Related Experiment Video

Updated: May 28, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

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
PubMed

Insights

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.

More Related Videos

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter11:32

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter

Published on: March 27, 2020

Related Concept Videos

The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a DNA...