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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SV40-transformed ataxia-telangiectasia (SV40-AT) fibroblasts were cotransfected with a plasmid carrying the neomycin-resistance gene as well as DNA from primary mouse embryo fibroblasts. The transfected fibroblasts were seeded under selective conditions and neomycin-resistant (neor) colonies were obtained and tested for the effect of the carcinogen neocarzinostatin (NCS) on DNA synthesis. Whereas the primary A-T and SV40-transformed A-T fibroblasts did not respond to carcinogen treatment and continued to synthesize DNA on damaged templates, normal fibroblasts stopped DNA synthesis after NCS treatment. Among the neomycin-resistant colonies, cells of two colonies responded to NCS treatment by the cessation of DNA synthesis like normal fibroblasts. When DNA from such a colony was transfected into SV40-AT cells, four neor colonies were isolated of which one had regained the normal phenotype. This study provides the first clue that mouse DNA can partly correct the A-T genetic defect expressed in SV40-transformed fibroblasts. Two of the neor colonies with the corrected phenotype expressed a 3.5 kb fibronectin RNA that was detectable by a rat fibronectin DNA probe but not by the human fibronectin DNA probe containing the cell attachment sequence. The latter probe did not detect fibronectin mRNA in the SV40-AT cells but detected expression of the 8.6 kb fibronectin RNA in the two neor colonies of transfected SV40-AT fibroblasts in which the response to NCS was repressed. The results suggest that "correction" of the A-T gene defect in SV40-AT fibroblasts might be associated with regulation of human fibronectin gene(s) expression.
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PMID:Transfection of SV40-transformed ataxia-telangiectasia fibroblasts with mouse DNA corrects hypersensitivity to neocarzinostatin and activates fibronectin gene expression. 133 42

The autosomal recessive genetic disorder ataxia telangiectasia (AT) has been characterized in the RNA transcripts of cultured cells. Molecular species of poly (A)+ RNA that are present in AT fibroblasts (ATFs) at levels different from those in normal human fibroblasts (NHFs) were cloned in the form of cDNAs. Treatment with bleomycin, which transiently inhibits DNA synthesis in NHFs but not in ATFs, differentiated ATFs and NHFs in the above cloning. Two cDNA clones with an identical DNA sequence were isolated, the corresponding RNA transcript of which was induced approximately twofold after bleomycin treatment in NHFs, but not in ATFs. The DNA sequence of these two cDNA clones, except for its polyadenylation part, was identical to the heavy-strand replication origin sequence of human mitochondrial DNA. The results indicate the possibility that the induction of this RNA transcript is involved in bleomycin-induced inhibition of DNA synthesis in normal human cells, while it is defective in AT cells. In addition, the previous observation that much fibronectin is produced in AT cells was confirmed in this study in terms of RNA transcription.
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PMID:Gene expression in ataxia telangiectasia cells as perturbed by bleomycin treatment. 137 97

Ataxia-telangiectasia and xeroderma pigmentosum are human hereditary diseases in which patients are cancer prone and demonstrate increased sensitivity to DNA damage by ionizing and ultraviolet radiation, respectively. In culture, both ataxia-telangiectasia and xeroderma pigmentosum skin fibroblasts show increased synthesis and secretion of the extracellular matrix proteins fibronectin and collagen. To determine whether these differences in protein production result from fundamental abnormalities in regulation of genes associated with cellular interactions, we compared the effects of trifluoperazine and 12-O-tetradecanoylphorbol-13-acetate on expression of the extracellular matrix-degrading metalloproteinases, procollagenase and prostromelysin, by normal, ataxia-telangiectasia, and xeroderma pigmentosum fibroblasts. After trifluoperazine treatment the overall levels of these metalloproteinases were much greater in three ataxia-telangiectasia cell strains and in cells from xeroderma pigmentosum complementation groups A and D than in normal cells. In contrast, cells from xeroderma pigmentosum complementation group C produced only slightly more procollagenase than normal cells. 12-O-tetradecanoylphorbol-13-acetate also induced higher than normal levels of procollagenase in some ataxia-telangiectasia and xeroderma pigmentosum strains, but less than that induced by trifluoperazine. Because increased extracellular accumulation of matrix-degrading enzymes has long been implicated in metastatic progression, this altered expression of procollagenase and prostromelysin in ataxia-telangiectasia and xeroderma pigmentosum cells could play an important role in the pathogenesis of various tumors in individuals with these genetic diseases.
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PMID:Enhanced expression of procollagenase in ataxia-telangiectasia and xeroderma pigmentosum fibroblasts. 217 6

