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)

Interleukin 4 (IL-4), a critical immunoregulatory cytokine, is produced by a subset of T lymphocytes and cells of the mast cell/basophil lineage. There are cell-specific differences in the regulatory elements that control IL-4 transcription in these two cell types. A 683-bp Bgl II fragment, located within the second intron of the murine IL-4 gene, was previously shown to exhibit mast cell-specific enhancer activity. To define critical cis-acting elements that regulate this enhancer, a series of deletions from the 5' and 3' ends of the Bgl II fragment were generated. Their effect on enhancer activity was assessed in IL-4-producing mast cell lines in transient transfection assays. Two functionally independent subregions, E1 and E2, were defined in this analysis. Both are required for full enhancer activity. Sequences identical to previously defined DNA-binding sites for SP1 and GATA are present within E1, and an ets binding site is located within E2. Although mutation of the SP1 sites had no effect on enhancer function, alteration of either the GATA or ets site reduced enhancer activity by 50-60%. Proteins that associate with the IL-4 intronic GATA and ets sites were detected in mast cell nuclear extracts by mobility-shift assays. Specific antibodies identified these factors as GATA-1 and GATA-2 and the ets family member PU.1. GATA-1, GATA-2, and PU.1 exhibit cell-specific expression, suggesting that these proteins play a critical role in the lineage-restricted activity of the IL-4 intronic enhancer in mast cells.
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PMID:PU.1 and GATA: components of a mast cell-specific interleukin 4 intronic enhancer. 805 53

The SCL gene, also known as tal-1, encodes a basic helix-loop-helix transcription factor that is pivotal for the normal development of all hematopoietic lineages. SCL is expressed in committed erythroid, mast, and megakaryocytic cells as well as in hematopoietic stem cells. Nothing is known about the regulation of SCL transcription in mast cells, and in other lineages GATA-1 is the only tissue-specific transcription factor recognized to regulate the SCL gene. We have therefore analyzed the molecular mechanisms underlying SCL expression in mast cells. In this paper, we demonstrate that SCL promoter 1a was regulated by GATA-1 together with Sp1 and Sp3 in a manner similar to the situation in erythroid cells. However, SCL promoter 1b was strongly active in mast cells, in marked contrast to the situation in erythroid cells. Full activity of promoter 1b was dependent on ETS and Sp1/3 motifs. Transcription factors PU.1, Elf-1, Sp1, and Sp3 were all present in mast cell extracts, bound to promoter 1b and transactivated promoter 1b reporter constructs. These data provide the first evidence that the SCL gene is a direct target for PU.1, Elf-1, and Sp3.
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PMID:Transcriptional regulation of the stem cell leukemia gene by PU.1 and Elf-1. 978 9

The cell type-specific expression of a gene is dependent on developmentally regulated modifications in chromatin structure that allow accessibility of basal and inducible transcription factors. In this study, we demonstrate that a cis-acting element in the second intron of the murine IL-4 gene has a dual function in regulating transcription in mast cells as well as chromatin accessibility of the IL-4 gene locus through its influence on the methylation state of the gene. Previous studies have shown that mast cell-restricted transcription factors GATA-1/2 and PU.1 associate with the intron element and regulate its activity. In this study, we use DNase I footprinting and mutational analyses to identify two additional sites that contribute to the element's ability to enhance transcription. One of these sites associates preferentially with STAT5a and STAT5b. We also demonstrate that deletion of the element or mutation of the GATA binding site in the context of a stably integrated IL-4 genomic construct prevents maintenance of a demethylated locus in IL-4-producing mast cells. These data indicate that, analogous to Ig and TCR intron regulatory elements, the intron enhancer has an essential role in maintaining developmentally regulated demethylation at the IL-4 gene locus. In addition, they indicate that members of the GATA family of transcription factors likely play an important role in these processes.
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PMID:An intron transcriptional enhancer element regulates IL-4 gene locus accessibility in mast cells. 1097 40

PU.1 and GATA transcription factors appear to antagonize each other's function in the development of distinct lineages of the hematopoietic system. In contrast, we demonstrate that PU.1, like GATA-2, is essential for the generation of mast cells. PU.1-/- hematopoietic progenitors can be propagated in IL-3 and differentiate into mast cells or macrophages upon restoration of PU.1 activity. Using these progenitors and a conditionally activatable PU.1 protein, we show that PU.1 can negatively regulate expression of the GATA-2 gene. In the absence of GATA-2, PU.1 promotes macrophage but not mast cell differentiation. Reexpression of GATA-2 in such progenitors enables the generation of mast cells. We propose a developmental model in which cooperative function or antagonistic crossregulation by PU.1 of GATA-2 promotes distinct myeloid cell fates.
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PMID:Cooperative and antagonistic interplay between PU.1 and GATA-2 in the specification of myeloid cell fates. 1243 72

The Ets family transcription factor PU.1 is required for development of various lymphoid and myeloid cell lineages, and regulates the expression of several genes in a cell type-specific manner. Mouse bone marrow-derived hematopoietic progenitor cells are programmed to differentiate into mast cells, when the cells are maintained in the presence of pokeweed mitogen-stimulated spleen-conditioned medium. However, by retroviral introduction of PU.1 cDNA, the progenitor cells expressed MHC class II, CD11b, CD11c, and F4/80, and acquired the ability to stimulate T cells. Furthermore, PU.1-overproducing cells exhibited the morphology, in part, similar to that of monocyte. These results indicate that the mast cell progenitors still have the ability to express monocyte-specific genes by increased expression of PU.1.
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PMID:Overproduction of PU.1 in mast cell progenitors: its effect on monocyte- and mast cell-specific gene expression. 1469 19

