The impact of Ca²⁺/calmodulin-dependent protein kinase II on insulin gene expression in MIN6 cells

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• 作者：Mihoshi Suefuji^a ; Noboru Furukawa^a ; ^b ; ^{n-furu@gpo.kumamoto-u.ac.jp} ; Kazuya Matsumoto^a ; ^c ; Hiroshi Oiso^a ; Seiya Shimoda^a ; Tomoaki Yoshinaga^a ; Rina Matsuyama^a ; Katsutoshi Miyagawa^a ; Tatsuya Kondo^a ; Junji Kawashima^a ; Kaku Tsuruzoe^a ; ^d ; Eiichi Araki^a
• 关键词：CaMKII未2 ; CREB ; CREB binding protein ; CREB Ser142 ; Phosphorylation ; Insulin gene promoter
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2012
• 期刊代码：159_0006291x
• 类别：bio
• 出版时间：18 May, 2012
• 卷：421
• 期：4
• 页码：801-807
• 文件大小：844 K

摘要

Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is expressed in insulin-secreting 尾 cells. However, the effects of CaMKII on insulin synthesis are unknown. Although Ser133 phosphorylation of cyclic AMP-responsive element-binding protein (CREB) typically increases CREB transcriptional activity, CaMKII phosphorylates CREB at Ser142 and at Ser133 to exert a dominant inhibitory effect. Our objective was to characterize the role of CaMKII in insulin gene expression. In MIN6 cells, insulin gene promoter activity was significantly down-regulated by wild-type (WT) CaMKII未2, but was significantly upregulated after small interfering RNA (siRNA) knockdown of CaMKII未 expression. These results were independent of glucose concentrations and membrane depolarization. Insulin mRNA levels were also decreased by WT CaMKII未2 and increased by CaMKII未 siRNA. Downregulation of insulin gene promoter activity by WT CaMKII未2 was partly mediated via cyclic AMP-responsive element 2 (CRE2). WT CaMKII未2 significantly increased CREB phosphorylation at Ser142 and significantly decreased binding to CREB binding protein (CBP), whereas kinase dead CaMKII未2 did not. Our results indicate that CaMKII未2 downregulates insulin gene expression by Ser142 phosphorylation of CREB and reducing binding of CREB to CBP.