Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The FcR beta-chain, a subunit of two related multisubunit receptor complexes, the FcepsilonRI and FcgammaRIII, amplifies the mast cell response and is necessary for the cell surface expression of FcepsilonRI in mouse. The transient reporter assay indicated that -69/+4 region is required for cell type-specific transcriptional regulation of mouse beta-chain gene. EMSA using Abs against transcription factors or competitive oligonucleotides demonstrated that -58/-40 region (containing overlapping three GATA-1 sites, -53/-48, -46/-51, and -42/-47) and -31/-26 region (containing one GATA-1 site) are recognized by GATA-1. The promoter activity of beta-chain was decreased by nucleotide replacements of the GATA-1 sites in mouse mast cell line PT18. Furthermore, exogenously produced GATA-1 up-regulated the promoter activity in CV-1 cells, which are negative in the beta-chain production and the up-regulation was apparently suppressed by GATA-1 site mutations. These results indicate that cell type-specific transcription of mouse beta-chain gene is regulated by GATA-1.
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PMID:Regulation of cell type-specific mouse Fc epsilon RI beta-chain gene expression by GATA-1 via four GATA motifs in the promoter. 1249 17

Here it is shown that the phenotype of adult mice lacking the first enhancer (DNA hypersensitive site I) and the distal promoter of the GATA-1 gene (neo Delta HS or GATA-1(low) mutants) reveals defects in mast cell development. These include the presence of morphologically abnormal alcian blue(+) mast cells and apoptotic metachromatic(-) mast cell precursors in connective tissues and peritoneal lavage and numerous (60-70% of all the progenitors) "unique" trilineage cells committed to erythroid, megakaryocytic, and mast pathways in the bone marrow and spleen. These abnormalities, which were mirrored by impaired mast differentiation in vitro, were reversed by retroviral-mediated expression of GATA-1 cDNA. These data indicate an essential role for GATA-1 in mast cell differentiation.
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PMID:GATA-1 as a regulator of mast cell differentiation revealed by the phenotype of the GATA-1low mouse mutant. 1256 12

Mammalian GATA transcription factors are expressed in various tissues in a temporally regulated manner. The prototypic member, GATA-1, is required for normal erythroid, megakaryocytic, and mast cell development. This family of DNA-binding proteins recognizes a consensus (A/T)GATA(A/G) motif and possesses homologous DNA binding domains consisting of two zinc fingers. The C-terminal finger of GATA-1 recognizes the consensus motif with nanomolar affinities, whereas the N-terminal finger shows a binding preference for a GATC motif, albeit with much reduced affinity (Kd approximately microm). The N-terminal finger of GATA-2 also shows a preference for an AGATCT binding site, with an increased affinity attributed to N- and C-terminal flanking basic residues (Kd approximately nm). To understand the differences in the binding specificities of the N- and C-terminal zinc fingers of GATA-1, we have constructed a series of swapped domain peptides. We show that the specificity for AGATAA over AGATCT arises from the C-terminal non-finger basic domain. Thus, the N-terminal finger binds preferentially to AGATAA once appended to the C-terminal arm of the C-terminal finger. We further show that this specificity arises from the highly conserved QTRNRK residues. The converse is, however, untrue in the case of the C-terminal finger; swapping of QTRNRK with the corresponding LVSKRA does not switch the DNA binding specificity from AGATAA to AGATCT. These results highlight the important role of residues adjacent to the CXXCX17CNAC zinc finger motif (i.e. non-finger residues) in the specific recognition of DNA residues.
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PMID:Determinants of GATA-1 binding to DNA: the role of non-finger residues. 1294 67

GATA-1 is essential for the generation of the erythroid, megakaryocytic, eosinophilic and mast cell lineages. It acts as an activator and repressor of different target genes, for example, in erythroid cells it represses cell proliferation and early hematopoietic genes while activating erythroid genes, yet it is not clear how both of these functions are mediated. Using a biotinylation tagging/proteomics approach in erythroid cells, we describe distinct GATA-1 interactions with the essential hematopoietic factor Gfi-1b, the repressive MeCP1 complex and the chromatin remodeling ACF/WCRF complex, in addition to the known GATA-1/FOG-1 and GATA-1/TAL-1 complexes. Importantly, we show that FOG-1 mediates GATA-1 interactions with the MeCP1 complex, thus providing an explanation for the overlapping functions of these two factors in erythropoiesis. We also show that subsets of GATA-1 gene targets are bound in vivo by distinct complexes, thus linking specific GATA-1 partners to distinct aspects of its functions. Based on these findings, we suggest a model for the different roles of GATA-1 in erythroid differentiation.
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PMID:GATA-1 forms distinct activating and repressive complexes in erythroid cells. 1592 Apr 71

