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)

Sprague-Dawley rats were exposed for 6 h daily to 0.8 ppm of ozone and 14.4 ppm of nitrogen dioxide. Approximately 7 to 10 wk after the initiation of exposure, animals began to demonstrate respiratory insufficiency and severe weight loss. About half of the rats died between Days 55 and 78 of exposure; no overt ill effects were observed in animals exposed to filtered air, to ozone alone, or to nitrogen dioxide. Biochemical findings in animals exposed to ozone and nitrogen dioxide included increased lung content of DNA, protein, collagen, and elastin, which was about 300% higher than the control values. The collagen-specific crosslink hydroxy-pyridinium, a biomarker for mature collagen in the lung, was decreased by about 40%. These results are consistent with extensive breakdown and remodeling of the lung parenchyma and its associated vasculature. Histopathologic evaluation showed severe fibrosis, alveolar collapse, honeycombing, macrophage and mast cell accumulation, vascular smooth muscle hypertrophy, and other indications of severe progressive interstitial pulmonary fibrosis and end-stage lung disease. This unique animal model of progressive pulmonary fibrosis resembles the final stages of human idiopathic pulmonary fibrosis and should facilitate studying underlying mechanisms and potential therapy of progressive pulmonary fibrosis.
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PMID:A new model of progressive pulmonary fibrosis in rats. 834 14

1. Chinese hamster ovary cells (CHO), maintained in cell culture, were stably transfected with DNA for the MK-1 voltage-activated potassium channel, previously cloned from a mouse brain library. 2. Voltage-activated currents were recorded by the whole cell patch clamp method. In CHO cells transfected with the vector only, there were no significant outward voltage activated currents. However, large outward voltage-activated potassium currents were always observed in those cells which had been transfected with the vector containing the DNA encoding for MK-1. 3. These potassium currents activated from -40 mV, and reversed at the potassium equilibrium potential. The half-maximal conductance of MK-1 was at -10 mV and had a slope factor of 11 mV when fitted with a Boltzmann function. There was only very slight (< 10%) inactivation of MK-1 even at very large positive voltages. 4. MK-1 was reversibly blocked by: 4-aminopyridine (4-AP, 0.1-4 mM), Toxin I 10-100 nM), mast cell degranulating peptide (1 microM), tetraethylammonium (TEA, 4-10 mM), tedisamil (100 microM), quinine (100 microM) and ciclazindol (100 microM); all applied to the outside of the cell from a 'U tube' rapid perfusion system. 4-AP may block closed as well as open MK-1 potassium channels. 5. A synthetic 20 amino acid peptide derived from the N-terminus sequence of the Shaker B potassium channel (the 'inactivation peptide') produced dramatic inactivation of MK-1 when applied to the inside, but not the outside of the cell. Reducing peptide concentration or 'degrading' the peptide produced less inactivation. 6. The block of MK-1 by the synthetic inactivation peptide was quite different in time dependence from block by internal TEA (0.4-4 mM), which probably blocks much more quickly but less potently than the peptide.
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PMID:Pharmacology of a cloned potassium channel from mouse brain (MK-1) expressed in CHO cells: effects of blockers and an 'inactivation peptide'. 835 68

IL-4 is a pleiotropic cytokine whose expression is limited to a subset of activated T cells and cells of the basophil/mast cell lineage. It plays a key role in regulating many immune responses; however, little is known about the intracellular signaling events that lead to the selective and transient IL-4 expression in either of these cell types. In this study, the molecular basis of stimulation-dependent transcription in T cells was explored. To identify cis elements that regulate IL-4 gene transcription, various amounts of the 5' flanking region of the murine IL-4 gene were linked to a chloramphenicol acetyl transferase (CAT) reporter gene and tested for the ability to modulate CAT gene transcription in PMA-stimulated EL-4 T cells. These experiments indicate that multiple positive and negative-acting elements contribute to the overall level of IL-4 transcription. These elements are located both proximal and distal to the transcription initiation site (TIS). An activation responsive element is located within 87 bp of the IL-4 gene TIS. This sequence is sufficient to confer responsiveness to PMA-mediated signals and results in a 10- to 20-fold induction of CAT reporter gene activity compared to activity detected in unstimulated cells. Proteins that specifically bind sequences within this region (-88 to -60) are detected in both unstimulated and stimulated EL-4 T cell nuclear extracts. An additional DNA-protein interaction is detected only when extracts from stimulated cells are analyzed. Base substitutions within the -88 to -60 sequence affect both transactivation function and protein/DNA interactions and demonstrate that sequences between -78 and -69 bp are critical. Together, these data support a model in which T cell activation signals stimulate binding of a nuclear protein(s) to a preexisting IL-4 DNA-protein complex. Proteins detected in these promoter proximal DNA-protein complexes are likely to be key elements in facilitating stimulation-dependent IL-4 transcription.
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PMID:An activation-responsive element in the murine IL-4 gene is the site of an inducible DNA-protein interaction. 837 97

