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

Insulin plays a crucial role in the regulation of glucose-homeostasis, and its synthesis is regulated by several stimuli. The transcription of the hum an insulin gene, enhanced by an elevated intracellular concentration of cal cium ions, was completely blocked by Ca2+/calmodulin-dependent protein kina se inhibitor. The activity of the transcription factor activating transcrip tion factor-2 (ATF-2), which binds to the cAMP responsive elements of the h uman insulin gene, was enhanced by Ca2+/ calmodulin-dependent protein kinas e 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-termina l protein kinase (JNK) or p38 mitogen-activated protein (MAP) kinase. Furth ermore, when transfected into rat primary cultured islets, ATF-2 enhanced g lucose-induced insulin promoter activity, whereas cAMP response element-bin ding protein (CREB) repressed it. These results suggest a mechanism in whic h ATF-2 regulates insulin gene expression in pancreatic beta-cells, with th e transcriptional activity of ATF-2 being increased by an elevated concentr ation of calcium ions.