Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because UV-induced epidermal macrophages (UV-Mph) preferentially activate CD4+ T suppressor-inducer cells and induce tolerance, we hypothesized that they differentially up-regulate T cell early activation genes compared with constitutive epidermal APC, Langerhans cells. We used epidermal cells from UV-exposed (UV-EC) and control (C-EC) human skin to stimulate allogeneic CD4+ T lymphocytes. Reverse transcriptase-PCR revealed that both C-EC (Langerhans cells) and UV-EC (UV-Mph) induced 10(3)- to 10(6)-fold increases in IL-2 mRNA. However, while T cells stimulated by C-EC for 48 h showed a greater than 10(3)-fold increase in IL-2R alpha mRNA, those stimulated by UV-EC did not (n = 5, p = 0.004). Flow cytometry demonstrated that 4.1 +/- 2.3% of unstimulated CD4+ lymphocytes expressed cell surface IL-2R alpha, which increased to 15.7 +/- 1.8% upon stimulation by C-EC for 48 h, but stimulation by UV-EC failed to increase the IL-2R alpha+ population (n = 3, p = 0.038). The addition of neutralizing anti-TGF-beta Abs to UV-EC-stimulated cultures restored CD4+ cell surface IL-2R alpha expression to 12.9 +/- 0.2%. CD4+ T cell activation by UV-Mph is distinct from previously described models of tolerance such as Th2 activation (IFN-gamma mRNA was induced and IL-4 mRNA was not) and Th1 anergy (IL-2 mRNA levels induced by UV-EC and C-EC were similar). Furthermore, costimulatory signals were provided by UV-Mph; CTLA4-Ig and LFA-3-Ig fusion proteins and Abs to CD2, LFA-3, LFA-1, and ICAM-1 inhibited UV-Mph-induced T cell proliferation. Thus, the altered immune outcome induced by UV-Mph (tolerization) compared with Langerhans cells (sensitization) is reflected as a novel mechanism of initial CD4+ T cell early activation gene expression characterized by TGF-beta-dependent deficient IL-2R alpha expression.
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PMID:Suppressor T cell-activating macrophages in ultraviolet-irradiated human skin induce a novel, TGF-beta-dependent form of T cell activation characterized by deficient IL-2r alpha expression. 749 43

We report that activin profoundly alters epithelial branching morphogenesis of embryonic mouse salivary gland, pancreas and kidney rudiments in culture, indicating that it may play a role as a morphogen during mammalian organogenesis. In developing pancreas and salivary gland rudiments, activin causes severe disruption of normal lobulation patterns of the epithelium whereas follistatin, an activin-binding protein, counteracts the effect of activin. In the kidney, activin delays branching of the ureter bud and reduces the number of secondary branches. TGF-beta induces a pattern of aberrant branching in the ureter bud derived epithelium distinct from that seen for activin. Reverse-transcriptase polymerase chain reaction, Northern hybridization and in situ hybridization analyses indicate that these developing tissues express the mRNA transcripts for activin subunits, follistatin or activin receptors. Our results are suggestive of a potential role for the activin-follistatin system as an intrinsic regulator of epithelial branching morphogenesis during mammalian organogenesis.
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PMID:Activin disrupts epithelial branching morphogenesis in developing glandular organs of the mouse. 761 33

CTLA4Ig, a fusion protein that blocks CD28-B7 costimulation, was studied in a LEW to F344 rat model of chronic cardiac rejection. In rats treated with a single dose of CTLA4Ig (0.5 mg intraperitoneally) 2 d after transplantation, allografts survived significantly longer ( > 70 d in 64%) than in untreated controls or rats treated with control Ig (all rejected within 25 d). Only 25% of grafts from rats treated with a single, high dose of cyclosporine A (25 mg/kg, 2 d after transplantation) survived longer than 70 d. Reverse transcriptase PCR and immunostaining analyses of tissue from 75-d, CTLA4Ig-treated allografts showed reduced expression of the T cell factor IFN-gamma and macrophage activation factors monocyte chemoattractant protein-1, inducible nitric oxide synthase, and galactose/N-acetylgalactosamine macrophage lectin, as well as TGF-beta. Grafts from longterm survivors ( > 120 d) treated with CTLA4Ig showed significant reductions in the frequency and severity of arteriosclerosis in comparison with cyclosporine A-treated rats. Thus, T cell activation is a proximal event in the cascade that culminates in the arteriosclerosis of chronic rejection. Strategies for blocking T cell costimulation may help prevent chronic rejection in clinical transplantation.
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PMID:Chronic cardiac rejection in the LEW to F344 rat model. Blockade of CD28-B7 costimulation by CTLA4Ig modulates T cell and macrophage activation and attenuates arteriosclerosis. 860 41

