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)

Trypsin-related serine proteases are encoded by a very large gene family in mammals. We describe here a comparative analysis of the genomic DNA sequences of mouse, rat, and human mast-cell-specific serine protease genes. Strong evidence was found for multiple exchanges of genetic information between closely related members of this gene family. The 5' regulatory regions of MMCP-1 and MMCP-L share a remarkably high degree of sequence identity (98%), starting 10 base pairs downstream of exon 1 and extending to the end of the presently sequenced region at position -1347 of the MMCP-1 gene. The remaining parts of the two genes share approximately 80% sequence identity. Evidence for at least two additional, but not so recent, exchanges was found in the 3' regions of the MMCP-4 and MMCP-L genes and in the 5' regions of the genes for MMCP-1 and MMCP-2. The 5' regulatory regions of all presently characterized mouse mast-cell-specific chymotrypsin-like serine protease genes exhibit over 88% sequence identity in the region from the transcription initiation site to approximately position -600. An exception is MMCP-5 which is the most distantly related member of this subfamily. The high degree of sequence similarities indicates a strong evolutionary homogenization of the 5' regulatory region, possibly by several gene conversion events. In addition, several insertions of genetic information have been identified in genes for mast-cell chymases and genes for T-cell granzymes. A number of these have been found to represent repetitive sequences, such as L1. The previously characterized tissue-specific enhancer element of the RMCP II gene was identified as a member of a middle repetitive sequence. A cDNA for a newly discovered pseudogene, closely related to the mouse mast cell chymases was isolated by polymerase chain reaction amplification from a mouse connective tissue-like mast cell line. The structure of this cDNA is presented. We also present the characterization of a novel spliced variant of MMCP-6 that contains an alternative 3' terminal exon (exon 6). The function of this variant, if any, is still unknown. A comparative analysis of amino acid sequence identities between different hematopoietic serine proteases shows that a high degree of sequence similarity does not always correlate with relateness in cleavage specificity. This indicates that the substrate specificity evolved with a higher evolutionary rate than the degree of overall amino acid sequence identity of these proteases.
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PMID:Genes for mast-cell serine protease and their molecular evolution. 795 52

Oxidant exposure of the airway mucosa may play a significant role in the pathophysiology of asthma and allergic rhinitis. Mast cells play an important role in asthma, and oxidant exposure has been reported to cause direct mast cell degranulation as well as augment immunoglobulin E (IgE)-mediated responses in vivo. H2O2 is an oxidant generated by inflammatory cells and by the interaction of ozone with lipids or aqueous solutions. In this study, the RBL-2H3 mast cell line was used to investigate the ability of H2O2 to induce mast cell responses as well as to effect mast cell responses to IgE and the calcium ionophore A23187. Although cytotoxicity of RBL-2H3 cells at the membrane level was not observed with any concentration of H2O2, DNA damage resulted from exposure to 0.2 and 2.0 mM H2O2, and cell proliferation was inhibited by 0.075-0.2 mM H2O2. RBL cell prostaglandin D2 generation was enhanced after 60- and 120-min exposure to 0.2-20 mM H2O2. Direct serotonin release required 120-min exposures to 2.0 mM and 60-min exposures to 20 mM H2O2. However, degranulation responses induced by either IgE or A23178 were diminished after exposure to 0.2-2.0 mM H2O2. Lesser amounts (0.005-0.02 mM) had no effect on mast cell function. In summary, H2O2-induced responses of RBL cells, as well as modification of responses to IgE and A23187, occurred only at high concentrations of H2O2, which also induced both intracellular damage and inhibition of cell proliferation. Concentrations of H2O2 more likely to be physiologically relevant had no effect on mast cell responses or cytotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hydrogen peroxide effects on rat mast cell function. 804 46

