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)

Human immunodeficiency virus-infected patients occasionally exhibit alveolar septal wall thickening and decreases in gas diffusion capacity, but the mechanism underlying these abnormalities is unknown. The present study evaluated septal wall thickness and gas exchange properties in a murine model of the acquired immunodeficiency syndrome and determined whether there were alterations in lung lymphocyte deposition and activation that could contribute to changes in respiratory structure and function. Although alveolar septal wall thickness did not differ from control at 1, 2, and 4 wk postimmunosuppressive virus infection, at 8 wk after infection, septal wall thickness was substantially increased. Immunohistochemical evaluation at this time revealed marked increases in the septal wall deposition of fibronectin and collagen type IV. Pulmonary function tests on anesthetized mice with virus-induced septal wall thickening demonstrated that, although total lung capacity, compliance, and functional residual capacity were unaltered, diffusion capacity for carbon monoxide was significantly impaired. A diffuse nonspecific interstitial pneumonitis was present in lungs of immunodeficient mice, and flow cytometry indicated that both lymphocytes and macrophages were activated. Reverse transcriptase-polymerase chain reaction analysis of lung lymphocytes demonstrated enhanced mRNA expression for several cytokines known to affect lung structure. These results show that impaired gas exchange occurs in a murine model of acquired immunodeficiency syndrome and suggest that such alterations may be mediated by elaboration of cytokines from activated lung lymphocytes and macrophages.
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PMID:Pulmonary mechanical and immunologic dysfunction in a murine model of AIDS. 914 44

This study aimed to establish patterns of cellular fibronectin mRNA splice variants in normal oral mucosa, oral squamous cell carcinoma, oral leukoplakias with and without atypia, and focal reactive overgrowths of oral mucosa. Particular emphasis was placed on evaluation of either the EDA or EDB domains as markers of malignancy. Total RNA was extracted from normal oral mucosa, oral squamous cell carcinoma, oral leukoplakias with and without atypia, reactive epulides, fibroepithelial polyps and denture-related hyperplasia. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to identify different fibronectin transcripts at three splice sites (EDA, EDB and IIICS). All the tissues investigated produced EDA+, EDA-, EDB+ and EDB- splice variants, and this study did not support RT-PCR-based detection of either EDA or EDB domains as markers of malignancy in oral tissues. Variations in IIICS splice patterns were observed, although these were not specific to any lesion group. In particular, there were differences in either the inclusion or omission of the domain coding for the CS-5 binding site for alpha 4 beta 1 integrin, whereas the CS-1 binding site for alpha 4 beta 1 integrin was typically present when additional domains were included at the IIICS splice site. In conclusion, complex patterns of fibronectin splice variant transcripts exist in normal and pathological oral mucosa. This may reflect the multiple biological functions identified for fibronectin proteins, although the significance of different specific fibronectin splice variants has yet to be fully elucidated.
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PMID:RT-PCR investigation of fibronectin mRNA isoforms in malignant, normal and reactive oral mucosa. 930 23

Localization of tenascin-C in vivo and cell culture experiments in vitro have provided evidence for stromal production of tenascin-C in malignant tumors of a variety of organs. Here we raised the question of whether the mesenchymal stroma in the case of endometrial adenocarcinoma is the unique source of tenascin-C. Therefore, the expression of tenascin-C mRNA by human endometrial adenocarcinoma cells and endometrial stroma cells was investigated. Several preparations of endometrial stroma cells produced tenascin-C mRNA. Using a serum-free defined cell culture medium, production of tenascin-C mRNA could be increased by adding either serum or 20 ng TGF-beta/mL to the cell culture medium. Reverse transcriptase polymerase chain reaction analysis revealed that five out of six endometrial adenocarcinoma cell lines produced tenascin-C mRNA. Northern blot experiments and ribonuclease protection assays provided evidence that the number of copies of tenascin-C mRNA was small. Analysis of expressed splice variants by reverse transcriptase polymerase chain reaction analysis revealed the abundance of one major splice variant that lacked all potential alternatively spliced fibronectin type-III-like repeats. Regarding larger splice variants, all fragment sizes that could theoretically originate from seven alternatively spliced fibronectin type-III-like repeats were observed. Evaluating relative signal intensities, the splice variants containing a single fibronectin type-III-like repeat and the variant possessing all but one alternatively spliced repeats were most frequent. In summary, evidence is provided that tenascin-C can originate from both tissue compartments of the human endometrium stroma and (tumor) epithelium. Splice variant analysis revealed a high number of splice variants and a relative high proportion of variants that have so far been regarded as minor constituents of expressed tenascin-C.
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PMID:Expression of tenascin-C by human endometrial adenocarcinoma and stroma cells: heterogeneity of splice variants and induction by TGF-beta. 959 65

