Differentially expressed Maf family transription factors, c-Maf and MafA, activate glucagon and insulin gene expression in pancreatic islet α- and β-cells

Abstract

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 β-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 β-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 α-cells and in a glucagonoma cell line (αTC1), but not in γ- and δ-cells. An insulinoma cell line, βTC6, also expressed c-Maf, albeit at a low level. Chromatin immunoprecipitation assays demonstrated that Maf proteins associate with insulin and glucagon promoters in β- and α-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 α-cell-enriched transcription factors, Cdx2, Pax6, and lsl-1. Furthermore, inhibition of c-Maf expression in αTC1 cells by specific short hairpin RNA resulted in marked reduction of the glucagon promoter activity. Thus, c-Maf and MafA are differentially expressed in α- and β-cells where they regulate glucagon and insulin gene expression, respectively. © 2004 Society for Endocrinology.