title: MafA is a glucose-regulated and pancreatic beta-cell-specific transcriptional activator for the insulin gene.
abstract: The insulin gene is specifically expressed in beta-cells of the Langerhans islets of the pancreas, and its transcription is regulated by the circulating glucose level. Previous reports have shown that an unidentified beta-cell-specific nuclear factor binds to a conserved cis-regulatory element called RIPE3b and is critical for its glucose-regulated expression. Based on the sequence similarity of the RIPE3b element and the consensus binding sequence of the Maf family of basic leucine zipper transcription factors, we here identified mammalian homologue of avian MafA/L-Maf, an eye-specific member of the Maf family, as the RIPE3b-binding transcriptional activator. Reverse transcription-PCR analysis showed that mafA mRNA is detected only in the eyes and in pancreatic beta-cells and not in alpha-cells. MafA protein as well as its mRNA is up-regulated by glucose, consistent with the glucose-regulated binding of MafA to the RIPE3b element in beta-cell nuclear extracts. In transient luciferase assays, we also showed that expression of MafA greatly enhanced insulin promoter activity and that a dominant-negative form of MafA inhibited it. Therefore, MafA is a beta-cell-specific and glucose-regulated transcriptional activator for insulin gene expression and thus may be involved in the function and development of beta-cells as well as in the pathogenesis of diabetes.
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D005123:Eye / Q000166:cytology; D005799:Genes, Dominant; D005947:Glucose / Q000378:metabolism*; D018398:Homeodomain Proteins; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D037181:Lectins, C-Type; D008156:Luciferases / Q000378:metabolism; D051473:Maf Transcription Factors, Large; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011971:Receptors, Immunologic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D018076:DNA, Complementary; D018398:Homeodomain Proteins; D007328:Insulin; C113413:KLRG1 protein, human; D037181:Lectins, C-Type; C485159:MAFA protein, human; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D012313:RNA; D008156:Luciferases; D005947:Glucose