Many studies using small-animal models suggest that angiotensin II (Ang II) plays an important role in neointimal formation after vascular injury. In the present study, we examined whether Ang II type 1 receptor (AT1)-mediated Ang II signaling is indispensable for the development of injury-induced neointimal formation using AT1a knockout (KO) mice. Reverse transcriptase-polymerase chain reaction analysis revealed that AT1 mRNA was not detectable in both uninjured and injured carotid arteries of KO mice, whereas the AT1 gene was expressed in uninjured carotid arteries of wild-type (WT) mice. At 14 days after injury, AT1 mRNA levels were increased by 1.5-fold in injured arteries of WT mice. Although AT2 mRNA was not detectable in uninjured arteries, expression of AT2 gene was induced in both animal groups at 2 weeks after injury. Vascular injury induced neointimal formation in KO mice as well as in WT mice. There were no significant differences between WT and KO mice in the extent of histological findings such as increased cross-sectional areas of the neointima and the media, the number of proliferating smooth muscle cells, and the amount of collagen and fibronectin. Treatment with subpressor doses of Ang II after injury enhanced the growth of neointima in WT mice but not in KO mice. Moreover, treatment with the selective AT1 antagonist CV-11974 before injury significantly decreased the formation of neointima in only WT mice, whereas treatment with the selective AT2 antagonist PD-123319 before injury had no effects in both animal groups. These results suggest that AT1-mediated Ang II signaling is not essential for the development of neointimal formation, although it may modify it.
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PMID:Vascular injury causes neointimal formation in angiotensin II type 1a receptor knockout mice. 993 49

This study examines endothelin-induced modulation of extracellular matrix synthesis and remodeling by fibroblasts, and its potential role in the pathogenesis of systemic sclerosis (scleroderma). Endothelin-1 promoted fibroblast synthesis of collagen types I and III, but not fibronectin, by a mechanism dependent upon both ETA and ETB receptors. Conversely, endothelin-1 inhibited both protein expression of matrix metalloproteinase 1 and zymographic activity exclusively via ETA receptors. A dual regulatory role for endothelin-1 in transcriptional regulation was suggested by the ability of endothelin-1 to enhance steady-state levels of collagen mRNA and activate the proalpha2(I) collagen (Col1a2) promoter, but in contrast to reduce matrix metalloproteinase 1 transcript expression and suppress transcription of a human matrix metalloproteinase 1 promoter reporter construct in transient transfection assays. Although endothelin-1 significantly enhanced remodeling of three-dimensional collagen lattices populated by normal fibroblasts, this was not observed for lattices populated by systemic sclerosis fibroblasts. Promotion of matrix remodeling was dependent upon ETA receptor expression and was blocked by specific inhibitors of tyrosine kinases or protein kinase C. Reverse transcriptase polymerase chain reaction, S1 nuclease, and functional cell surface binding studies showed that normal and systemic sclerosis fibroblasts express both ETA and ETB receptors (predominantly ETA), but that ETA receptor mRNA levels and ETA binding sites on fibroblasts cultured from systemic sclerosis skin biopsies are reduced by almost 50%. Endothelin-1 is thus able to induce a fibrogenic phenotype in normal fibroblasts that is similar to that of lesional systemic sclerosis fibroblasts. Moreover, reduced responsiveness to exogenous endothelin-1 in systemic sclerosis suggests that downstream pathways may have already been activated in vivo. These data further implicate dysregulated endothelin-receptor pathways in fibroblasts in the pathogenesis of connective tissue fibrosis.
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PMID:Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1. 1123 16

