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Transcription factor Ets-1 inhibits glucose-stimulated insulin secretion of pancreatic β-cells partly through up-regulation of COX-2 gene expression

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Abstract

Increased cyclooxygenase-2 (COX-2) expression is associated with pancreatic β-cell dysfunction. We previously demonstrated that the transcription factor Ets-1 significantly up-regulated COX-2 gene promoter activity. In this report, we used the pancreatic β-cell line INS-1 and isolated rat islets to investigate whether Ets-1 could induce β-cell dysfunction through up-regulating COX-2 gene expression. We investigated the effects of ETS-1 overexpression and the effects of ETS-1 RNA interference on endogenous COX-2 expression in INS-1 cells. We used site-directed mutagenesis and a dual luciferase reporter assay to study putative Ets-1 binding sites in the COX-2 promoter. The effect of ETS-1 1 overexpression on the insulin secretion function of INS-1 cells and rat islets and the potential reversal of these effects by a COX-2 inhibitor were determined in a glucose-stimulated insulin secretion (GSIS) assay. ETS-1 overexpression significantly induces endogenous COX-2 expression, but ETS-1 RNA interference has no effect on basal COX-2 expression in INS-1 cells. Ets-1 protein significantly increases COX-2 promoter activity through the binding site located in the −195/−186 region of the COX-2 promoter. ETS-1 overexpression significantly inhibited the GSIS function of INS-1 cells and islet cells and COX-2 inhibitor treatment partly reversed this effect. These findings indicated that ETS-1 overexpression induces β-cell dysfunction partly through up-regulation of COX-2 gene expression. Moreover, Ets-1, the transcriptional regulator of COX-2 expression, may be a potential target for the prevention of β-cell dysfunction mediated by COX-2.

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Acknowledgments

This work was supported in part by the National Natural Science Foundation of China (81001079, 81101802), the Natural Science Foundation of Zhejiang Province (Y2110310), the Natural Science Foundation of Jiangsu Province (BK2011845), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD, JX10231801).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biochemistry, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China

    Xiong-Fei Zhang

  2. Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, People’s Republic of China

    Yi Zhu & Jing-Jing Zhang

  3. Institute of Tumor Biology, Jiangsu Province Academy of Clinical Medicine, 300 Guangzhou Road, Nanjing, 210029, People’s Republic of China

    Yi Zhu & Jing-Jing Zhang

  4. Transfusion Laboratory, Jiangsu Province Blood Center, Nanjing, 210042, People’s Republic of China

    Wen-Biao Liang

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Correspondence to Jing-Jing Zhang.

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Xiong-Fei Zhang and Yi Zhu have contributed equally to this study.

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Zhang, XF., Zhu, Y., Liang, WB. et al. Transcription factor Ets-1 inhibits glucose-stimulated insulin secretion of pancreatic β-cells partly through up-regulation of COX-2 gene expression. Endocrine 46, 470–476 (2014). https://doi.org/10.1007/s12020-013-0114-9

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  • DOI: https://doi.org/10.1007/s12020-013-0114-9

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