A novel molecular mechanism involved in multiple myeloma development revealed by targeting MafB to haematopoietic progenitors

Vicente-Dueñas, Carolina; Romero-Camarero, Isabel; González-Herrero, Inés; Alonso-Escudero, Esther; Abollo-Jiménez, Fernando; Jiang, Xiaoyu; Gutiérrez, Norma C.; Órfão, Alberto; Marín, Nieves; Villar, Luisa M.; Criado, Ma Carmen Fernández; Pintado, Belén; Flores, Teresa; Alonso-López, Diego; Rivas, Javier De Las; Jiménez, Rafael; Criado, Francisco Javier García; Cenador, María Begoña García; Lossos, Izidore S.; Cobaleda, César; Sánchez-Garcı́a, Isidro

doi:10.1038/emboj.2012.227

Cited by 62 publications

(65 citation statements)

References 66 publications

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“…This result is supported by the increased expression of factors such as MafB that are transiently expressed in endocrine progenitors of the embryonic pancreas. MafB is also upregulated in the dedifferentiated beta cells of beta cellspecific Foxo1 KO mice with metabolic stress and Pdx1 KO mice [8,14], and induces genome-wide changes in DNA methylation [39]. Thus, MafB may be responsible for the upregulation of molecules including those beta cell disallowed genes in dedifferentiated beta cells by inducing epigenetic changes, which have been shown to regulate Slc16a1 expression [35,40].…”

Section: Discussionmentioning

confidence: 97%

MafA is critical for maintenance of the mature beta cell phenotype in mice

2014

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Aims/hypothesis The plasticity of adult somatic cells allows for their dedifferentiation or conversion to different cell types, although the relevance of this to disease remains elusive. Perturbation of beta cell identity leading to dedifferentiation may be implicated in the compromised functions of beta cells in diabetes, which is a current topic of islet research. This study aims to investigate whether or not v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), a mature beta cell marker, is involved in maintaining mature beta cell phenotypes. Methods The fate and gene expression of beta cells were analysed in Mafa knockout (KO) mice and mouse models of diabetes in which the expression of MafA was reduced in the majority of beta cells. Results Loss of MafA reduced the beta to alpha cell ratio in pancreatic islets without elevating blood glucose to diabetic levels. Lineage tracing analyses showed reduced/lost expression of insulin in most beta cells, with a minority of the former beta cells converted to glucagon-expressing cells in Mafa KO mice. The upregulation of genes that are normally repressed in mature beta cells or transcription factors that are transiently expressed in endocrine progenitors was identified in Mafa KO islets as a hallmark of dedifferentiation. The compromised beta cells in db/db and multiple low-dose streptozotocin mice underwent similar dedifferentiation with expression of Mafb, which is expressed in immature beta cells. Conclusions/interpretation The maturation factor MafA is critical for the homeostasis of mature beta cells and regulates cell plasticity. The loss of MafA in beta cells leads to a deeper loss of cell identity, which is implicated in diabetes pathology.

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Section: Discussionmentioning

confidence: 97%

MafA is critical for maintenance of the mature beta cell phenotype in mice

2014

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“…So far, the functions of MafB have been rarely reported and mainly focus on its roles in islet β cells [16][17][18][19], macrophages [10,[20][21][22][23][24] and multiple myeloma [25][26][27][28][29][30][31]. Here we uncovered its new function in dendritic cell maturation.…”

Section: Mafb Regulated the Phenotypic Maturation Of Dcsmentioning

confidence: 91%

MafB, a target of microRNA-155, regulates dendritic cell maturation

Yang

Xiang

et al. 2016

Open Life Sciences

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MafB is a member of bZip transcription factors that share similar basic region/leucine zipper DNA binding motifs and N-terminal activation domains. It is well known that MafB is highly expressed in macrophages and promotes differentiation of myeloid progenitors into macrophage. However, little is known about its function in dendritic cells. Here, we report that MafB, as a target of miR-155, which had been reported to be required for dendritic cell maturation and function, regulated dendritic cell maturation. MafB and miR-155were reversely correlated during DC maturation induced by LPS and forced expression of miR-155 reduced MafB expression. The luciferase reporter assay showed that MafB 3’UTR was directly targeted bymiR-155. In addition, knockdown of MafB promoted the phenotypic maturation of DC2.4 cells. Forced expression of MafB could significantly attenuate the phenotypic maturation of DC2.4 cells caused by overexpression of miR-155. Overall, our data demonstrates that MafB, inhibited by miR-155, was a negative regulator of DC maturation.

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“…We also reported that the promoter activity of MafB is increased in b-cells of diabetes model mice such as db/db mice and mice that have received low-dose streptozotocin (Nishimura et al 2015). Because MafB induces genome-wide changes in DNA methylation (Vicente-Dueñas et al 2012), we speculated the MafB may be a key molecule for the upregulation of b-cell disallowed genes in dedifferentiated b-cells. Thus, we investigated the activity and methylation status of the MafB promoter using an in vitro model of compromised b-cells.…”

Section: Introductionmentioning

confidence: 88%

Demethylation of the MafB promoter in a compromised β-cell model

Nishimura¹,

Ishibashi²,

Eto³

et al. 2015

Journal of Molecular Endocrinology

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Recent studies suggest that dedifferentiation of pancreatic b-cells is involved in compromised b-cell function in diabetes mellitus. We have previously shown that the promoter activity of MafB, which is expressed in a-cells of adult islets and immature b-cells in embryonic pancreas but not in mature b-cells in mice, is increased in compromised b-cells of diabetic model mice. Here, we investigated a rat b-cell line of INS1 cells with late-passage numbers, which showed extremely low expression of MafA and insulin, as an in vitro model of compromised b-cells. In these INS1 cells, the mRNA expression and the promoter activity of MafB were upregulated compared with the early-passage ('conventional') INS1 cells. Analysis of the MafB promoter in these late-passage INS1 cells revealed that specific CpG sites in the MafB promoter were partially demethylated. The reporter assay revealed that the unmethylated promoter activity of the 373 bp region containing these CpG sites was higher than the in vitro methylated promoter activity. These results suggest that the chronic culture of the rat b-cell line resulted in partial DNA demethylation of the MafB promoter, which may have a role in MafB promoter activation and possible dedifferentiation in our compromised b-cell model.

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A novel molecular mechanism involved in multiple myeloma development revealed by targeting MafB to haematopoietic progenitors

Abstract: Transgenic expression of the MafB oncogene in haematopoietic stem/progenitor cells induces plasma cell neoplasia reminiscent of human multiple myeloma and suggests DNA methylation as cause of malignant transformation.

Cited by 62 publications

References 66 publications

MafA is critical for maintenance of the mature beta cell phenotype in mice

MafA is critical for maintenance of the mature beta cell phenotype in mice

MafB, a target of microRNA-155, regulates dendritic cell maturation

Demethylation of the MafB promoter in a compromised β-cell model

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