To investigate the cellular functions of sulfated glycosphingolipids, we introduced the cerebroside sulfotransferase (CST) gene into J5 cells, a subclone of 3LL Lewis lung carcinoma cells. The J5 cells lack acidic glycosphingolipids but accumulate their common biosynthetic precursor, lactosylceramide. We established the stable CST transfectants, J5/CST-1 and J5/CST-2 clones, highly expressing sulfated lactosylceramide (SM3). Both clones exhibited more spherical morphology in comparison to mock transfectant, and their adhesiveness to fibronectin and laminin was significantly lower. The loss of cell-substratum interactions in these SM3-expressing cells could be attributed to decreased expression of integrins (alpha(5), alpha(6), and beta(1)) on the cell surface and their whole cellular levels. However, the levels of H-2K(b) and H-2D(b) antigens remained unchanged. Reverse transcriptase-polymerase chain reaction and Northern blot analyses for these integrins exhibited significant decrease of beta(1) gene expression in J5/CST-1 and 2, but there was no change in the levels of alpha(5) and alpha(6) transcripts. Deglycosylation by endoglycosidase H treatment clearly demonstrated that the precursor form of beta(1) integrin, possessing high mannose oligosaccharide chains, was preferentially decreased in the CST transfectants. These results demonstrate that endogenous SM3 negatively regulates beta(1) integrin expression at the transcriptional level, and the decrease of alpha integrin proteins in the CST transfectants was due to the post-transcriptional modification. We suggest the putative importance of the intracellular pre-beta(1) integrin pool for normal integrin maturation and subsequent function. Although the rates of cell proliferation in vitro for mock and CST transfectants were similar, tumorigenicity of J5/CST-1 and -2 cells inoculated into syngeneic C57/BL6 mice was greatly decreased or even absent. This was probably due to global loss of the efficient cell-matrix interactions, which are essential for the development of malignant tumors in vivo. Thus, we showed the evidence that cellular SM3 negatively regulates the cell-substratum interaction, resulting in the loss of tumorigenicity.
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PMID:Suppression of integrin expression and tumorigenicity by sulfation of lactosylceramide in 3LL Lewis lung carcinoma cells. 1135 5

Although rupture of an atherosclerotic plaque is the major cause of acute vascular occlusion, the exact molecular mechanisms underlying this process are still poorly understood. In this study, we used suppression subtractive hybridization to make an inventory of genes that are differentially expressed in whole-mount human stable and ruptured plaques. Two libraries were generated, one containing 3000 clones upregulated and one containing 2000 clones downregulated in ruptured plaques. Macroarray analysis of 500 randomly chosen clones showed differential expression of 45 clones. Among the 25 clones that showed at least a 2-fold difference in expression was the gene of perilipin, upregulated in ruptured plaques, and the genes coding for fibronectin and immunoglobulin lambda chain, which were downregulated in ruptured plaques. Reverse transcriptase-polymerase chain reaction analysis on 10 individual ruptured and 10 individual stable plaques showed a striking consistency of expression for the clones SSH6, present in 8 ruptured and 2 stable plaques, and perilipin, expressed in 8 ruptured plaques and completely absent in stable plaques. Localization studies of both perilipin mRNA and protein revealed expression in cells surrounding the cholesterol clefts and in foam cells of ruptured atherosclerotic plaques. No expression was observed in nondiseased artery, and only a few cells in the shoulder region of stable plaques tested positive for perilipin. In conclusion, this study shows that it is possible to identify genes that are differentially expressed in whole-mount stable or ruptured atherosclerotic plaques. This approach may yield several potential regulators of plaque destabilization.
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PMID:Identification of genes potentially involved in rupture of human atherosclerotic plaques. 1155 31

The mechanism of peritoneal fibrosis in patients on continuous ambulatory peritoneal dialysis is poorly understood. The production of basic fibroblast growth factor (bFGF) by human peritoneal mesothelial cells cultured in high glucose medium was investigated, and the behavior of peritoneal fibroblasts, as well as the inhibitory effect of prednisolone, was assessed. Reverse transcriptase-PCR and immunocytochemistry showed the expression of glucocorticoid receptors in mesothelial cells. The semiquantitative reverse transcriptase-PCR showed that high glucose medium (4.0%) increased bFGF mRNA by 2.5-fold relative to control medium (0.1% glucose), with 83% suppression of the increase by 1 microM prednisolone. The bFGF protein level in culture supernatant was also increased by 1.5-fold in high glucose medium, with this change showing 45% suppression by 1 microM prednisolone. These effects of prednisolone were prevented by a glucocorticoid receptor antagonist (RU486) in a concentration-dependent manner. The proliferation of peritoneal fibroblasts was increased 1.9-fold by the supernatant of mesothelial cells cultured in high glucose medium, with 85% suppression by 1 microM prednisolone and suppression to 16% below basal proliferation by an anti-bFGF neutralizing antibody (10 microg/ml), whereas proliferation showed a concentration-dependent increase on addition of an anti-transforming growth factor beta-neutralizing antibody. Recombinant bFGF (50 to 1000 pg/ml) likewise caused a concentration-dependent increase of peritoneal fibroblast proliferation and fibronectin release by these cells was also increased (at 50 to 5000 pg/ml). These results suggest the potential importance of bFGF for initiation of peritoneal fibrosis and the possible efficacy of glucocorticoids for preventing such fibrosis in patients receiving peritoneal dialysis.
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PMID:Glucose and prednisolone alter basic fibroblast growth factor expression in peritoneal mesothelial cells and fibroblasts. 1172 49

