The minimal promoter region of the dense-core vesicle protein IA-2: transcriptional regulation by CREB

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• 作者：Tao Cai ; Hiroki Hirai ; Huanyu Xu ; Abner L. Notkins
• 关键词：Dense ; core vesicle ; Insulin ; IA ; 2 ; Promoter ; PKA pathway ; CREB ; binding site
• 刊名：Acta Diabetologica
• 出版年：2015
• 出版时间：June 2015
• 年：2015
• 卷：52
• 期：3
• 页码：573-580
• 全文大小：756 KB
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• 作者单位：Tao Cai (1)
  Hiroki Hirai (1)
  Huanyu Xu (1)
  Abner L. Notkins (1)
  
  1. Experimental Medicine Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), B30/Rm106, Bethesda, MD, 20892, USA
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Internal Medicine
  Diabetes
  Metabolic Diseases
  
• 出版者：Springer Milan
• ISSN：1432-5233

文摘

Aims IA-2 is a transmembrane protein found in the dense-core vesicles (DCV) of neuroendocrine cells and one of the major autoantigens in type 1 diabetes. DCV are involved in the secretion of hormones (e.g., insulin) and neurotransmitters. Stimulation of pancreatic β cells with glucose upregulates the expression of IA-2 and an increase in IA-2 results in an increase in the number of DCV. Little is known, however, about the promoter region of IA-2 or the transcriptional factors that regulate the expression of this gene. Methods In the present study, we constructed eight deletion fragments from the upstream region of the IA-2 transcription start site and linked them to a luciferase reporter. Results By this approach, we have identified a short bp region (?16 to +115) that has strong promoter activity. We also identified a transcription factor, cAMP responsive element-binding protein (CREB), which binds to two CREB-related binding sites located in this region. The binding of CREB to these sites enhanced IA-2 transcription by more than fivefold. We confirmed these findings by site-directed mutagenesis, chromatin immunoprecipitation assays and RNAi inhibition. Conclusion Based on these findings, we conclude that the PKA pathway is a critical, but not the exclusive signaling pathway involved in IA-2 gene expression.