title: ATF3 inhibits PDX-1-stimulated transactivation.
abstract: Chronic endoplasmic reticulum (ER) stress leads to β-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 β-cells are unclear. Previously, we showed that ATF3 downregulates PDX-1 gene expression in MIN6N8 pancreatic β-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 β-cell dysfunction by ER stress.
authors: Division of Metabolic Disease, Department of Biomedical Science, National Institutes of Health, #194 Tongillo, Eunpyung-gu, Seoul 122-701, South Korea.
authors: Won-Ho
authors: WH
authors: Kim
authors: Min Kyung
authors: MK
authors: Jang
authors: Choi Hee
authors: CH
authors: Kim
authors: Hwa Kyoung
authors: HK
authors: Shin
authors: Myeong Ho
authors: MH
authors: Jung
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D013312:Stress, Physiological / Q000235:genetics*; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015533:Transcriptional Activation; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D050880:p300-CBP Transcription Factors