MafB

Artner, Isabella; Lay, John Le; Hang, Yan; Elghazi, Lynda; Schisler, Jonathan C.; Henderson, Eva; Sosa–Pineda, Beatriz; Stein, Roland

doi:10.2337/diabetes.55.02.06.db05-0946

Cited by 184 publications

(215 citation statements)

References 53 publications

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“…Mafb is required for beta cell maturation and directly regulates expression of Mafa, Pdx1, Nkx6-1, Glut2 and insulin [28]. Activin A did not increase Mafb expression in primary mouse islet cells, as it did in MIN6, probably because islet alpha cells express high levels of Mafb [41] and a small increase in beta cell Mafb expression with activin A treatment might not have been detectable above control.…”

Section: Discussionmentioning

confidence: 84%

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

2010

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Aims/hypothesis The functional maturity of pancreatic beta cells is impaired in diabetes mellitus. We sought to define factors that can influence adult beta cell maturation status and function. Methods MIN6 cells labelled with a Pdx1 monomeric red fluorescent protein-Ins1 enhanced green fluorescent protein dual reporter lentivirus were used to screen candidate growth and/or differentiation factors using image-based approaches with confirmation by real-time RT-PCR and assays of beta cell function using primary mouse islets.Results Activin A strikingly decreased the number of mature beta cells and increased the number of immature beta cells. While activins are critical for pancreatic morphogenesis, their role in adult beta cells remains controversial. In primary islets and MIN6 cells, activin A significantly decreased the expression of insulin and several genes associated with beta cell maturity (e.g. Pdx1, Mafa, Glut2 [also known as Slc2a2]). Genes found in immature beta cells (e.g. Mafb) tended to be upregulated by activin A. Insulin secretion was also reduced by activin A. In addition, activin A-treated MIN6 cells proliferated faster than non-treated cells. The effects of endogenous activin A on beta cells were completely reversed by exogenous follistatin. Conclusions/interpretation These results suggest that autocrine and/or paracrine activin A signalling exerts a suppressive effect on adult beta cell maturation and function. Thus, the maturation state of adult beta cells can be modulated by external factors in culture. Interventions inhibiting activin or its signalling pathways may improve beta cell function. Understanding of maturation and plasticity of adult pancreatic tissue has significant implications for islet regeneration and for in vitro generation of functional beta cells.

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Section: Discussionmentioning

confidence: 84%

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

2010

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“…Pax4 and Nkx6.1) lineages and others acting later in cell maintenance and maturation (e.g. MafB, Foxa2, Isl-1, and Pdx1) (12)(13)(14)(15)(16)(17)(18)(19)(20).Arx plays an essential role in islet ␣-cell formation. Expression of this transcription factor is first detected in the pancreatic anlage at E9.5, then in differentiating pancreatic endocrine precursors, and subsequently in islet ␣-cells (15).…”

mentioning

confidence: 99%

“…Pax4 and Nkx6.1) lineages and others acting later in cell maintenance and maturation (e.g. MafB, Foxa2, Isl-1, and Pdx1) (12)(13)(14)(15)(16)(17)(18)(19)(20).…”