Post-mitotic cultures of human mesangial cells were maintained in media containing 4-30 mM D-glucose for up to 28 days. Changes in mRNA and protein levels for specific macromolecules occurred between 7 and 14 days after initiating hyperglycaemic conditions. Slot blot analysis showed 2-3-fold increases in mRNAs for collagen type I, fibronectin, versican and perlecan, whereas mRNA for decorin was increased by up to 20-fold. Levels of mRNAs for biglycan and syndecan were unaffected by hyperglycaemic culture. Reverse transcriptase PCR (RT-PCR) confirmed that decorin mRNA levels are greatly elevated and also showed increased transcription of the TGF-beta 1 gene in hyperglycaemic cultures. Western analysis and ELISA indicated accumulations of collagen types I and III, laminin and fibronectin in the cell layers and media of hyperglycaemic cultures with increasing time. Type IV collagen did not accumulate in either compartment of hyperglycaemic mesangial cell cultures. Collagen types I, III, and fibronectin did not accumulate in the cell layers of hyperglycaemic human dermal fibroblasts, indicating a cell-specific response in mesangial cultures. Decorin and versican, but not biglycan, were increased in the hyperglycaemic mesangial cell culture media. There were no apparent changes in core proteins for decorin and biglycan in fibroblast media. Transforming growth factor beta 1 (TGF-beta 1) in hyperglycaemic mesangial cell cultures increased 5-fold after 7 days, but decreased thereafter to only approx. 2-fold after 28 days. The changes in TGF-beta 1 mRNA, as detected by RT-PCR, and protein followed one another closely.
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PMID:Expression of extracellular matrix molecules in human mesangial cells in response to prolonged hyperglycaemia. 867 Jan 79

Polyomavirus large T-antigen transgenic mice develop cardiac hypertrophy characterized by an increase in atrial natriuretic factor and beta-myosin heavy chain isoform expression. The aim of this study was to examine changes in proto-oncogene expression in hypertrophied hearts from the transgenic mice. Expression of early growth response-1 (Egr-1) mRNA was detected in hearts from all 15 transgenic mice, but was not detectable in 13 control mice. Reverse transcriptase-polymerase chain reaction experiments using Egr-1-specific primers confirmed the increase in Egr-1 mRNA in enlarged hearts from the transgenic mice. Expression of c-jun, junD and Ha-ras mRNAs was increased in the transgenic hearts 3, 17 and 2.8-fold respectively. Western blots showed an increase in c-myc, c-jun and ras protein in hypertrophied transgenic hearts. Immunofluorescence analyses confirmed an increase in Egr-1 and c-jun protein in transgenic cardiomyocytes. Proliferating cell nuclear antigen, Ki-ras and HSP 90 mRNAs were decreased 22, 2.7 and 3-fold, respectively in the transgenic hearts. Not altered in most hypertrophied hearts was expression of c-fos, junB, p53, c-neu, c-myc, HSP70, HSP27, TGF-beta or IGF 1 mRNAs. Proto-oncogene and growth factor gene expression in hypertrophy induced by PVLT expression is modulated with some proto-oncogenes increased and others decreased in expression.
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PMID:Molecular remodelling in hypertrophied hearts from polyomavirus large T-antigen transgenic mice. 875 Nov 59

Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to identify intrarenal expression of cytotoxic attack molecules (granzyme B and perforin) and immunoregulatory cytokines (IL-2, IL-4, IL-10, IFN-gamma, and TGF-beta 1) in 127 human renal allograft biopsies. The biopsies were classified using the Banff criteria, and intrarenal gene expression was correlated with the histological diagnosis. Molecular analyses revealed that intragraft display of mRNA encoding granzyme B, IL-10 or IL-2 is a correlate of acute rejection, and intrarenal expression of TGF beta 1 mRNA, of chronic rejection. These data, in addition to demonstrating differential and highly selective intragraft gene expression during rejection, suggest that therapeutic strategies directed at the molecular correlates of rejection might refine existing anti-rejection strategies.
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PMID:Molecular analyses of human renal allografts: differential intragraft gene expression during rejection. 906 37

Spontaneous tumor regression, which is observed clinically and histologically in some primary melanomas, occurs in the absence of any effective therapy. It is probably immunologically mediated, because regressing melanomas are infiltrated with larger numbers of activated T cells, primarily CD4+, than nonregressing melanomas. To investigate the hypothesis that spontaneous regression of melanomas is caused by T-cell cytokine production, cytokine mRNA expression in 20 primary melanomas was examined using a noncompetitive, quantitative reverse-transcriptase polymerase chain reaction method. DNA standards were used to generate known numbers of molecules in each sample. Results were standardized to the internal control, glyceraldehyde-3-phosphate dehydrogenase. mRNA for CD35, lymphotoxin (TNF-beta), and IL-2 were significantly elevated in the ten regressing melanomas compared to the ten nonregressing melanomas. IFN-gamma mRNA was also elevated in regressing melanomas but failed to reach statistical significance. The Th2 cytokines IL-10 and IL-13 did not show differences in the regressing melanomas compared to nonregressing melanomas; neither did the pro-inflammatory cytokines IL-1alpha, IL-1beta, IL-6, IL-8, and TNF-alpha, nor the growth factors, bFGF and TGF-beta or GM-CSF. This study shows an association between Th1 cytokines and spontaneously regressing melanomas. Although we have not shown that these cytokines cause regression, these findings support our hypothesis that activated CD4+ T cells may mediate melanoma regression by secretion of Th1 cytokines.
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PMID:T helper 1 cytokine mRNA is increased in spontaneously regressing primary melanomas. 918 21