The expression of fibronectin, integrin and beta-actin genes in skin fibroblasts from patients with the genetic disorder ataxia-telangiectasia (A-T) was studied. These three genes were selected because their protein products contribute to the shape and function of the fibroblast. Expression of mRNA by these genes was compared with that in fibroblasts from normal individuals and from patients with the genetic disorder, hereditary hemorrhagic telangiectasia (HHT). A-T fibroblasts were found to produce less fibronectin mRNA than normal and HHT fibroblasts. A-T fibroblasts senesce around passage level 15 while normal and HHT fibroblasts can be propagated for many more passages in vitro. However, the expression of the integrin gene in A-T fibroblasts was similar to that in normal fibroblasts, while the beta-actin gene was expressed at a higher level. The increased beta-actin mRNA levels were similar in fibroblasts of patients with the two genetic disorders, A-T and HHT, but higher than in normal fibroblasts. HHT fibroblasts differed markedly from A-T fibroblasts in having a high level of fibronectin and integrin mRNA expression. The results indicate that regulation of the fibronectin gene in A-T fibroblasts differs from that of the integrin and beta-actin genes, and that the decline in fibronectin mRNA may be linked to the shortened in vitro life-span of these cells.
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PMID:Ataxia-telangiectasia fibroblasts have less fibronectin mRNA than control cells but have the same levels of integrin and beta-actin mRNA. 278 78

In this study Epstein-Barr virus-transformed lymphoblastoid cells were shown to contain fibronectin. A marked difference in the number of fibronectin-positive cells was observed in control and ataxia-telangiectasia lymphoblastoid cells. Three control cell lines varied between 60% and 80% in the number of cells containing fibronectin. Only a small percentage of ataxia-telangiectasia cells (1-5%) had fibronectin present. Control and ataxia-telangiectasia fibroblasts had similar amounts and distributions of fibronectin. An asymmetric distribution of fibronectin was evident in many control and ataxia-telangiectasia lymphoblastoid cells. The increased frequency of fibronectin-containing cells in the control populations cannot be accounted for by different growth rates or variation in the various phases of the cell cycle in the two cell types.
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PMID:Reduced levels of fibronectin in ataxia-telangiectasia lymphoblastoid cells. 636 1

Glomerular mesangial cells and cardiac fibroblasts have been called "myofibroblasts" because of their phenotypic characteristics (resembling both the fibroblast and muscle cells). Thus, it is not surprising that AII would have similar effects on both cell types, which play critical roles in target organ stress response and wound healing, ultimately leading to remodeling changes. These effects are primarily mediated by the AT1 receptor and include: 1) growth: hyperplasia in cardiac fibroblasts and hypertrophy in normal adult mesangial cells and 2) matrix production: there appears to be an early upregulation of fibronectin message which is later followed by an increase in collagens. It is likely that elevated production of fibronectin may activate signal transduction pathways which lead to increased expression of collagen genes, and which may be critical for the organization and laying down of collagens. Thus, an overall theme that emerges is the impact of AII on both growth and wound repair. Other potential important cellular effects of AII in these systems include: 1) stimulation of growth factors, cytokines, and arachidonic acid products that could have autocrine or paracrine effects, 2) regulation of cell migration and adhesion, 3) alteration of responses to neurohormones, 4) development and maintenance of a differentiated phenotype, and others. Molecular techniques including subtraction hybridization, differential display, antisense knockout, and development of transgenic and embryonic stem cell models will be important in defining the specific role of AII in cardiovascular and renal disease.
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PMID:Angiotensin II in cell growth and matrix production. 748 24

Tenascin (TN) is an extracellular matrix protein that is expressed widely in the fetus and sparingly in the adult, but reappears at high levels in certain areas of tissue insult such as tumor matrices and sites of wound healing. We show here that soluble TN inhibits proliferation of human T cells in response to alpha CD3 Ab co-immobilized with the extracellular matrix protein fibronectin (FN). TN also inhibits proliferation driven by alpha CD3/IL-2 or by phorbol ester/IL-2, and it prevents high level induction of IL-2R. The presence of TN in culture medium does not detectably alter the pattern of tyrosine phosphorylation resulting from T cell triggering with alpha CD3, but at later time points prevents the appearance of functional NF-AT1 transcription factor complexes in T cell nuclear extracts. These findings are consistent with the postulated role for TN as a natural antagonist to FN action, and suggest that T cell responses occurring at tissue sites in which TN is expressed could be influenced by its presence.
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PMID:Inhibition of T cell activation by the extracellular matrix protein tenascin. 751 30

