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The Repression of IRS2 Gene by ATF3, a Stress-Inducible Gene, Contributes to Pancreatic β-Cell Apoptosis

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

Key Words: ATF3, activating transcription factor 3 • ChIP, chromatin immunoprecipitation • CREB, cAMP response element-binding protein • FACS, fluorescence-activated cell sorting • GLP, glucagon-like peptide • IFN-, -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-, tumor necrosis factor-

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.

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