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ATF3 inhibits PDX-1-stimulated transactivation
Won-Ho Kim1, Min Kyung Jang, Choi Hee Kim
1Division of Metabolic Disease, Department of Biomedical Science, National Institutes of Health, #194 Tongillo, Eunpyung-gu, Seoul 122-701, South Korea.
Biochemical and Biophysical Research Communications
|October 12, 2011
Summary
Endoplasmic reticulum (ER) stress impairs pancreatic beta-cell function by reducing PDX-1 activity. ATF3 protein inhibits PDX-1 activity by blocking p300 coactivation, contributing to type 2 diabetes pathogenesis.
Area of Science:
- Molecular Biology
- Endocrinology
- Cell Biology
Background:
- Chronic endoplasmic reticulum (ER) stress is implicated in pancreatic beta-cell failure and type 2 diabetes.
- Pancreatic and duodenal homeobox-1 (PDX-1) activity is crucial for beta-cell function, and its reduction contributes to diabetes pathogenesis.
- The precise mechanisms by which ER stress diminishes PDX-1 activity remain incompletely understood.
Purpose of the Study:
- To elucidate the role of ATF3 in regulating PDX-1 activity in pancreatic beta-cells under ER stress conditions.
- To investigate how ATF3 modulates PDX-1-mediated gene transactivation and its interaction with coactivators.
Main Methods:
- Reporter gene assays to assess PDX-1 transactivation.
- Co-immunoprecipitation to study protein-protein interactions between ATF3, PDX-1, and p300.
- Chromatin immunoprecipitation to analyze the recruitment of p300 to the insulin promoter.
Main Results:
- ATF3 significantly inhibited PDX-1-stimulated transactivation of reporter plasmids containing PDX-1 binding elements and the glucokinase promoter.
- This inhibition was dependent on the C-terminal domain of ATF3 and involved interaction with PDX-1.
- ATF3 blocked p300-mediated coactivation of PDX-1 and decreased the interaction between p300 and PDX-1.
- ER stress (tunicamycin) and ATF3 overexpression reduced p300 recruitment to PDX-1 on the insulin promoter.
Conclusions:
- ATF3 inhibits PDX-1-mediated transactivation by interfering with p300 coactivation.
- This ATF3-mediated mechanism contributes to ER stress-induced beta-cell dysfunction.
- Understanding this pathway offers potential therapeutic targets for type 2 diabetes.
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