Muscle cell migration plays an important role in the incorporation of transplanted myoblasts in muscle fibers. Understanding the mechanisms underlying the high migration capacity of the C(2)C(12) myoblast cell line may help to develop approaches to improve the migration of normal myoblasts and consequently to increase their participation to the host myofiber regeneration. We have previously shown that matrix metalloproteinases are implicated in the in vivo migration of C(2)C(12). Here, we studied the role of urokinase plasminogen activator (uPA) in this process. The expression of uPA mRNA and the enzymatic activity of uPA were studied in both normal myoblasts and the C(2)C(12) myoblast cell line. Reverse transcriptase polymerase chain reaction analysis showed that uPA mRNA was more strongly expressed in C(2)C(12) cells than in normal myoblasts. The enzymatic activity of secreted uPA analyzed by casein zymography is higher in medium conditioned by C(2)C(12) cells than in medium conditioned by normal myoblasts. Using our previously described microtube technique to assess in vivo cell migration, we showed that uPA is implicated in the in vivo migration of C(2)C(12) cells since this migration was abrogated in the presence of aprotinin (a general serine protease inhibitor) or amiloride (a uPA-specific inhibitor). We, therefore, hypothesized that increasing endogenous uPA expression by normal myoblasts may improve their migration capacity. Since an accumulating body of evidence has shown that growth factors regulate expression of uPA in a wide range of cells, we treated normal myoblasts with several growth factors alone or in combination with components of the extracellular matrix (ECM). All stimulants tested showed a minimal to strong effect on uPA enzymatic activity as assayed by zymography analysis. The positive effect of basic fibroblast growth factor (bFGF) on uPA enzymatic activity was slightly potentiated in the presence of fibronectin. Moreover, the pretreatment and coinjection of mouse myoblasts with bFGF alone or in combination with fibronectin improved significantly their in vivo migration throughout the tibialis anterior muscle of mdx mice. These results suggest that increasing uPA expression by an appropriate combination of growth factors and ECM components constitutes a possible approach to improving the migration of myogenic cells after transplantation.
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PMID:The urokinase plasminogen activator: an interesting way to improve myoblast migration following their transplantation. 1241 83

Genetic responses that characterize experimental autoimmune myocarditis (EAM) have not yet been determined. To investigate gene expression in the myocardium of EAM, absolute copy numbers of 44 mRNA species [calcium-handling proteins, contractile proteins, natriuretic peptides (NPs), cytokines, chemokines, growth factors, renin-angiotensin-aldosterone (RAA) system, endothelins (ETs) and extracellular matrix] in synthesized cDNA from a fixed quantity of total heart RNA were assessed using real-time reverse-transcriptase PCR at days 0, 14, 21 and 28 after immunization. alpha-Cardiac myosin showed a 26.3-fold decrease and beta-cardiac myosin a 3.75-fold increase at day 14. Atrial NP and brain NP increased 47.7- and 6.35-fold at days 21 and 14 respectively. Angiotensin II type 1 receptor, angiotensin-converting enzyme and ET1 increased 22.3-fold at day 21, 6.30-fold at day 21 and 16.8-fold at day 14 respectively. Aldosterone receptor decreased 2.15-fold at day 14, but aldosterone synthetase was detected only at days 14 and 21. Interleukin (IL)-2, IL-10, interferon-gamma and monocyte chemo-attractant protein-1 increased 9.08-fold at day 14, 398-fold at day 21, 43.1-fold at day 14 and 142-fold at day 14 respectively. Collagen type 3, collagen type 1 and fibronectin increased 34.6-, 1.74- and 44.4-fold respectively at day 21. Interestingly, osteopontin showed a 4540-fold increase and it was the highest mRNA of all at day 14. An isoform of cardiac myosin and NP are dramatically changed in EAM. RAA system and ET expressions are changed differently during the EAM time course. Cytokine, chemokine and extracellular matrix greatly increase and, in particular, large numbers of osteopontin mRNA are expressed in early EAM.
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PMID:Time course of gene expression in rat experimental autoimmune myocarditis. 1244 15


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