The mouse microphthalmia phenotype is complex and consists of one or more of the following phenotypic alterations: a lack of pigmentation, small eyes, a mast cell defect, and bone abnormalities. The locus for this allele has been assigned to chromosome 6. A single gene defect that produces such a pleiotropic effect has suggested some involvement at a control point in development. Recently a mutant line of mice carrying a transgene insertion, which represents a new allelic form of mi, was described. The integration site of the transgene from these mi(tg) mice was cloned and analyzed. An exon sequence was discovered adjacent to the insertion. Computer analysis of this nucleotide sequence revealed the presence of a motif indicative of the helix-loop-helix class of transcription factors. The gene was expressed in a number of tissues from wild type animals but was absent in the tissue RNA from mi(tg) mice. Southern blot analysis demonstrated a deletion of some of the genetic material for this gene in the mi(tg) mice. This is consistent with the lack of expression in the mi(tg) mice. Interestingly, when DNA from other mi allelic variants was subjected to a similar analysis, a deletion was also observed in this gene in two other mi lines. Taken together, these data suggest that the gene encoding this new helix-loop-helix DNA-binding protein, and residing in the mi locus, is a strong candidate for the mi gene.
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PMID:A helix-loop-helix transcription factor-like gene is located at the mi locus. 840 85

Serum induces the expression of the fos and jun gene families, which encode the transcription factor AP-1. Since we previously found that activation of mast cells by IgE-antigen (Ag) induces the mRNA accumulation of c-fos, c-jun, junB and junD proto-oncogenes, we were prompted to investigate whether serum could affect such accumulation in these cells. In addition, we investigated whether serum could modulate inhibition of DNA synthesis in immunologically stimulated mast cells. Mast cells, which were cultured in the presence of fetal calf serum (FCS), were characterized by a high proliferation rate and high accumulation of the mRNA of c-fos, junB and junD proto-oncogenes. After sustained FCS deprivation both DNA synthesis and the level of c-fos mRNA were significantly decreased, as expected, whereas the level of c-jun, junB and junD mRNA were not affected. As opposed to mast cells which were cultured in the presence of FCS, immunological stimulation of FCS-deprived cells resulted in DNA synthesis inhibition and an increase in c-fos expression. The results also show that the level of c-fos mRNA was increased by either IgE-Ag or FCS up to a similar level, while these two triggers could not act synergistically to enhance this expression further. Thus, changes in DNA synthesis, induced by FCS, block the ability of the immunological challenge to inhibit mast cell growth and to enhance c-fos mRNA accumulation.
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PMID:Serum modulates mast cell responses to IgE antigen stimulation. 841 82

The nuclear DNA-binding protein NF-E2 is thought to mediate the powerful erythroid enhancer activity of the alpha- and beta-globin locus control regions and participates in the control of genes encoding two enzymes of haem biosynthesis (porphobilinogen deaminase and ferrochelatase). The major component of NF-E2 is a 45K polypeptide (designated p45 NF-E2) that belongs to the basic region-leucine zipper family of transcription factors. This subunit of NF-E2 is specifically expressed in haematopoietic progenitor cells and differentiated cells of the erythroid, megakaryocyte and mast cell lineages. The gene encoding p45 NF-E2 (murine gene Nfe2) has been mapped to mouse chromosome 15 near the mutation microcytosis (mk). Homozygous mk mice have severe hypochromic microcytic anaemia as a result of decreased globin synthesis and defects in intestinal and erythroid iron absorption. Here we investigate whether the mk mutation lies within Nfe2 by characterizing the p45 NF-E2 gene and determining its DNA sequence in wild-type and mk alleles. The mk allele carries a missense mutation that causes substitution of valine by alanine at amino acid 173 of the p45 NF-E2 protein. Expression of p45 NF-E2 messenger RNA was detected in erythroid tissues of normal mice and in the duodenum of normal and severely anaemic beta-thalassaemic (Hbbd-th3/Hbbd-th3) mice. We propose that the mk mutation results in an impaired form of NF-E2 which fails to regulate both globin production and iron metabolism properly.
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PMID:Mouse microcytic anaemia caused by a defect in the gene encoding the globin enhancer-binding protein NF-E2. 846 89

Hybrid antibodies, including bifunctional antibody, were obtained by fusing two different drug-resistant clones of human hybridomas HB4C5 and SU-1. One hybridoma, producing human IgM-class monoclonal antibody reactive to porcine carboxypeptidase A (Cpase), was a 6-thioguanine resistant clone (6T-C5) of HB4C5 cell line. Another, secreting human IgM-class anti-double-stranded DNA (ds DNA) monoclonal antibody, was a 5-bromodeoxyuridine resistant clone (5B-SU) of SU-1. Hybrid hybridomas were generated by fusing the 6T-C5 and 5B-SU lines and screened by HAT selection. Among many hybrid hybridomas, A9C11 cells produced bifunctional antibody having dual specificity for Cpase and ds DNA, and the light chains of the antibody consisted of the only ones derived from 5B-SU antibody, indicating that bifunctional antibody could be generated by heterologous association of heavy and light chains.
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PMID:Human bifunctional antibody generated by heterologous association of heavy and light chains. 851 64

