Activating transcription factor-2 is a positive regulator in CaM kinase IV-induced human insulin gene expression.
- N Ban,
- Y Yamada,
- Y Someya,
- Y Ihara,
- T Adachi,
- A Kubota,
- R Watanabe,
- A Kuroe,
- A Inada,
- K Miyawaki,
- Y Sunaga,
- Z P Shen,
- T Iwakura,
- K Tsukiyama,
- S Toyokuni,
- K Tsuda and
- Y Seino
- 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.