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confidence: 99%

Islet-1 Regulates Arx Transcription during Pancreatic Islet α-Cell Development

Liu

Hunter

et al. 2011

Journal of Biological Chemistry

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Aristaless related homeodomain protein (Arx) specifies the formation of the pancreatic islet ␣-cell during development. This cell type produces glucagon, a major counteracting hormone to insulin in regulating glucose homeostasis in adults. However, little is known about the factors that regulate Arx transcription in the pancreas. In this study, we showed that the number of Arx ؉ cells was significantly reduced in the pancreata of embryos deficient for the Islet-1 (Isl-1) transcription factor, which was also supported by the reduction in Arx mRNA levels. Chromatin immunoprecipitation analysis localized Isl-1 activator binding sites within two highly conserved noncoding regulatory regions (Re) in the Arx locus, termed Re1 (؉5.6 to ؉6.1 kb) and Re2 (؉23.6 to ؉24 kb). Using cell line-based transfection assays, we demonstrated that a Re1-and Re2-driven reporter was selectively activated in islet ␣-cells, a process mediated by Isl-1 in overexpression, knockdown, and site-directed mutation experiments. Moreover, Arx mRNA levels were upregulated in islet ␣-cells upon Isl-1 overexpression in vivo. Isl-1 represents the first known activator of Arx transcription in ␣-cells, here established to be acting through the conserved Re1 and Re2 control domains.Pancreatic islets play an important role in regulating carbohydrate metabolism through the production and secretion of hormones. The five cell types found in the islet are ␣-, ␤-, ␦-, ⑀-, and pancreatic polypeptide cells that, respectively, produce the hormones glucagon, insulin, somatostatin, ghrelin, and pancreatic polypeptide (1). The hormonal products of the predominant ␣-and ␤-cells act in peripheral tissues in a counter-regulatory manner to control blood glucose homeostasis, with insulin promoting cellular glucose uptake and storage and glucagon promoting its release. Notably, although insulin resistance and ␤-cell dysfunction are the major causes of diabetes, the sustained, unregulated secretion of glucagon from ␣-cells also contributes to hyperglycemia and the associated complications (2-6). In fact, suppression of glucagon activity or levels has been shown to be a promising treatment for diabetics (3, 6 -9). Unfortunately, and in contrast to islet ␤-cells, our understanding of the factors involved in controlling ␣-cell differentiation and function is quite limited (1, 10).Glucagon ϩ cells first appear at embryonic day (E) 9.5 3 in mice, followed by insulin ϩ cells a day later (1). At around E13.5, a major expansion of a distinct population of hormone-producing cells begins to occur, with only these cells becoming mature islet ␣-and ␤-cells (11). A variety of distinct transcription factors are required during development for their production (1), including those that are necessary early in specifying the ␣-(e.g. Arx) and ␤-(e.g. Pax4 and Nkx6.1) lineages and others acting later in cell maintenance and maturation (e.g. MafB, Foxa2, Isl-1, and Pdx1) (12)(13)(14)(15)(16)(17)(18)(19)(20).Arx plays an essential role in islet ␣-cell formation. Expression of this transcrip...

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“…The Maf family of transcription factors regulate the transcription of a variety of genes during cell development and differentiation (Artner et al, 2006;Kawauchi et al, 1999;Kelly et al, 2000;Manzanares et al, 1999;Ogino & Yasuda, 1998). Characterized by sequence homology with the founding member, the v-maf oncogene, several maf-related genes have been isolated from vertebrates (Kawai et al, 1992;Nishizawa et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

Expression, purification, crystallization and preliminary crystallographic analysis of the mouse transcription factor MafB in complex with its DNA-recognition motif Cmare

Textor¹,

Wilmanns²,

Holton³

2007

Acta Cryst Sect F

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The MafB transcription factor (residues 211-305) has been overexpressed in and purified from Escherichia coli. A protein-DNA complex between the MafB homodimer and the 21 bp Maf-recognition sequence known as Cmare has been successfully reconstituted in vitro and subsequently crystallized. The diffraction properties of the protein-DNA complex crystals were improved using a combination of protein-construct boundary optimization and targeted mutagenesis to promote crystal lattice stability. Both native and mercury-derivatized crystals have been prepared using these optimized conditions. The crystals belong to space group P4 1 2 1 2 or P4 3 2 1 2, with unit-cell parameters a = b = 94.8, c = 197.9 Å . An anomalous difference Patterson map computed using data collected from crystals grown in the presence of HgCl 2 reveals four peaks. This corresponds to two copies of the protein-DNA complex in the asymmetric unit, with a solvent content of 62% and a Matthews coefficient of 3.22 Å 3 Da À1 .

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MafB

Cited by 184 publications

References 53 publications

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

Islet-1 Regulates Arx Transcription during Pancreatic Islet α-Cell Development

Expression, purification, crystallization and preliminary crystallographic analysis of the mouse transcription factor MafB in complex with its DNA-recognition motif Cmare

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