Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A basic-leucine zipper transcription factor, MafA, was recently identified as one of the most important transactivators of insulin gene expression. This protein controls the glucose-regulated and pancreatic beta-cell-specific expression of the insulin gene through a cis-regulatory element called RIPE3b/MARE (Maf-recognition element). Here, we show that MafA expression is restricted to beta-cells of pancreatic islets in vivo and in insulinoma cell lines. We also demonstrate that c-Maf, another member of the Maf family of transcription factors, is expressed in islet alpha-cells and in a glucagonoma cell line (alphaTC1), but not in gamma- and delta-cells. An insulinoma cell line, betaTC6, also expressed c-Maf, albeit at a low level. Chromatin immunoprecipitation assays demonstrated that Maf proteins associate with insulin and glucagon promoters in beta- and alpha-cell lines, respectively. c-Maf protein stimulated glucagon promoter activity in a transient luciferase assay, and activation of the glucagon promoter by c-Maf was more efficient than by the other alpha-cell-enriched transcription factors, Cdx2, Pax6, and Isl-1. Furthermore, inhibition of c-Maf expression in alphaTC1 cells by specific short hairpin RNA resulted in marked reduction of the glucagon promoter activity. Thus, c-Maf and MafA are differentially expressed in alpha- and beta-cells where they regulate glucagon and insulin gene expression, respectively.
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PMID:Differentially expressed Maf family transcription factors, c-Maf and MafA, activate glucagon and insulin gene expression in pancreatic islet alpha- and beta-cells. 1476 89

Major insulin gene transcription factors, such as PDX-1 or NeuroD1, have equally important roles in pancreatic development and the differentiation of pancreatic endocrine cells. Previously, we identified and cloned another critical insulin gene transcription factor MafA (RIPE3b1) and reported that other Maf factors were expressed in pancreatic endocrine cells. Maf factors are important regulators of cellular differentiation; to understand their role in differentiation of pancreatic endocrine cells, we analyzed the expression pattern of large-Maf factors in the pancreas of embryonic and adult mice. Ectopically expressed large-Maf factors, MafA, MafB, or cMaf, induced expression from insulin and glucagon reporter constructs, demonstrating a redundancy in their function. Yet in adult pancreas, cMaf was expressed in both alpha- and beta-cells, and MafA and MafB showed selective expression in the beta- and alpha-cells, respectively. Interestingly, during embryonic development, a significant proportion of MafB-expressing cells also expressed insulin. In embryos, MafB is expressed before MafA, and our results suggest that the differentiation of beta-cells proceeds through a MafB+ MafA- Ins+ intermediate cell to MafB- MafA+ Ins+ cells. Furthermore, the MafB to MafA transition follows induction of PDX-1 expression (Pdx-1(high)) in MafB+ Ins+ cells. We suggest that MafB may have a dual role in regulating embryonic differentiation of both beta- and alpha-cells while MafA may regulate replication/survival and function of beta-cells after birth. Thus, this redundancy in the function and expression of the large-Maf factors may explain the normal islet morphology observed in the MafA knockout mice at birth.
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PMID:A switch from MafB to MafA expression accompanies differentiation to pancreatic beta-cells. 1658 Jun 60

The homeodomain protein Nkx2.2 (Nkx2-2) is a key regulator of pancreatic islet cell specification in mice; Nkx2.2 is essential for the differentiation of all insulin-producing beta-cells and of the majority of glucagon-producing alpha-cells, and, in its absence, these cell types are converted to a ghrelin cell fate. To understand the molecular functions of Nkx2.2 that regulate these early cell-fate decisions during pancreatic islet development, we created Nkx2.2-dominant-derivative transgenic mice. In the absence of endogenous Nkx2.2, the Nkx2.2-Engrailed-repressor derivative is sufficient to fully rescue glucagon-producing alpha-cells and to partially rescue insulin-producing beta-cells. Interestingly, the insulin-positive cells that do form in the rescued mice do not express the mature beta-cell markers MafA or Glut2 (Slc2a2), suggesting that additional activator functions of Nkx2.2 are required for beta-cell maturation. To explore the mechanism by which Nkx2.2 functions as a repressor in the islet, we assessed the pancreatic expression of the Groucho co-repressors, Grg1, Grg2, Grg3 and Grg4 (Tle1-Tle4), which have been shown to interact with and modulate Nkx2.2 function. We determined that Grg3 is highly expressed in the embryonic pancreas in a pattern similar to Nkx2.2. Furthermore, we show that Grg3 physically interacts with Nkx2.2 through its TN domain. These studies suggest that Nkx2.2 functions predominantly as a transcriptional repressor during specification of endocrine cell types in the pancreas.
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PMID:Nkx2.2-repressor activity is sufficient to specify alpha-cells and a small number of beta-cells in the pancreatic islet. 1720 86

