MAFA controls genes implicated in insulin biosynthesis and secretion.
OBJECTIVE
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.


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
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.
Wang
H
H
Department of Cell Physiology and Metabolism, University Medical Center, 1, Michel-Servet, CH-1211, Geneva 4, Switzerland. haiyan.wang.hw2@Roche.com
Brun
T
T
Kataoka
K
K
Sharma
A J
AJ
Wollheim
C B
CB
D000818:Animals; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D007340:Insulinoma; D037181:Lectins, C-Type / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms; D051381:Rats; D014158:Transcription, Genetic
D007328:Insulin; C094696:Klrg1 protein, rat; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins