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Diabetologia

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01-02-2007 | Article

MAFA controls genes implicated in insulin biosynthesis and secretion

Authors: H. Wang, T. Brun, K. Kataoka, A. J. Sharma, C. B. Wollheim

Published in: Diabetologia | Issue 2/2007

Abstract

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.

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Title: MAFA controls genes implicated in insulin biosynthesis and secretion
Authors: H. Wang
T. Brun
K. Kataoka
A. J. Sharma
C. B. Wollheim
Publication date: 01-02-2007
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 2/2007
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-006-0490-2

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Abstract

Aims/hypothesis

Materials and methods

Results

Conclusions/interpretation

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