Transcription factors, such as PDX-1, that normally mediate pancreatic development are capable of inducing hepatic progenitor cells to differentiate into cells with pancreatic islet characteristics. We hypothesized that simultaneous expression of multiple transcription factors involved in islet development might enhance the differentiation of hepatic progenitor cells. Bi- or tri-cistronic constructs were generated in hybrid adenovirus/adeno-associated virus (Ad/AAV) vectors containing neurogenin 3 (NGN3), BETA2 (NeuroD), and RIPE3b1 (MafA), each of which plays a role in islet cell differentiation. These vectors efficiently express multiple transcription factors and stimulate insulin promoter activity in a combinatorial manner. When these multi-cistronic constructs were administered in vivo, they induce hepatic expression of islet-specific markers, including PDX-1, insulin, glucagon, somatostatin, and islet-amyloid peptide. Administration of the Ad/AAV hybrid vectors to streptozotocin-induced diabetic mice reversed hyperglycemia, consistent the differentiation of functional hepatic insulin-secreting cells. These results indicate that Ad/AAV hybrid vectors can be used to administer combinations of factors that induce islet cell differentiation in hepatic progenitor cells.
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PMID:Islet cell differentiation in liver by combinatorial expression of transcription factors neurogenin-3, BETA2, and RIPE3b1. 1723 20

Pancreatic endocrine cell differentiation depends on transcription factors that also contribute in adult insulin and glucagon gene expression. Islet cell development was examined in mice lacking MafB, a transcription factor expressed in immature alpha (glucagon(+)) and beta (insulin(+)) cells and capable of activating insulin and glucagon expression in vitro. We observed that MafB(-/-) embryos had reduced numbers of insulin(+) and glucagon(+) cells throughout development, whereas the total number of endocrine cells was unchanged. Moreover, production of insulin(+) cells was delayed until embryonic day (E) 13.5 in mutant mice and coincided with the onset of MafA expression, a MafB-related activator of insulin transcription. MafA expression was only detected in the insulin(+) cell population in MafB mutants, whereas many important regulatory proteins continued to be expressed in insulin(-) beta cells. However, Pdx1, Nkx6.1, and GLUT2 were selectively lost in these insulin-deficient cells between E15.5 and E18.5. MafB appears to directly regulate transcription of these genes, because binding was observed within endogenous control region sequences. These results demonstrate that MafB plays a previously uncharacterized role by regulating transcription of key factors during development that are required for the production of mature alpha and beta cells.
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PMID:MafB is required for islet beta cell maturation. 1736 Apr 42

Forkhead transcription factors of the FoxO family play a critical role in cellular differentiation, proliferation, apoptosis and stress resistance. FoxO1 regulates glucose and lipid production in liver; food intake in the hypothalamus and cell differentiation in preadipocytes, myoblasts and vascular endothelium. In this review, we summarize recent literature on the role of FoxO1 in pancreatic beta cells. FoxO1 regulates beta-cell proliferation and protects against beta-cell failure induced by oxidative stress through NeuroD and MafA induction. In addition, FoxO1 nuclear exclusion is required for the proliferative effects of glucoincretin glucagon-like peptide-1 in islets. The data begin to outline an overarching role of FoxO1 in beta-cell function.
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PMID:Regulation of pancreatic beta-cell function by the forkhead protein FoxO1. 1791 88

A large number of mammalian transcription factors possess the evolutionary conserved basic and leucine zipper domain (bZIP). The basic domain interacts with DNA while the leucine zipper facilitates homo- and hetero-dimerization. These factors can be grouped into at least seven families: AP-1, ATF/CREB, CNC, C/EBP, Maf, PAR, and virus-encoded bZIPs. Here, we focus on a group of four large Maf proteins: MafA, MafB, c-Maf, and NRL. They act as key regulators of terminal differentiation in many tissues such as bone, brain, kidney, lens, pancreas, and retina, as well as in blood. The DNA-binding mechanism of large Mafs involves cooperation between the basic domain and an adjacent ancillary DNA-binding domain. Many genes regulated by Mafs during cellular differentiation use functional interactions between the Pax/Maf, Sox/Maf, and Ets/Maf promoter and enhancer modules. The prime examples are crystallin genes in lens and glucagon and insulin in pancreas. Novel roles for large Mafs emerged from studying generations of MafA and MafB knockouts and analysis of combined phenotypes in double or triple null mice. In addition, studies of this group of factors in invertebrates revealed the evolutionarily conserved function of these genes in the development of multicellular organisms.
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PMID:Large Maf Transcription Factors: Cousins of AP-1 Proteins and Important Regulators of Cellular Differentiation. 1815 20

