Transcriptional regulation of the IAPP gene in pancreatic beta-cells.
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.
Shepherd
Louisa M A
LM
School of Cell and Molecular Biosciences, University of Newcastle upon Tyne, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
Campbell
Susan C
SC
Macfarlane
Wendy M
WM
D000682:Amyloid / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000897:Anti-Ulcer Agents / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D005934:Glucagon / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051542:Hepatocyte Nuclear Factor 3-beta; D007328:Insulin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011498:Protein Precursors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013004:Somatostatin / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000682:Amyloid; D000897:Anti-Ulcer Agents; D004268:DNA-Binding Proteins; C496503:Foxa2 protein, mouse; C496504:Foxa2 protein, rat; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496489:Hnf1a protein, rat; D007328:Insulin; D007375:Interleukin-1; D058228:Islet Amyloid Polypeptide; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011498:Protein Precursors; D012333:RNA, Messenger; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D051537:Hepatocyte Nuclear Factor 1; D051542:Hepatocyte Nuclear Factor 3-beta; D013004:Somatostatin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon