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 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.
Department of Metabolism and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Japan.
N
N
Ban
Y
Y
Yamada
Y
Y
Someya
Y
Y
Ihara
T
T
Adachi
A
A
Kubota
R
R
Watanabe
A
A
Kuroe
A
A
Inada
K
K
Miyawaki
Y
Y
Sunaga
Z P
ZP
Shen
T
T
Iwakura
K
K
Tsukiyama
S
S
Toyokuni
K
K
Tsuda
Y
Y
Seino
D051698:Activating Transcription Factor 2; D019943:Amino Acid Substitution; D000818:Animals; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000235:genetics*; D007515:Islets of Langerhans / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D008297:Male; D051379:Mice; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; C497107:Atf2 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D007328:Insulin; D011994:Recombinant Proteins; D014157:Transcription Factors; D008156:Luciferases; C517683:CAMK4 protein, human; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517685:Camk4 protein, mouse; C517686:Camk4 protein, rat; D005947:Glucose