Eosinophil lineage-committed progenitors (EoPs) are phenotypically isolatable in the steady-state murine bone marrow. Purified granulocyte/monocyte progenitors (GMPs) gave rise to eosinophils as well as neutrophils and monocytes at the single cell level. Within the short-term culture of GMPs, the eosinophil potential was found exclusively in cells activating the transgenic reporter for GATA-1, a transcription factor capable of instructing eosinophil lineage commitment. These GATA-1-activating cells possessed an IL-5Ralpha(+)CD34(+)c-Kit(lo) phenotype. Normal bone marrow cells also contained IL-5Ralpha(+)CD34(+)c-Kit(lo) EoPs that gave rise exclusively to eosinophils. EoPs significantly increased in number in response to helminth infection, suggesting that the EoP stage is physiologically involved in eosinophil production in vivo. EoPs expressed eosinophil-related genes, such as the eosinophil peroxidase and the major basic protein, but did not express basophil/mast cell-related mast cell proteases. The enforced retroviral expression of IL-5Ralpha in GMPs did not enhance the frequency of eosinophil lineage read-outs, whereas IL-5Ralpha(+) GMPs displayed normal neutrophil/monocyte differentiation in the presence of IL-5 alone. Thus, IL-5Ralpha might be expressed specifically at the EoP stage as a result of commitment into the eosinophil lineage. The newly identified EoPs could be the cellular target in the treatment of a variety of disorders mediated by eosinophils.
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PMID:Identification of eosinophil lineage-committed progenitors in the murine bone marrow. 1595 40

The high-affinity receptor for IgE (FcepsilonRI) that is expressed on the surface of mast cells plays an important role in antigen/IgE-mediated allergic reactions. We have previously found that critical elements in the promoter of the FcepsilonRI alpha- and beta-chain genes are recognized by the transcription factor GATA-1 in electrophoretic mobility shift assays coupled with a transient expression system for the alpha- and beta-chain promoters. To confirm that GATA-1 is involved in the expression of FcepsilonRI definitively, we generated bone marrow-derived mast cells from GATA-1 knockdown (KD) heterozygous mice. FACS analysis showed that the frequency of FcepsilonRI-positive cells was significantly decreased in mast cells derived from bone marrow of GATA-1 KD mice. Reverse transcription-PCR analysis showed that the level of transcripts not only for GATA-1 but also for both the alpha- and beta-chains was significantly lower in KD mast cells, whereas that of the FcepsilonRI gamma-chain was not affected. Degranulation caused by cross-linking of FcepsilonRI on mast cells prepared from KD mice was markedly repressed in comparison with that of wild-type mast cells. We concluded that the transcription factor GATA-1 positively regulates FcepsilonRI alpha- and beta-chain expression and therefore is involved in mast cell development.
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PMID:GATA-1 is required for expression of Fc{epsilon}RI on mast cells: analysis of mast cells derived from GATA-1 knockdown mouse bone marrow. 1596 81