TCV-116 [(+/-)-(cyclohexyloxycarbony-loxy)ethyl2-ethoxy-1-[[2' -(1H- tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate ], a nonpeptide selective angiotensin II type I receptor (AT1 receptor) antagonist, at the dose of 0.1, 1 or 10 mg kg-1 day-1, was orally given to 22-week-old stroke-prone spontaneously hypertensive rats (SHRSP) for 10 weeks (from the age of 22-32 weeks) to examine the effects on gene expression of transforming growth factor-beta 1 (TGF-beta 1) and extracellular matrix proteins in the heart and blood vessels. Tissue messenger RNA (mRNA) was measured by northern blot analysis, with a specific complementary DNA probe. In the heart, left ventricular mRNA levels for fibronectin; types I, III and IV collagen; and laminin were significantly higher in SHRSP than control Wistar-Kyoto rats. In the mesenteric artery and aorta of SHRSP, TGF-beta 1 mRNA and the mentioned extracellular matrix protein mRNAs were increased compared with Wistar-Kyoto rats. Thus, the expression of various genes was up-regulated in cardiovascular tissues of SHRSP. Treatment of SHRSP with TCV-116 suppressed the gene expression of the mentioned extracellular matrix proteins and TGF-beta 1 in both heart and blood vessels in a dose-dependent fashion. Furthermore, TCV-116 regressed cardiac hypertrophy and lessened the medial hypertrophy of the aorta in SHRSP. These results show that angiotensin AT1 receptor antagonist in vivo can inhibit the gene expression of TGF-beta 1 and extracellular matrix proteins in hypertensive cardiovascular tissues. These effects may contribute to the beneficial effects of AT1 receptor antagonist on hypertensive cardiac hypertrophy and vascular thickening.
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PMID:Angiotensin II type I receptor antagonist inhibits the gene expression of transforming growth factor-beta 1 and extracellular matrix in cardiac and vascular tissues of hypertensive rats. 771 6

The in vivo effects of alacepril (1-[(S)-3-acetylthio-2-methylpropanoyl]- L-prolyl-L-phenylalanine), an angiotensin converting enzyme inhibitor, and SC-52458 (5-[(3,5-dibutyl-1H-1,2,4-triazol-1- yl)methyl]-2-[2-(1H-tetrazol-5-ylphenyl)]pyridine), an angiotensin AT1 receptor antagonist, were examined on the cardiac and aortic gene expressions of extracellular matrices and TGF-beta 1 in young spontaneously hypertensive rats (SHR). In SHR, types I and III collagen mRNAs were increased in the left ventricle, and in contrast, fibronectin, collagen IV, and transforming growth factor-beta 1 (TGF-beta 1) mRNAs were increased in aorta, compared with those in Wistar-Kyoto rats. All the enhanced mRNAs in both organs in SHR were significantly inhibited by the short-term treatment with the above two drugs. Thus, angiotensin AT1 receptor may play an important role in the regulation of extracellular matrices and TGF-beta 1 expressions in SHR.
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PMID:Role of angiotensin II in extracellular matrix and transforming growth factor-beta 1 expression in hypertensive rats. 782 53

Recent evidence indicates that transforming growth factor-beta 1 (TGF-beta 1) plays an important role in renal fibrosis via stimulation of extracellular matrix synthesis. The present study was undertaken to investigate the role of angiotensin II type I receptor (AT1 receptor) in hypertension-induced renal injury. Twenty-two-week-old stroke-prone spontaneously hypertensive rats (SHRSP), which had established hypertension and moderate renal damage, were orally given TCV-116, a selective non-peptide AT1 receptor antagonist (0.1, 1 or 10 mg/kg/day), enalapril (10 mg/kg/day) or vehicle once a day for 10 weeks. At the end point of the treatment, we examined renal function, the gene expressions of TGF-beta 1 and extracellular matrix components in the interstitium [collagen types I (COI) and III (COIII), fibronectin (FN)] and the basement membrane (COIV and laminin), and renal microscopic morphology in rats aged 32 weeks. In vehicle-treated 32 week-old SHRSP with renal dysfunction and nephrosclerosis, renal mRNA levels for TGF-beta 1, COI, COIII, FN, COIV were all several-fold higher than in WKY. Thus, renal TGF-beta 1 gene expression was enhanced in SHRSP, which may contribute to the increased renal expressions of COI, COIII, FN, COIV in SHRSP. Treatment with TCV-116 (0.1 mg/kg/day) in SHRSP, in spite of no reduction of blood pressure, decreased renal mRNA levels for TGF-beta 1, COI, COIII, FN, COIV, being accompanied by the significant decrease in urinary protein and albumin excretion, blood urea nitrogen and plasma creatinine. Treatment with TCV-116 (10 mg/kg/day) in SHRSP decreased mRNAs for TGF-beta 1, COI, COIII, FN and COIV to almost the same levels as WKY, being associated with normalization of urinary protein and albumin excretion and the prevention of nephrosclerosis, as judged by microscopic histological observations. On the other hand, the effects of enalapril (10 mg/kg/day) on the above mentioned mRNA levels, renal function and renal morphology were weaker than those of TCV-116 (10 mg/kg/day) and were as much as TCV-116 (1 mg/kg/day). These results suggest that independently of hypotensive action, AT1 receptor antagonist has a potent renal protective effect by inhibiting the gene expression of renal TGF-beta 1 and extracellular matrix components.
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PMID:Contribution of renal angiotensin II type I receptor to gene expressions in hypertension-induced renal injury. 785 93


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