Reexpression of oncoprotein MafB in proliferative β-cells and Men1 insulinomas in mouse

Abstract

MafB, a member of the large Maf transcription factor family, is essential for the embryonic and terminal differentiation of pancreatic a-and b-cells. However, the role of MafB in the control of adult islet-cell proliferation remains unknown. Considering its oncogenic potential in several other tissues, we investigated the possible alteration of its expression in adult mouse b-cells under different conditions of proliferation. We found that MafB, in general silenced in these cells, was reexpressed in B30% of adaptive b-cells both in gestational female mice and in mice fed with a high-fat diet. Importantly, reactivated MafB expression was also observed in the early b-cell lesions and insulinomas that developed in b-cell specific Men1 mutant mice, appearing in >80% of b-cells in hyperplasic or dysplastic islets from the mutant mice >4 months of age. Moreover, MafB expression could be induced by glucose stimulation in INS-1 rat insulinoma cells. The induction was further reinforced following Men1 knockdown by siRNA. Furthermore, MafB overexpression in cultured bTC3 cells enhanced cell foci formation both in culture medium and on soft agar, accompanied with the increased expression of Cyclin B1 and D2. Conversely, MafB downregulation by siRNA transfection reduced BrdU incorporation in INS-1E cells. Taken together, our data reveal that Men1 inactivation leads to MafB reexpression in mouse b-cells in vivo, and provides evidence that deregulated ectopic MafB expression may have a hitherto unknown role in adult b-cell proliferation and Men1-related tumorigenesis.

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

“…Interestingly, a recent study showed that Mafb was re-expressed in proliferative beta cells [31]. Despite the GAS6-induced reduction in Mafa observed in this study, the Mafb mRNA content in GAS6-treated neonatal rat islets was unchanged.…”

SUMOylated MAFB promotes colorectal cancer tumorigenesis

“…Murine MafB reportedly promotes cell proliferation with detectable changes in cell cycle factors [15]. As the percentage of S phase CRC cells was reduced following MAFB knockdown in our study, we speculated that MAFB may play important roles in regulating the expression of some cell cycle factors.…”

“…Yang, et al [14] found that miR-223 suppresses nasopharyngeal carcinoma cell proliferation and migration by targeting MAFB mRNA. Lu, et al [15] reported that MafB overexpression enhanced cell foci formation and increased cyclin B1 and D2 expression. MafB downregulation reduced BrdU incorporation in the same insulinoma cell lines.…”

Twenty years of menin: emerging opportunities for restoration of transcriptional regulation in MEN1

“…In addition, MNX1/HLXB9 was found to interact with menin in overexpression experiments in MIN6 mouse insulin producing cells and to induce apoptosis and reduced proliferation in this cell model (Shi, et al 2013). In a broader sense, differential Men1 -dependent expression of pancreatic transcription factors, such as MNX1/HLXB9, Foxa2, MafA, MafB and Pdx1 has been described in several reports (Fontaniere, et al 2006; Hamze, et al 2013; Lu, et al 2012; Scacheri et al 2006; Zhang et al 2011). In fact, the Men1 gene appears to be essential for normal development of the endocrine but not of the exocrine pancreas in mice.…”