胰岛β细胞中IAPP基因的转录调控

Transcriptional regulation of the IAPP gene in pancreatic beta-cells.

作者信息

Shepherd Louisa M A, Campbell Susan C, Macfarlane Wendy M

机构信息

School of Cell and Molecular Biosciences, University of Newcastle upon Tyne, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.

出版信息

Biochim Biophys Acta. 2004 Nov 24;1681(1):28-37. doi: 10.1016/j.bbaexp.2004.09.009.

DOI:10.1016/j.bbaexp.2004.09.009

PMID:15566941

Abstract

Islet amyloid polypeptide (IAPP or amylin) is co-secreted with insulin from the pancreatic beta-cells. Transcription of the IAPP gene is controlled by a complex promoter region, spanning from -2798 to +450 relative to the transcriptional start site. In the present study, we have used reporter gene analysis and semi-quantitative RT-PCR to establish that insulin, glucagon, glucagon-like peptide-1 (GLP-1) and the GLP-1 derivatives GLP(7-36)Amide and Exendin-4 all stimulate IAPP promoter activity, as well as endogenous IAPP mRNA levels in isolated islets of Langerhans. In contrast, somatostatin had no effect, and whilst the inflammatory cytokines TNF-alpha, IL-1alpha and IL-1beta had no effect on promoter activity, they all decreased IAPP mRNA levels in isolated islets. Finally, utilising a series of deletion reporter gene constructs of the human IAPP gene promoter, we used overexpression studies to establish that HNF-3beta (FoxA2) negatively regulates the IAPP promoter, whilst the MODY3 transcription factor HNF-1alpha positively regulates promoter activity.

摘要

胰岛淀粉样多肽（IAPP或胰淀素）与胰岛素一起从胰腺β细胞共同分泌。IAPP基因的转录由一个复杂的启动子区域控制，该区域相对于转录起始位点从-2798到+450。在本研究中，我们使用报告基因分析和半定量RT-PCR来确定胰岛素、胰高血糖素、胰高血糖素样肽-1（GLP-1）以及GLP-1衍生物GLP（7-36）酰胺和艾塞那肽-4均能刺激IAPP启动子活性，以及在分离的胰岛中内源性IAPP mRNA水平。相比之下，生长抑素没有作用，并且虽然炎性细胞因子TNF-α、IL-1α和IL-1β对启动子活性没有影响，但它们均降低了分离胰岛中的IAPP mRNA水平。最后，利用一系列人IAPP基因启动子的缺失报告基因构建体，我们通过过表达研究确定HNF-3β（FoxA2）负向调节IAPP启动子，而MODY3转录因子HNF-1α正向调节启动子活性。