Potential Roles of Large Mafs in Cell Lineages and Developing Pancreas

Tsuchiya, Masaharu; Taniguchi, Shigeki; Yasuda, Kazuki; Nitta, Kosaku; Maeda, Atsushi; Shigemoto, Mutsuo; Tsuchiya, Ken

doi:10.1097/01.mpa.0000220867.64787.99

Cited by 21 publications

(15 citation statements)

References 33 publications

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“…MAF encodes the transcription factor c-Maf, a member of the Maf family of basic-Zip (bZip) transcription factors. c-Maf is involved in development and differentiation of the lens [74],[75], kidney [76], immune system [77], adipose tissue [78], and pancreas [79]. It is expressed in α cells of the pancreatic islets [80], and is a strong transactivator of the glucagon promoter that regulates glucagon gene expression [80],[81].…”

Section: Discussionmentioning

confidence: 99%

A Genome-Wide Association Study Identifies Susceptibility Variants for Type 2 Diabetes in Han Chinese

et al. 2010

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To investigate the underlying mechanisms of T2D pathogenesis, we looked for diabetes susceptibility genes that increase the risk of type 2 diabetes (T2D) in a Han Chinese population. A two-stage genome-wide association (GWA) study was conducted, in which 995 patients and 894 controls were genotyped using the Illumina HumanHap550-Duo BeadChip for the first genome scan stage. This was further replicated in 1,803 patients and 1,473 controls in stage 2. We found two loci not previously associated with diabetes susceptibility in and around the genes protein tyrosine phosphatase receptor type D (PTPRD) (P = 8.54×10−10; odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.36–1.82), and serine racemase (SRR) (P = 3.06×10−9; OR = 1.28; 95% CI = 1.18–1.39). We also confirmed that variants in KCNQ1 were associated with T2D risk, with the strongest signal at rs2237895 (P = 9.65×10−10; OR = 1.29, 95% CI = 1.19–1.40). By identifying two novel genetic susceptibility loci in a Han Chinese population and confirming the involvement of KCNQ1, which was previously reported to be associated with T2D in Japanese and European descent populations, our results may lead to a better understanding of differences in the molecular pathogenesis of T2D among various populations.

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Section: Discussionmentioning

confidence: 99%

A Genome-Wide Association Study Identifies Susceptibility Variants for Type 2 Diabetes in Han Chinese

et al. 2010

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“…The results have revealed a novel transcriptional regulation of thymus development by mesenchymal cells and offer a novel molecular pathway that mediates mesenchymal contribution to thymus development via Wnts, BMPs, and chemokines. Because it is shown that transcription factors belonging to the large Maf family, including MafB, MafA, and c-Maf, can exert partly overlapping roles in organ development and cellular functions, 70,71 it is possible that MafA and c-Maf may also be involved in controlling thymus development. An improved understanding of the molecular mechanisms of thymus development should aid in the formulation of strategies to enhance thymus regeneration in the elderly or those following chemotherapy and/or radiotherapy.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profile of the third pharyngeal pouch reveals role of mesenchymal MafB in embryonic thymus development

Sultana

Tomita

Hamada

et al. 2009

Blood

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The thymus provides a microenvironment that induces the differentiation of T-progenitor cells into functional T cells and that establishes a diverse yet selftolerant T-cell repertoire. However, the mechanisms that lead to the development of the thymus are incompletely understood. We report herein the results of screening for genes that are expressed in the third pharyngeal pouch, which contains thymic primordium. Polymerase chain reaction (PCR)-based cDNA subtraction screening for genes expressed in microdissected tissues of the third pharyngeal pouch rather than the second pharyngeal arch yielded one transcription factor, MafB, which was predominantly expressed in CD45 ؊ IA ؊ PDGFR␣ ؉ mesenchymal cells and was detectable even in the third pharyngeal pouch of FoxN1-deficient nude mice. Interestingly, the number of CD45 ؉ cells that initially accumulated in the embryonic thymus was significantly decreased in MafB-

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“…MAFA is a key regulator of insulin gene transcription, whereas c-MAF and MAFB are produced specifically in adult alpha cells and control the glucagon promoter activity [4,10]. Recent studies, however, suggest that MAFB is not only important for islet alpha cell function, but may also be involved in regulating genes required for both alpha and beta cell differentiation during development [11][12][13]. It is noteworthy that reduced MAFA function has been implicated in the development of beta cell dysfunction [14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

MAFA controls genes implicated in insulin biosynthesis and secretion

Wang¹,

Brun²,

et al. 2006

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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.

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Potential Roles of Large Mafs in Cell Lineages and Developing Pancreas

Abstract: Large mafs were identified in normal porcine and human pancreas, and the expression levels and localizations of the large mafs in newborn and adult pancreatic tissues differed. Mafs may play important roles in establishing endocrine function during pancreatic cell differentiation.

Cited by 21 publications

References 33 publications

A Genome-Wide Association Study Identifies Susceptibility Variants for Type 2 Diabetes in Han Chinese

A Genome-Wide Association Study Identifies Susceptibility Variants for Type 2 Diabetes in Han Chinese

Gene expression profile of the third pharyngeal pouch reveals role of mesenchymal MafB in embryonic thymus development

MAFA controls genes implicated in insulin biosynthesis and secretion

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