| First Author | Kim WH | Year | 2011 |
| Journal | Biochem Biophys Res Commun | Volume | 414 |
| Issue | 4 | Pages | 681-7 |
| PubMed ID | 21986529 | Mgi Jnum | J:178442 |
| Mgi Id | MGI:5298409 | Doi | 10.1016/j.bbrc.2011.09.132 |
| Citation | Kim WH, et al. (2011) ATF3 inhibits PDX-1-stimulated transactivation. Biochem Biophys Res Commun 414(4):681-7 |
| abstractText | Chronic endoplasmic reticulum (ER) stress leads to beta-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. |