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

Mouse mast cells differentially express at least four chymases (mouse mast cell protease (mMCP) 1, mMCP-2, mMCP-4, and mMCP-5), a tryptase (mMCP-6), and an exopeptidase (mouse mast cell carboxypeptidase A (mMC-CPA)). The previously uncharacterized 2.5-kilobase mMCP-2 gene was isolated and found to consist of 5 exons. The 5'-flanking region of this gene is 89, 93, and 42% similar to that of the mMCP-1, mMCP-4, and mMCP-5 genes, respectively. Inheritance patterns of restriction-enzyme fragment length polymorphisms of these six mast cell protease genes in recombinant inbred mouse strains and interspecific backcrosses were used to determine their chromosomal locations. The mMCP-6 and mMC-CPA genes are located on chromosomes 17 and 3, respectively, whereas the four mast cell chymase genes all reside on chromosome 14 linked to a gene complex that encodes four cytotoxic T lymphocyte granzymes. Pulsed-field gel electrophoresis of genomic DNA digests demonstrated that the mMCP-1, mMCP-2, and mMCP-5 genes are within 850 kilobases of each other. Although clustering of the serine protease genes on chromosome 14 may be important at a higher level of genomic organization, the ability to independently induce or suppress the steady-state levels of the four chymase transcripts by treatment of mast cells with cytokines suggests that gene clustering is not the most critical factor for coordinate expression of these proteases. Because of the unique features of their tertiary structures, the substrate specificities of the serine proteases encoded by genes at the chromosome 14 complex are predicted to be more limited than those of pancreatic chymotrypsin and pancreatic trypsin, whose genes reside on chromosomes 8 and 6, respectively. Based on present day genomic distribution and sequence similarities, we propose that a primordial gene that encoded a serine protease with restricted substrate specificity underwent extensive duplication and divergence to form a family of cytokine-regulated transcripts from genes on chromosome 14.
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PMID:A closely linked complex of mouse mast cell-specific chymase genes on chromosome 14. 809 10

The Fc epsilon RI couples the mast cell-surface binding of IgE and Ag to a complex series of intracellular events culminating in cell activation and degranulation. The alpha-chain of Fc epsilon RI constitutes the Ig-binding subunit of this heterotetrameric receptor, and is itself a member of the Ig gene superfamily. We have isolated a human genomic DNA clone containing the entire Fc epsilon RI alpha gene, and completely sequenced a region from 1257 bp 5' of the transcription start site, to 513 bp 3' of the last exon of the gene. As with the previously characterized rat and mouse genes, human Fc epsilon RI alpha consists of five exons and four introns, and spans 5889 bp of genomic DNA. The splice donor and acceptor sites deduced by comparison with the cDNA sequence corresponded exactly to the locations found in analogous rodent genes. By mapping the 5' end of Fc epsilon RI alpha transcripts we found three major transcription initiation sites 24, 27, and 29 bp upstream of the ATG translation initiation codon. As well, several longer minor transcripts were seen, with a maximum of 60 nt of 5'-untranslated sequence. About 650 bp of DNA upstream of the ATG translation initiation codon were compared among human, rat, and mouse Fc epsilon RI alpha sequences in search of common motifs that might mediate conserved regulatory interactions with DNA binding proteins. A 172-bp region of the human Fc epsilon RI alpha 5'-flanking sequence was highly conserved in both rodent species. Further studies will be required to determine whether these or other sequences are involved in Fc epsilon RI alpha gene regulation.
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PMID:Characterization of the gene for the human high affinity IgE receptor (Fc epsilon RI) alpha-chain. 824 59

The GATA-1 transcription factor has been shown to be important in the regulation of globin and non-globin genes in erythroid, megakaryocytic and mast cell lineages. It is a member of a family of GATA proteins which both overlap in their expression patterns and bind the motif (A/T)GATA(A/G). The GATA family of proteins are also members of the superfamily of zinc finger-like domain proteins and have two similar domains of the type Cys-X2-Cys-X17-Cys-X2-Cys which direct the DNA binding of the protein. A random oligonucleotide selection procedure has been employed to further elucidate the mechanism of GATA-1-DNA recognition. The resulting oligonucleotides were tested for binding activity to both wild-type and mutant GATA-1 proteins. Two classes of GATA-1-DNA interaction have been defined, the first requiring only the carboxy finger of GATA-1 to bind and having the motif GAT(A/T), the second requiring both finger domains to bind and having the core motif (T/C)AAG. By using sequence comparison and depurination analysis it is concluded that the two finger-like domains of GATA-1 have different DNA binding recognition motifs. Binding of GATA-1 to GAT(A/T) motifs is associated with transcriptional activation of linked genes. The only known (T/C)AAG motif is in the distal CAAT-box promoter region of the human A gamma-globin gene where the binding of GATA-1 appears to regulate the correct developmental suppression of gamma-globin expression.
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PMID:The two zinc finger-like domains of GATA-1 have different DNA binding specificities. 826 42