During pancreatic development insulin(+) cells co-express the transcription factors MafB and Pax6, and transition from a MafA(-) to MafA(+) state. To examine the role of Pax6 and MafB in the development of beta-cells, we analyzed embryonic pancreata from Pax6- and MafB-deficient mice. Pax6 deficiency, as manifest in the Pax6(Sey-Neu) allele, reduced not only the number of cells expressing insulin or glucagon, but also the number of MafB, PDX-1 and MafA expressing cells. We show that MafB can directly activate expression of insulin and glucagon, and a MafB protein engineered to contain N248S mutation in the MafB (kr(ENU)) results in significantly reduced activation. Furthermore, pancreata from MafB deficient (kr(ENU)/kr(ENU)) mice exhibited reduced number of cells expressing insulin, glucagon, PDX-1 and MafA, with only a minor reduction in MafB expressing cells. MafB deficiency does not affect endocrine specification but does affect the lineage commitment of the endocrine cells and their maturation. Similar to Pax6 deficient mice, MafB deficient mice showed reductions both in insulin and glucagon expressing cells and in the ability of MafB and PDX-1 expressing cells to activate expression of these hormones. However, MafB deficient mice exhibited no effect on Pax6 expression. These results suggest that MafB may function as a downstream mediator of Pax6 in regulating the specification of insulin and glucagon expressing cells. Interestingly, the remaining insulin(+) cells in these knockouts preferentially express Hb9, suggesting the existence of an alternate pathway for the generation of insulin expressing cells, even in the absence of Pax6 and MafB function. Thus, Pax6 acts upstream of MafB, which in turn may trigger the expression of insulin and regulate the PDX-1 and MafA expression required for beta-cell maturation.
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PMID:Preferential reduction of beta cells derived from Pax6-MafB pathway in MafB deficient mice. 1819 33

The African ice rat, Otomys sloggetti robertsi, is a member of the subfamily Otomyinae, in the superfamily of Muroidea, to which all rodents belong. Very little is known about this unique family of rodents. The study reported here examines the endocrine pancreas of this species using immunohistochemical techniques. The islets of Langerhans were scattered in the exocrine pancreas and tended to be quite small. Scattered single endocrine cells (mostly immunoreactive for insulin) were found in the exocrine pancreas and were not generally associated with ducts (as marked by pan-cytokeratin labeling). The normal islet architecture of insulin in the center and glucagon, somatostatin (SS) and pancreatic polypeptide (PP) in the rim was observed, but the islets tended to have 2-3 layers of glucagon immunoreactive cells. Examining for rarer endocrine cell types, we found that cocaine amphetamine regulated transcript (CART) immunoreactive cells were co-localized with SS; and peptide YY (PYY) immunoreactive cells could be found that were singly immunoreactive or co-localized with either PP or glucagon. Ghrelin cells were not found. MafA co-localized only with the insulin cells, while MafB, which localizes to the glucagon cells, also showed a low level of immunoreactivity in most insulin immunoreactive cells. The Nkx family of transcription factors (Nkx6.1 and 2.2) and PDX-1 were all detected in the pancreas in a similar manner to that seen in mouse and rat. In conclusion, the endocrine pancreas of the African ice rat is quite similar to that of other studied rodents, but these animals have more glucagon and SS cells than rat (Rattus) or mouse (Mus) species.
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PMID:An immunohistochemical study of the endocrine pancreas of the African ice rat, Otomys sloggetti robertsi. 1840 49

As successful generation of insulin-producing cells could be used for diabetes treatment, a concerted effort is being made to understand the molecular programs underlying islet beta-cell formation and function. The closely related MafA and MafB transcription factors are both key mammalian beta-cell regulators. MafA and MafB are co-expressed in insulin+beta-cells during embryogenesis, while in the adult pancreas only MafA is produced in beta-cells and MafB in glucagon+alpha-cells. MafB-/- animals are also deficient in insulin+ and glucagon+ cell production during embryogenesis. However, only MafA over-expression selectively induced endogenous Insulin mRNA production in cell line-based assays, while MafB specifically promoted Glucagon expression. Here, we analyzed whether these factors were sufficient to induce insulin+ and/or glucagon+ cell formation within embryonic endoderm using the chick in ovo electroporation assay. Ectopic expression of MafA, but not MafB, promoted Insulin production; however, neither MafA nor MafB were capable of inducing Glucagon. Co-electroporation of MafA with the Ngn3 transcription factor resulted in the development of more organized cell clusters containing both insulin- and glucagon-producing cells. Analysis of chimeric proteins of MafA and MafB demonstrated that chick Insulin activation depended on sequences within the MafA C-terminal DNA-binding domain. MafA was also bound to Insulin and Glucagon transcriptional control sequences in mouse embryonic pancreas and beta-cell lines. Collectively, these results demonstrate a unique ability for MafA to independently activate Insulin transcription.
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PMID:MafA is a dedicated activator of the insulin gene in vivo. 1851 95


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