ATF3 inhibits PDX-1-stimulated transactivation

作者：Kim Won Ho; Jang Min Kyung; Kim Choi Hee; Shin Hwa Kyoung; Jung Myeong Ho^*

来源：Biochemical and Biophysical Research Communications, 2011, 414(4): 681-687.

DOI：10.1016/j.bbrc.2011.09.132

• Type 2 diabetes
• ER stress
• ATF3
• PDX-1
• beta-Cell dysfunction

Chronic endoplasmic reticulum (ER) stress leads to p-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 beta-cells are unclear. Previously, we showed that ATF3 downregulates PDX-1 gene expression in MIN6N8 pancreatic beta-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 beta-cell dysfunction by ER stress.

• 出版日期2011-11-4