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

¹Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, The Ohio State Biochemistry Program
²Molecular, Cellular and Developmental Biology Program
³Integrated Biomedical Graduate Program
⁴Ohio State University, Columbus, OH 43210, Children's Hospital, Harvard Medical School, Boston, MA 02115
⁵Howard Hughes Medical Institute

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 pro-apoptotic gene, down-regulates 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 (ChIP) assay and the transcription of the IRS2 gene by polymerase II occupancy assay. Furthermore, we tested the ability of IRS2 to alleviate the pro-apoptotic effects of ATF3 in both cultured β cells and transgenic mice using the rat insulin promoter (RIP) 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 down-regulate 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. Since 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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