Although the TGF-beta family of growth factors probably regulates skin and hair follicle development, its exact role is still quite ill-defined. Here, we characterize the correlative expression pattern of the interdependent high affinity receptor proteins for TGF-beta1 and TGF-beta3, TGF-beta receptor type I (TGF-betaRI) and TGF-beta receptor type II (TGF-betaRII), during hair follicle development and cycling in C57BL/6 mice. During neonatal follicle development, TGF-betaRII immunoreactivity is confined to epithelial cells. Focal epidermal TGF-betaRII expression is seen even before actual hair placode formation. In contrast to the TGF-betaRII immunoreactivity in the outer root sheath, precortical hair matrix and inner root sheath cells were TGF-betaRII negative during hair bulb morphogenesis. TGF-betaRI (Alk-5) immunoreactivity largely overlapped the TGF-betaRII expression pattern, but was more widespread. During hair follicle cycling in adolescent mice, TGF-betaRII immunoreactivity was restricted to follicles, and was strikingly hair cycle dependent (maximal immunoreactivity: anagen VI and early catagen). Again, TGF-betaRI (Alk-5) immunoreactivity co-localized with TGF-betaRII immunoreactivity, but was more extensive. Reverse transcriptase polymerase chain reaction analysis of TGF-betaRII mRNA confirmed peak transcript levels in back skin with most hair follicles in the anagen VI-catagen transformation. mRNA levels of TGF-betaRI (Alk-5) did not vary significantly during the hair cycle, whereas those of TGF-betaRI (threonine-serine kinase 7 L) declined during early anagen, and were maximal during the anagen-catagen transition. This provides a basis for defining the choreography of TGF-beta-related signalling during hair follicle morphogenesis and cycling, introduces intraepidermal TGF-betaRII immunoreactivity as a marker for imminent follicle development, and supports the concept that both TGF-betaRII and TGF-betaRI stimulation is involved in, but not restricted to, the control of catagen induction.
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PMID:Transforming growth factor-beta receptor type I and type II expression during murine hair follicle development and cycling. 932 84

We investigated the regulatory influence of several cytokines on the expression of preproenkephalin (PPE) mRNA in human peripheral blood mononuclear cells (PBMC). By use of a quantitative reverse-transcriptase-polymerase chain reaction (RT-PCR), we demonstrate that the T helper 2 cytokines IL-4 and IL-10 are more potent in upregulating PPE mRNA expression in human PBMC than the T helper 1 cytokines IL-2 and gamma-IFN. In addition, TGF-beta is also an effective inducer of PPE mRNA. TGF-beta, IL-4 and IL-10 increase the cytoplasmatic concentration of met-enkephalin in PBMC. Secretion of met-enkephalin in the culture supernatant of IL-4- or IL-10-stimulated PBMC could not be observed, but proenkephalin A-derived met-enkephalin containing peptides could be demonstrated. IL-4 and IL-10 do not induce PPE mRNA via the same pathways. We could observe that PKA is involved in IL-4 mediated PPE mRNA induction, whereas IL-10 apparently uses another route.
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PMID:T helper 2 cytokines induce preproenkephalin mRNA expression and proenkephalin A in human peripheral blood mononuclear cells. 935 52

One of the loci for neuroblastoma suppressor genes is chromosome 18q21 where the DPC4 tumor suppressor gene, as well as the DCC and MADR2 genes, is located. DPC4 is a molecule of the TGF-beta signal which regulates differentiation of the neural crest precursor cells from which neuroblastoma originates. During the search for the significance of DPC4 as a candidate neuroblastoma suppressor gene, we found that there are at least two variant forms of the DPC4 transcripts by using the reverse-transcriptase-PCR procedure. The subsequent sequencing analysis has revealed that one is missing exons 5 and 6 and the other is missing exons 4-6. Both splice variants were frequently observed in neuroblastomas and at low levels in normal tissues. Though the functional role of the DPC4 splice variants is unknown, they might be important in regulating the TGF-beta signaling not only in neuroblastomas but also in other tumors and normal tissues.
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PMID:DPC4 splice variants in neuroblastoma. 946 9


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