MAFA controls genes implicated in insulin biosynthesis and secretion

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 dominantnegative 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), glucagonlike 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.

Elevation of transcription factor Islet-1 levels in vivo increases β-cell function but not β-cell mass

“…In addition, Neurogenin3 has also been A portion of our phenotype observed may be due to an increase in the expression of MafA, which is known to control genes implicated in insulin secretion. [38][39][40] However, we have also identified ~135 differentially expressed genes from our microarray and were able to confirm an increase in expression in a subset of these genes by real-time PCR in islets of Pdx1 PB -Isl-1-Myc mice. These genes are implicated to function in protein trafficking and metabolism, and may play important roles in β-cell biology.…”

Inhibition of MafA transcriptional activity and human insulin gene transcription by interleukin-1β and mitogen-activated protein kinase kinase kinase in pancreatic islet beta cells

“…During development, MafA was shown to be exclusively produced in insulinpositive cells and essential for insulin gene transcription [19]. In addition, MafA was shown to be a master regulator of genes implicated in maintaining beta cell function [47]. In mice lacking MafA, reduced insulin 1 and 2 gene transcription, glucose intolerance and development of diabetes mellitus was observed [12].…”

Growth arrest specific protein (GAS) 6: a role in the regulation of proliferation and functional capacity of the perinatal rat beta cell

“…MAFA is a master regulator of genes implicated in beta cell function, including proinsulin processing (prohormone convertase 1/3) in INS1 cells [28], glucose sensing (Slc2a2), vesicle maturation (Slc30a8), Ca 2+ signalling (Camk2b) and insulin secretion (Nnat) [14,29]. Accordingly, Mafa overexpression enhances GSIS in neonatal rat beta cells [15].…”