The Ets family transcription factor PU.1 is required for the development of various lymphoid and myeloid cell lineages, and regulates the expression of several genes in a cell type-specific manner. Recently we found that overproduction of PU.1 in mouse bone marrow-derived mast cell progenitors induced the expression of monocyte-specific genes. This prompted us to analyze the functions of each domain of PU.1 in monocyte-specific gene expression, using transfection of mast cell progenitors with a series of retrovirus vectors for overexpression of various truncation mutants. Both the acidic region and the Ets domain of PU.1 were required for expression of monocyte-specific genes, and for enhanced interleukin-6 production in response to lipopolysaccharide. The Gln-rich region was suggested to be involved in expression of both MHC class II and F4/80. On the other hand, when PU.1 protein lacking the PEST domain was produced in the progenitor cells, expression of monocyte-specific genes was substantially enhanced, suggesting that the PEST domain plays a negative role in monocyte-specific gene expression.
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PMID:Functional analysis of PU.1 domains in monocyte-specific gene regulation. 1501 52

PU.1 is a myeloid- and lymphoid-specific transcription factor that belongs to the Ets family. Recently, we found that overproduction of PU.1 in mouse bone marrow-derived hemopoietic progenitor cells induced monocyte-specific gene expression and caused their monocyte-like morphological change. In the present study, PU.1 was overproduced by using retrovirus expression system in differentiated bone marrow-derived mast cells. By overexpression of PU.1, cell surface expression of MHC class II, CD11b, CD11c, and F4/80 was induced, accompanied by reduced expression of c-kit, a mast cell-specific marker. Morphology of PU.1-transfected cells was altered toward monocyte-like one. PU.1-overproducing cells acquired T cell stimulatory ability and showed an increase in response to LPS stimulation, while response through FcepsilonRI was markedly reduced by overproduction of PU.1. These results suggest that the differentiated mast cells still have potential to display monocytic features. When PU.1 was overproduced in a different type of mast cell, peritoneal mast cells, similar monocyte-like morphological change, and the expression of CD11b and F4/80 were induced. However, surface level of CD11c and MHC class II was not affected. These results indicate that the potential capacity to exhibit monocytic features is different between both the mast cells.
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PMID:Mast cells acquire monocyte-specific gene expression and monocyte-like morphology by overproduction of PU.1. 1561 Dec 61

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

Over-expression of PU.1, a myeloid- and lymphoid-specific transcription factor belonging to the Ets family, induces monocyte-specific gene expression in mast cells. However, the effects of PU.1 on each target gene and the involvement of cytokine signaling in PU.1-mediated gene expression are largely unknown. In the present study, PU.1 was over-expressed in two different types of bone marrow-derived cultured mast cells (BMMCs): BMMCs cultured with IL-3 plus stem cell factor (SCF) and BMMCs cultured with pokeweed mitogen-stimulated spleen-conditioned medium (PWM-SCM). PU.1 over-expression induced expression of MHC class II, CD11b, CD11c and F4/80 on PWM-SCM-cultured BMMCs, whereas IL-3/SCF-cultured BMMCs expressed CD11b and F4/80, but not MHC class II or CD11c. When IFN-gamma was added to the IL-3/SCF-based medium, PU.1 transfectant acquired MHC class II expression, which was abolished by antibody neutralization or in Ifngr(-/-) BMMCs, through the induction of expression of the MHC class II transactivator, CIITA. Real-time PCR detected CIITA mRNA driven by the fourth promoter, pIV, and chromatin immunoprecipitation indicated direct binding of PU.1 to pIV in PU.1-over-expressing BMMCs. PU.1-over-expressing cells showed a marked increase in IL-6 production in response to LPS stimulation in both IL-3/SCF and PWM-SCM cultures. These results suggest that PU.1 overproduction alone is sufficient for both expression of CD11b and F4/80 and for amplification of LPS-induced IL-6 production. However, IFN-gamma stimulation is essential for PU.1-mediated transactivation of CIITA pIV. Reduced expression of mast cell-related molecules and transcription factors GATA-1/2 and up-regulation of C/EBPalpha in PU.1 transfectants indicate that enforced PU.1 suppresses mast cell-specific gene expression through these transcription factors.
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PMID:Roles of PU.1 in monocyte- and mast cell-specific gene regulation: PU.1 transactivates CIITA pIV in cooperation with IFN-gamma. 1950 84

Coexpression of PU.1 and GATA-1 is required for proper specification of the mast cell lineage; however, in the myeloid and erythroid lineages, PU.1 and GATA-1 are functionally antagonistic. In this study, we report a transcriptional network in which PU.1 positively regulates GATA-1 expression in mast cell development. We isolated a variant mRNA isoform of GATA-1 in murine mast cells that is significantly upregulated during mast cell differentiation. This isoform contains an alternatively spliced first exon (IB) that is distinct from the first exon (IE) incorporated in the major erythroid mRNA transcript. In contrast to erythroid and megakaryocyte cells, in mast cells we show that PU.1 and GATA-2 predominantly occupy potential cis-regulatory elements in the IB exon region in vivo. Using reporter assays, we identify an enhancer flanking the IB exon that is activated by PU.1. Furthermore, we observe that in PU.1(-/-) fetal liver cells, low levels of the IE GATA-1 isoform is expressed, but the variant IB isoform is absent. Reintroduction of PU.1 restores variant IB isoform and upregulates total GATA-1 protein expression, which is concurrent with mast cell differentiation. Our results are consistent with a transcriptional hierarchy in which PU.1, possibly in concert with GATA-2, activates GATA-1 expression in mast cells in a pathway distinct from that seen in the erythroid and megakaryocytic lineages.
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PMID:PU.1 positively regulates GATA-1 expression in mast cells. 2030 27


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