ATF3 inhibits PDX-1-stimulated transactivation

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• 作者：Won-Ho  ; Kim^b ;   ; ¹ ; Min Kyung  ; Jang^a ;   ; ¹ ; Choi Hee  ; Kim^a ; Hwa Kyoung  ; Shin^a ; Myeong Ho  ; Jung^a ;   ; ^{jung0603@pusan.ac.kr}
• 关键词：Type 2 diabetes ; ER stress ; ATF3 ; PDX-1 ; ¦Â-Cell dysfunction
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2011
• 出版时间：4 November 2011
• 年：2011
• 卷：414
• 期：4
• 页码：681-687
• 全文大小：638 K

文摘

Chronic endoplasmic reticulum (ER) stress leads to ¦Â-cell failure via reduction of pancreatic and duodenal homeobox-1 (PDX-1) activity, which contributes to the pathogenesis of type 2 diabetes. However, the exact mechanisms by which ER stress reduces PDX-1 activity in pancreatic ¦Â-cells are unclear. Previously, we showed that ATF3 downregulates PDX-1 gene expression in MIN6N8 pancreatic ¦Â-cells. Here, we investigated another role of ATF3 on the regulation of PDX-1 activity. ATF3 significantly inhibited PDX-1-stimulated transactivation of reporter plasmid containing promoters for PDX-1 binding element and the PDX-1 target gene glucokinase, which is dependent on C-terminal domain of ATF3. ATF3 interacted with PDX-1, and effectively inhibited p300-mediated transcriptional coactivation of the PBE-containing promoter, whereas C-terminal domain-deleted ATF3 did not inhibit the transcoactivation of p300. ATF3 decreased the interaction of p300 with PDX-1 in MIN6N8 cells coexpressing PDX-1 and ATF3. In addition, chromatin immunoprecipitation analysis demonstrated that both tunicamycin treatment and ATF3 overexpression inhibited the recruitment of p300 to PDX-1 on the insulin promoter in MIN6N8 cells. Taken together, these results suggest that ATF3 inhibits PDX-1-mediated transactivation through the inhibition of p300-stimulated coactivation, which may lead to ¦Â-cell dysfunction by ER stress.