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MAFA controls genes implicated in insulin biosynthesis and secretion

Wang, H. ; Brun, T. ; Kataoka, K. ; Sharma, A. ; Wollheim, C.

In: Diabetologia, 2007, vol. 50, no. 2, p. 348-358

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    Titre
    • MAFA controls genes implicated in insulin biosynthesis and secretion
    Auteur
    • Wang, H.. Department of Cell Physiology and Metabolism, University Medical Center, 1, Michel-Servet, CH-1211, Geneva 4, Switzerland
    • Brun, T.. Department of Cell Physiology and Metabolism, University Medical Center, 1, Michel-Servet, CH-1211, Geneva 4, Switzerland
    • Kataoka, K.. Laboratory of Molecular and Developmental Biology, Graduate School of Biological Science, Nara Institute of Science and Technology, Takayama-cho, Ikoma, Japan
    • Sharma, A.. Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center, Boston, MA, USA
    • Wollheim, C.. Department of Cell Physiology and Metabolism, University Medical Center, 1, Michel-Servet, CH-1211, Geneva 4, Switzerland
    Type de document
    • Postprint
    Identifiant OAI-PMH
    • oai:doc.rero.ch:310739
    Summary
    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