Transcriptional regulation of the IAPP gene in pancreatic beta-cells

Abstract

Islet amyloid polypeptide (IAPP or amylin) is co-secreted with insulin from the pancreatic β-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-α, IL-1α and IL-1β 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-3β (FoxA2) negatively regulates the IAPP promoter, whilst the MODY3 transcription factor HNF-1α positively regulates promoter activity.