To stimulate conditions wherein humans might be exposed to tumor promoters prior to carcinogenic stimulus, female S/RV Cri mice were treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 10 weeks followed by a sc injection of 3-methylcholanthrene (MCA). Six weeks after MCA administration, tissue alterations in different skin layers were analysed by histology, morphometry and autoradiography. Multiple application of TPA prior to MCA injection induced moderate to marked epidermal hyperplasia with an increase in the thickness of nucleated cell layers and stratum granulosum. As compared to control, number of basal and suprabasal cells per 7.5 mm of interfollicular epidermal (IFE) length was significantly higher in the skin of animals treated with TPA + MCA. The hyperplastic response was accompanied by a significant increase in epidermal mitotic activity, number of cells in DNA-synthetic phase in epidermis, dermis and subcutis and subepidermal mast cell population. Histological observations of induced tumors revealed a significant increase in the incidence of carcinomas and mixed neoplasms of epithelial and mesenchymal histogenesis. The findings suggest that stimulated cellular proliferation in different layers of mouse skin by TPA treatment prior to MCA injection may play a major role in enhanced expression of histogenetically distinct tumors.
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PMID:Inversion of carcinogen-promoter sequence: effects on mouse skin tumorigenesis and cellular growth kinetics. 827 Feb 78

The detailed mechanisms which can explain the inherent radiosensitivity of salivary glands remain to be elucidated. Although DNA is the most plausible critical target for the lethal effects of irradiation, interactions with other constituents, such as cell membrane and neuropeptides, have been suggested to cause important physiological changes. Moreover, mast cells seem to be closely linked to radiation-induced pneumonitis. Therefore, in the present study the effects of fractionated irradiation on salivary glands have been assessed with special regard to the appearance of mast cells and its correlation with damage to gland parenchyma. Sprague-Dawley strain rats were unilaterally irradiated to the head and neck with the salivary glands within the radiation field. The irradiation was delivered once daily for 5 days to a total dose of 20, 35 and 45 Gy. The contralateral parotid and submandibular glands served as intra-animal controls and parallel analysis of glands was performed 2, 4, 10 or 180 days following the last radiation treatment. Morphological analysis revealed no obvious changes up to 10 days after the irradiation. At 180 days a radiation dose-dependent loss of gland parenchyma was seen, especially with regard to serious acinar cells in parotid gland and acinar cells and serous CGT (convoluted granular tubule) cells in the submandibular gland. These changes displayed a close correlation with a concomitant dose-dependent enhanced density of mast cells and staining for hyaluronic acid. This cell population seems to conform with the features of the connective tissue mast cell type. The parotid seems to be more sensitive to irradiation than the submandibular gland. Thus, the present results further strengthen the role of and the potential interaction of mast cells with radiation-induced tissue injury and alterations in normal tissue integrity.
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PMID:Increase in mast cells and hyaluronic acid correlates to radiation-induced damage and loss of serous acinar cells in salivary glands: the parotid and submandibular glands differ in radiation sensitivity. 829 28

Purified rat peritoneal mast cells in vitro die over a period of 2-6 days in conventional serum-containing medium. As mast cells die, they become pyknotic and undergo DNA fragmentation suggestive of an apoptotic process. Treatment of in vitro mast cells with nerve growth factor (NGF) greatly retards and reduces the death of mast cells (EC50 approximately 1 nM), with no effect on mast cell proliferation. Other neurotrophins have no such effect. NGF also induces the immediate early genes c-fos and NGFI-A with a similar dose dependence. In contrast to the secretagogue activity of NGF, neither the survival-promoting effect nor immediate early gene induction requires lysophosphatidylserine. The ability of NGF to promote mast cell survival is cell density-dependent and appears to be primarily because of induction of the synthesis and/or secretion of an autocrine survival factor by stimulated mast cells. These results suggest that the previously observed effects of NGF on mast cell numbers in vivo may in part be because of enhanced survival and that NGF may be an important mediator of mast cell function in normal and pathological states.
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PMID:Effects of nerve growth factor on rat peritoneal mast cells. Survival promotion and immediate-early gene induction. 830 May 99

The number of stromal mast cells was counted in 187 breast carcinomas. The number of mast cells/mm2 of tumour stroma was studied in relation to clinical, histological and quantitative prognostic factors and survival. A high number of mast cells in tumour stroma was significantly related to low S phase fraction (p = 0.001), DNA diploidy (p = 0.028), high proportion of intraductal growth (p = 0.003) and high degree of tubule formation (p = 0.044). Large tumours showed a lower number of mast cells in stroma (p = 0.08). A non-significant trend was found between mast cell count and axillary lymph node status, sex steroid receptor content, histological type, morphometric nuclear factors and mitotic frequency. In survival analysis a high mast cell count (over 10 g per mm2 of tumour stroma) was related to a favorable prognosis (p = 0.04). The present results confirm previous results in that changes in mast cell count are related to histopathological characteristics and clinical outcome in breast cancer.
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PMID:Mast cells in breast cancer. 831 12


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