The Repression of IRS2 Gene by ATF3, a Stress-Inducible Gene, Contributes to Pancreatic β-Cell Apoptosis
The Repression of IRS2 Gene by ATF3, a Stress-Inducible Gene, Contributes to Pancreatic β-Cell Apoptosis Dan Li 1 , Xin Yin 1 , Erik J. Zmuda 1 , 2 , Christopher C. Wolford 1 , 3 , Xiaocheng Dong 4 , Morris F. White 4 , 5 and Tsonwin Hai 1 , 2 , 3 1 Department of Molecular and Cellular Biochemistry,...
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Published in | Diabetes (New York, N.Y.) Vol. 57; no. 3; pp. 635 - 644 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Alexandria, VA
American Diabetes Association
01.03.2008
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Subjects | |
Online Access | Get full text |
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Summary: | The Repression of IRS2 Gene by ATF3, a Stress-Inducible Gene, Contributes to Pancreatic β-Cell Apoptosis
Dan Li 1 ,
Xin Yin 1 ,
Erik J. Zmuda 1 , 2 ,
Christopher C. Wolford 1 , 3 ,
Xiaocheng Dong 4 ,
Morris F. White 4 , 5 and
Tsonwin Hai 1 , 2 , 3
1 Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, the Ohio State Biochemistry Program,
Ohio State University, Columbus, Ohio
2 Molecular, Cellular and Developmental Biology Program, Ohio State University, Columbus, Ohio
3 Integrated Biomedical Graduate Program, Ohio State University, Columbus, Ohio
4 Children's Hospital, Harvard Medical School, Boston, Massachusetts
5 Howard Hughes Medical Institute, Boston, Massachusetts
Address correspondence and reprint requests to Tsonwin Hai, Room 174 Rightmire Hall, 1060 Carmack Rd., Ohio State University,
Columbus, OH 43210. E-mail: hai.2{at}osu.edu
Abstract
OBJECTIVE —β-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 β-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 β-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 β-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 β-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.
ATF3, activating transcription factor 3
ChIP, chromatin immunoprecipitation
CREB, cAMP response element-binding protein
FACS, fluorescence-activated cell sorting
GLP, glucagon-like peptide
IFN-γ, γ-interferon
IL-1β, interleukin-1β
IRS2, insulin receptor substrate 2
MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
RIP, rat insulin promoter
TNF-α, tumor necrosis factor-α
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 5 December 2007. DOI: 10.2337/db07-0717.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0717 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received May 28, 2007.
Accepted November 20, 2007.
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0012-1797 1939-327X |
DOI: | 10.2337/db07-0717 |