Activating transcription factor-2 is a positive regulator in CaM kinase IV - Induced human insulin gene expression
Activating transcription factor-2 is a positive regulator in CaM kinase IV - Induced human insulin gene expression
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DOI：
10.2337/diabetes.49.7.1142
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发表时间：
2000-07-01
期刊：
影响因子：
7.7
通讯作者：
Seino, Y
中科院分区：
文献类型：
--
作者：
Ban, N;Yamada, Y;Seino, Y
胰岛素在葡萄糖稳态调节中起着至关重要的作用，其合成受多种刺激物的调节。人胰岛素基因的转录，提高了细胞内钙离子浓度，被完全阻断的Ca 2 +/钙调蛋白依赖性蛋白激酶抑制剂。转录因子激活转录因子-2（ATF-2）与人胰岛素基因的cAMP反应元件结合，其活性通过Ca 2 +/钙调蛋白依赖性蛋白激酶IV（CaMKIV）增强。突变研究表明ATF-2的Thr（69）、Thr（71）和Thr（73）都是CaMKIV激活所必需的。CaMKIV诱导的ATF-2转录活性不受c-Jun NH 2-末端蛋白激酶（JNK）或p38丝裂原活化蛋白（MAP）激酶激活的影响。此外，当转染到大鼠原代培养的胰岛，ATF-2增强葡萄糖诱导的胰岛素启动子的活性，而cAMP反应元件结合蛋白（CREB）repressedit. These结果表明，ATF-2调节胰岛素基因表达的胰腺β细胞的机制，与ATF-2的转录活性增加的钙离子浓度升高。
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 Thr(69), Thr(71), and Thr(73) of ATF-2 are all required for activation by CaMKIV. CaMKIV-induced ATF-2 transcriptional activity was not altered by activation of c-Jun 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.