RGD Reference Report - MAFA controls genes implicated in insulin biosynthesis and secretion. - Rat Genome Database

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MAFA controls genes implicated in insulin biosynthesis and secretion.

Authors: Wang, H  Brun, T  Kataoka, K  Sharma, AJ  Wollheim, CB 
Citation: Wang H, etal., Diabetologia. 2007 Feb;50(2):348-58. Epub 2006 Dec 6.
RGD ID: 2308897
Pubmed: PMID:17149590   (View Abstract at PubMed)
PMCID: PMC2196442   (View Article at PubMed Central)
DOI: DOI:10.1007/s00125-006-0490-2   (Journal Full-text)

AIMS/HYPOTHESIS: Effects of the transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MAFA) on the regulation of beta cell gene expression and function were investigated. MATERIALS AND METHODS: INS-1 stable cell lines permitting inducible up- or downregulation of this transcription factor were established. RESULTS: MAFA overproduction enhanced and its dominant-negative mutant (DN-MAFA) diminished binding of the factor to the insulin promoter, correlating with insulin mRNA levels and cellular protein content. Glucose-stimulated insulin secretion was facilitated by MAFA and blunted by DN-MAFA. This is partly due to alterations in glucokinase production, the glucose sensor of beta cells. In addition, the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA. CONCLUSIONS/INTERPRETATION: The data suggest that MAFA is not only a key activator of insulin transcription, but also a master regulator of genes implicated in maintaining beta cell function, in particular metabolism-secretion coupling, proinsulin processing and GLP1R signalling. Our in vitro study provides molecular targets that explain the phenotype of recently reported Mafa-null mice. We also demonstrate that MAFA is produced specifically in beta cells of human islets. Glucose influenced DNA-binding activity of MAFA in rat islets in a bell-shaped manner. MAFA thus qualifies as a master regulator of beta-cell-specific gene expression and function.

Objects referenced in this article
Gene Pcsk1 proprotein convertase subtilisin/kexin type 1 Rattus norvegicus

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