Cell-type-specific transcription of mouse high-affinity IgE receptor (FcepsilonRI) beta-chain is positively regulated by the transcription factor GATA-1. Although GATA-1 is expressed in erythroid cells, megakaryocytes, and mast cells, the expression of mouse FcepsilonRI beta-chain is restricted to mast cells. In the present study, we characterized the role of GATA-associated cofactor FOG-1 in the regulation of the FcepsilonRI beta-chain promoter. The expression levels of FOG-1, GATA-1, and beta-chain in each hematopoietic cell line were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting. FOG-1 expression was higher in the beta-chain-negative hematopoietic progenitor cell line Ba/F3 than in the beta-chain-positive mast cell line PT18. By contrast, GATA-1 expression was similar when comparing the 2 cell lines. A transient reporter assay demonstrated that the beta-chain promoter functioned in PT18 but not in Ba/F3 and that the transcription activity of the beta-chain promoter in PT18 was markedly suppressed by overexpression of FOG-1. Although the activity of the beta-chain promoter, which was upregulated by coexpression of GATA-1, was significantly suppressed by coexpression of FOG-1 in the simian kidney CV-1 cells (beta-chain(-), GATA-1(-), and FOG-1(-)), the transactivation of the beta-chain promoter by the GATA-1 mutant V205G, which cannot bind FOG-1, was not affected by coexpression of FOG-1. Further, overexpression of FOG-1 in PT18 resulted in decreases in cell surface expression of FcepsilonRI and beta-chain transcription. Finally, suppression of FOG-1 expression using an siRNA approach resulted in increased beta-chain promoter activity in Ba/F3. These results suggest that FOG-1 expression level regulates the GATA-1-dependent FcepsilonRI beta-chain promoter.
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PMID:FOG-1 represses GATA-1-dependent FcepsilonRI beta-chain transcription: transcriptional mechanism of mast-cell-specific gene expression in mice. 1652 18

Mast cells are able to produce a huge panel of mediators including the Th2-type cytokine IL-9, which is considered to be a key mediator for the pathogenesis of allergic asthma, but detailed information on the regulation of IL-9 transcription in mast cells has been scarce. Herein we provide evidence that the erythroid/myeloid transcription factor GATA-1, which is not expressed in Th2 cells, is a potent activator of IL-9 expression in murine bone marrow-derived mast cells (BMMC). Furthermore, in mast cells, but not in Th2 cells, production of IL-9 is sensitive to inhibition of p38 MAP kinase. As transactivation mediated by GATA-1 is also sensitive to inhibition of p38 MAP kinase, and GATA-1 is a target for p38 MAP kinase-mediated phosphorylation in vitro, we conclude that both signaling molecules represent a part of a mast cell-specific signaling network that regulates the expression of IL-9.
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PMID:p38 MAP kinase drives the expression of mast cell-derived IL-9 via activation of the transcription factor GATA-1. 1665 Aug 98

Mast cells are progeny of multipotential hematopoietic stem cells (MHSCs). MHSCs commit to the mast cell lineage in the bone marrow, and the mast cell-committed progenitors leave the bone marrow, migrate in blood, invade connective or mucosal tissue, and then proliferate and differentiate to connective tissue-type or mucosal mast cell. GATA-1, GATA-2, and PU.1 transcription factors seem to be involved i the commitment to mast cells, and MITF, a basic helix-loop-helix leucine zipper-type transcription factor, seems to be involved in the migration, phenotypic expression, and survival of mast cells. KIT ligand (KITL) is the most important cytoline for development of mast cells, and KIT is the receptor of KITL. Tissues of loss-of-function mutants of KIT, KITL, or MITF are deficient in mast cells.
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PMID:Molecular mechanisms of mast cell development. 1693 Dec 85

The development of mature blood cells from hematopoietic stem cells is regulated by transcription factors that control and coordinate the expression of lineage-specific genes. The GATA family consists of six transcription factors that function in hematopoietic and endodermal development. Among them, GATA-1 is expressed in erythroid, megakaryocytic, eosinophil and mast cell lineages, and GATA-2 is expressed in stem and progenitor cells, at more immature stage compared with GATA-1. Based on the characteristic phenotypes of GATA-1 and GATA-2 mutant mice, it has been suggested that mutations of these GATA genes in humans may result in the onset of certain clinical diseases. To date, mutations of GATA-1 gene have been found in inherited anemia and thrombocytopenia, and Down syndrome-related acute leukemia, which exhibits megakaryocytic phenotypes and frequently occurs in patients with Down syndrome. In contrast, no mutation of GATA-2 gene has been identified in hematological diseases; however, we found the expression level of GATA-2 is significantly decreased in CD34 positive cells in patients with aplastic anemia. Since GATA-2 functions in the proliferation of hematopoietic stem cells, the reduction of GATA-2 expression in CD34 positive cells may result in the decreased number of hematopoietic stem cells, which is the characteristic feature of aplastic anemia. Based on these lines of evidence, some types of hematological diseases may be defined as transcription factor diseases.
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PMID:GATA transcription factors and hematological diseases. 1696 Mar 39


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