Activating transcription factor-2 is a positive regulator in CaM kinase IV-induced human insulin gene expression.

  1. N Ban,
  2. Y Yamada,
  3. Y Someya,
  4. Y Ihara,
  5. T Adachi,
  6. A Kubota,
  7. R Watanabe,
  8. A Kuroe,
  9. A Inada,
  10. K Miyawaki,
  11. Y Sunaga,
  12. Z P Shen,
  13. T Iwakura,
  14. K Tsukiyama,
  15. S Toyokuni,
  16. K Tsuda and
  17. Y Seino
  1. Department of Metabolism and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Japan.

    Abstract

    Insulin plays a crucial role in the regulation of glucose-homeostasis, and its synthesis is regulated by several stimuli. The transcription of the human insulin gene, enhanced by an elevated intracellular concentration of calcium ions, was completely blocked by Ca2+/calmodulin-dependent protein kinase inhibitor. The activity of the transcription factor activating transcription factor-2 (ATF-2), which binds to the cAMP responsive elements of the human insulin gene, was enhanced by Ca2+/calmodulin-dependent protein kinase IV (CaMKIV). Mutagenesis studies showed that Thr69, Thr71, and Thr73 of ATF-2 are all required for activation by CaMKIV. CaMKIV-induced ATF-2 transcriptional activity was not altered by activation of cJun NH2-terminal protein kinase (JNK) or p38 mitogen-activated protein (MAP) kinase. Furthermore, when transfected into rat primary cultured islets, ATF-2 enhanced glucose-induced insulin promoter activity, whereas cAMP response element-binding protein (CREB) repressed it. These results suggest a mechanism in which ATF-2 regulates insulin gene expression in pancreatic beta-cells, with the transcriptional activity of ATF-2 being increased by an elevated concentration of calcium ions.

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