Ban N, Yamada Y, Someya Y, Ihara Y, Adachi T, Kubota A, Watanabe R, Kuroe A, Inada A, Miyawaki K, Sunaga Y, Shen Z P, Iwakura T, Tsukiyama K, Toyokuni S, Tsuda K, Seino Y
Department of Metabolism and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Japan.
Diabetes. 2000 Jul;49(7):1142-8. doi: 10.2337/diabetes.49.7.1142.
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.
胰岛素在葡萄糖稳态调节中起关键作用，其合成受多种刺激调控。人胰岛素基因的转录受细胞内钙离子浓度升高增强，而被Ca2+/钙调蛋白依赖性蛋白激酶抑制剂完全阻断。与人类胰岛素基因的cAMP反应元件结合的转录因子激活转录因子-2（ATF-2）的活性，被Ca2+/钙调蛋白依赖性蛋白激酶IV（CaMKIV）增强。诱变研究表明，ATF-2的苏氨酸69、苏氨酸71和苏氨酸73都是CaMKIV激活所必需的。CaMKIV诱导的ATF-2转录活性不会因cJun NH2末端蛋白激酶（JNK）或p38丝裂原活化蛋白（MAP）激酶的激活而改变。此外，当转染到大鼠原代培养胰岛中时，ATF-2增强葡萄糖诱导的胰岛素启动子活性，而cAMP反应元件结合蛋白（CREB）则抑制该活性。这些结果提示了一种机制，即ATF-2在胰岛β细胞中调节胰岛素基因表达，且钙离子浓度升高会增加ATF-2的转录活性。
