4.7 Article

The repression of IRS2 gene by ATF3, a stress-inducible gene, contributes to pancreatic β-cell apoptosis

Journal

DIABETES
Volume 57, Issue 3, Pages 635-644

Publisher

AMER DIABETES ASSOC
DOI: 10.2337/db07-0717

Keywords

-

Funding

  1. NIDDK NIH HHS [R01-DK-064938, R01-DK-59605, R01 DK059605, R01 DK064938] Funding Source: Medline
  2. NINDS NIH HHS [P30-NS-045758] Funding Source: Medline

Ask authors/readers for more resources

OBJECTIVE-P-Cell failure is an essential component of all types of diabetes, and the insulin receptor substrate 2 (IRS2) branch of signaling plays a key role in beta-cell survival and function. We tested the hypothesis that activating transcription factor 3 (ATF3), a stress-inducible proapoptotic gene, downregulates the expression of IRS2 in beta-cells. RESEARCH DESIGN AND METHODS-We used both the gain- and loss-of-function approaches to test the effects of ATF3 on IRS2 gene expression. We also analyzed the binding of ATF3 to the IRS2 promoter by chromatin immunoprecipitation assay and the transcription of the IRS2 gene by polymerase II occupancy assay. Furthermore, we tested the ability of IRS2 to alleviate the proapoptotic effects of ATF3 in cultured beta-cells and in transgenic mice using the rat insulin promoter to drive the transgenes. RESULTS-Expression of ATF3 is sufficient to reduce IRS2 gene expression; in contrast, knockdown or knockout of ATF3 reduces the ability of stress signals to downregulate IRS2 expression. ATF3 binds to the IRS2 promoter in vivo, and the binding of ATF3 correlates with decreased IRS2 gene transcription. Functionally, expression of IRS2 protects beta-cells from ATF3-induced apoptosis. CONCLUSIONS-IRS2 is a target gene of ATF3, and its repression by ATF3 contributes, at least partly, to the apoptosis induced by ATF3. Because ATF3 is a stress-inducible gene, our work provides a direct link to explain how environmental stress factors can modulate IRS2 gene transcription.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available