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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid / genetics*
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Amyloid / metabolism
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Animals
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Anti-Ulcer Agents / metabolism*
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Cells, Cultured
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation*
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Glucagon / pharmacology
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Glucagon-Like Peptide 1
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Hepatocyte Nuclear Factor 1
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Hepatocyte Nuclear Factor 1-alpha
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Hepatocyte Nuclear Factor 3-beta
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Insulin / pharmacology
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Interleukin-1 / pharmacology
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Islet Amyloid Polypeptide
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Islets of Langerhans / cytology
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Islets of Langerhans / metabolism*
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Male
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Mice
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Mice, Transgenic
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Nuclear Proteins / metabolism
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Peptide Fragments / pharmacology
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Promoter Regions, Genetic / genetics*
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Protein Precursors / pharmacology
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RNA, Messenger / genetics
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Rats
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Rats, Wistar
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Reverse Transcriptase Polymerase Chain Reaction
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Somatostatin / pharmacology
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Transcription Factors / metabolism
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Transcription, Genetic*
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Amyloid
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Anti-Ulcer Agents
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DNA-Binding Proteins
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Foxa2 protein, mouse
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Foxa2 protein, rat
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Hepatocyte Nuclear Factor 1-alpha
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Hnf1a protein, mouse
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Hnf1a protein, rat
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Insulin
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Interleukin-1
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Islet Amyloid Polypeptide
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Nuclear Proteins
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Peptide Fragments
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Protein Precursors
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RNA, Messenger
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Hepatocyte Nuclear Factor 1
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Hepatocyte Nuclear Factor 3-beta
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Somatostatin
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Glucagon-Like Peptide 1
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Glucagon