Differentially expressed Maf family transcription factors, c-Maf and MafA, activate glucagon and insulin gene expression in pancreatic islet alpha- and beta-cells

• Published in: Journal of molecular endocrinology Vol. 32; no. 1; pp. 9 - 20
• Main Authors: Kataoka, K, Shioda, S, Ando, K, Sakagami, K, Handa, H, Yasuda, K
• Format: Journal Article
• Language: English
• Published: England BioScientifica 01-02-2004
• Subjects: Animals; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Glucagon - genetics; Glucagon - metabolism; HeLa Cells; Humans; Insulin - metabolism; Islets of Langerhans - metabolism; Maf Transcription Factors, Large; Mice; NIH 3T3 Cells; Promoter Regions, Genetic - genetics; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-maf; RNA, Small Interfering - metabolism; Trans-Activators - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation; Tumor Cells, Cultured
• ISSN: 0952-5041; 1479-6813
• DOI: 10.1677/jme.0.0320009

A basic-leucine zipper transcription factor, MafA, was recently identified as one of the most important transactivators of insulin gene expression. This protein controls the glucose-regulated and pancreatic beta-cell-specific expression of the insulin gene through a cis-regulatory element called RIPE3b/MARE (Maf-recognition element). Here, we show that MafA expression is restricted to beta-cells of pancreatic islets in vivo and in insulinoma cell lines. We also demonstrate that c-Maf, another member of the Maf family of transcription factors, is expressed in islet alpha-cells and in a glucagonoma cell line (alphaTC1), but not in gamma- and delta-cells. An insulinoma cell line, betaTC6, also expressed c-Maf, albeit at a low level. Chromatin immunoprecipitation assays demonstrated that Maf proteins associate with insulin and glucagon promoters in beta- and alpha-cell lines, respectively. c-Maf protein stimulated glucagon promoter activity in a transient luciferase assay, and activation of the glucagon promoter by c-Maf was more efficient than by the other alpha-cell-enriched transcription factors, Cdx2, Pax6, and Isl-1. Furthermore, inhibition of c-Maf expression in alphaTC1 cells by specific short hairpin RNA resulted in marked reduction of the glucagon promoter activity. Thus, c-Maf and MafA are differentially expressed in alpha- and beta-cells where they regulate glucagon and insulin gene expression, respectively.