Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is expressed in insulin-secreting β 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) CaMKIIδ2, but was significantly upregulated after small interfering RNA (siRNA) knockdown of CaMKIIδ expression. These results were independent of glucose concentrations and membrane depolarization. Insulin mRNA levels were also decreased by WT CaMKIIδ2 and increased by CaMKIIδ siRNA. Downregulation of insulin gene promoter activity by WT CaMKIIδ2 was partly mediated via cyclic AMP-responsive element 2 (CRE2). WT CaMKIIδ2 significantly increased CREB phosphorylation at Ser142 and significantly decreased binding to CREB binding protein (CBP), whereas kinase dead CaMKIIδ2 did not. Our results indicate that CaMKIIδ2 downregulates insulin gene expression by Ser142 phosphorylation of CREB and reducing binding of CREB to CBP.
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