Interleukin 4 (IL-4), an immunoregulatory cytokine, is produced only by a subset of activated T cells and cells of the mast cell-basophil lineage. The production of IL-4 by mast cells likely represents a significant source of this protein in local immune-inflammatory responses in the skin, brain, gastrointestinal, and respiratory tracts, in which mast cells are prevalent. In the present study, the cis- and trans-acting elements that control inducible mast cell IL-4 gene transcription were examined and compared with those that function in T cells. We demonstrate that, as in T cells, sequences between bp -87 and -70 are critical for protein association and activation-dependent gene transcription and that this region (termed the activation-responsive element region) is the target of an inducible, cyclosporin A-sensitive, DNA-protein interaction. When assessed by electrophoretic mobility shift assays and UV cross-linking analyses, multiple proteins in both T- and mast cell nuclear extracts associate with the activation-responsive element in vitro, and some of these appear identical. However, distinct proteins are associated with each of the complexes as well. AP-1 family members are unique to the T-cell-stimulation-dependent complex, whereas mast cell complexes contain factors that are reactive with anti-nuclear factor of activated T cells p (NF-ATp) and anti-NF-ATc antibodies but have distinct molecular masses compared with those of T-cell-derived NF-AT. Furthermore, an anti-NF-ATp-reactive factor with a molecular mass of approximately 41 kDa is present in the nuclei of unstimulated cells and binds independently of cell activation, unlike the previously described NF-AT family members. These data support the idea that there are uniquely regulated, cell lineage-specific transcription factors related to T-cell-derived NF-AT that mediate inducible IL-4 transcription in mast cells. These differences likely reflect the distinct cell surface signaling requirements for IL-4 production in T and mast cells.
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PMID:Nuclear factor of activated T cells is associated with a mast cell interleukin 4 transcription complex. 852

We have examined the effects of mercuric chloride (HgCl2) on growth and IL-4, IL-8, TNF-alpha and MHC class II gene expression in the HMC-1 human leukemic mast cell line. Proliferation, measured by [3H]thymidine incorporation or production of a formazan product (MTT assay), was substantially inhibited by HgCl2 at concentrations of 10(-6) M and above. Inspection of the DNA by agarose gel electrophoresis from HgCl2-treated cells revealed that it was intact, indicating inhibition of DNA synthesis, but not denaturation. HgCl2 inhibited expression of mRNA for IL-8, TNF-alpha and MHC class II at 4 x 10(-6) M and inhibited expression of IL-4 mRNA at 8 x 10(-6) M and above. At a concentration of 10(-5)M, HgCl2 almost completely blocked mRNA expression for IL-4, IL-8, TNF-alpha and MHC class II, but produced negligible inhibition of expression of mRNA encoding the housekeeping gene beta-actin, thus demonstrating selective toxicity for the cytokine and MHC class II genes studied. Pre-exposure of the cells to human recombinant IL-4 prior to treatment with HgCl2 had no effect on expression levels of any of the genes examined. The effects seen in this study are consistent with previous reports showing immunotoxic effects of HgCl2 on other cell types, therefore, the HMC-1 mast cell line may prove useful in further studies of mast cell cytokine gene expression and the mechanisms involved in cytokine gene toxicity.
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PMID:The effects of mercuric chloride on growth, cytokine and MHC class II gene expression in a human leukemic mast cell line. 856 Apr 97

The ability of c-Fos to dimerize with various proteins creates transcription complexes which can exert their regulatory function on a variety of genes. One of the transcription factors that binds to c-Fos is the newly discovered Fos-interacting protein (FIP). In this report we present evidence for the regulation of the synthesis of FIP by a physiological stimulus. We found that the aggregation of the mast cell high affinity receptor for IgE (Fc epsilon RI) induced the synthesis of FIP and increased its DNA binding activity. Moreover, down-regulation of the isoenzyme protein kinase C-beta (PKC-beta) by a specific antisense phosphorothioate oligonucleotide resulted in profound inhibition of FIP-Fos DNA binding activity. Thus, aggregation of the Fc epsilon RI on mast cells elicits a PKC-beta dependent signaling pathway which regulates FIP-Fos DNA binding activity.
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PMID:Aggregation of the Fc epsilon RI in mast cells induces the synthesis of Fos-interacting protein and increases its DNA binding-activity: the dependence on protein kinase C-beta. 857 46


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