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:3.1.27.1 (RNase)
16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease in which cytokines are thought to play an important role in beta-cell destruction and immune regulation. A major target of beta-cell autoimmunity in IDDM is the enzyme glutamate decarboxylase (GAD). We hypothesized that cytokines in the insulitis lesion modulate the synthesis of GAD. This may, in turn, modify the rate of beta-cell destruction. Accordingly we cultured rat islets in the presence and absence of cytokines, and measured synthesis of both isoforms of GAD, GAD65 and GAD67, by [35S]methionine incorporation and immunoprecipitation with a rabbit antiserum that recognizes both GAD65 and GAD67. Incubation of islets with interleukin (IL)-1 beta (1 ng/ml, 24 h), tumour necrosis factor alpha (TNF-alpha; 200 units/ml, 24 h) or interferon gamma (IFN-gamma; 500 units/ml, 72 h) significantly decreased the synthesis of both GAD65 and GAD67, but reduced neither total protein synthesis nor insulin accumulation in the medium or content. Incubation of islets for 24 h in IFN-alpha (1000 units/ml), TNF-beta (50 ng/ml), IL 2 (1000 units/ml), IL-4 (100 ng/ml), IL-6 (10 ng/ml), IL-10 (20 ng/ml), IL-12 (10 ng/ml) or transforming growth factor beta 2 (TGF-beta 2; 5 ng/ml) did not significantly alter GAD65 or GAD67 synthesis. Inhibition of GAD65 and GAD67 protein synthesis by IL-1 beta, TNF-alpha or IFN-gamma was reversed by co-incubation with the nitric oxide synthase inhibitor, NG-monomethyl arginine (NMMA). Expression of both GAD65 and GAD67 mRNA, measured by RNase protection assay, was also decreased by IL-1 beta and completely restored to baseline levels by NMMA. Thus the synthesis of both isoforms of islet GAD is selectively decreased in the presence of IL-1 beta, TNF-alpha or IFN-gamma by a NO-mediated mechanism, probably at the level of cytokine gene transcription. As GAD autoimmunity has been previously shown to have a pathogenic role in an animal model of IDDM, its inhibition by cytokines might limit the immune response, thereby regulating the rate of beta-cell destruction in IDDM.
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PMID:Cytokine regulation of glutamate decarboxylase biosynthesis in isolated rat islets of Langerhans. 876 Mar 54

Chondrocytes derived from rat xiphoid cartilage dedifferentiated into fibroblast-like cells as the number of passages of the cells in culture increased. During in vitro dedifferentiation the growth of the cells was markedly suppressed. We had proposed previously that C-type natriuretic peptide (CNP) might be a potent antimitogenic factor for chondrocytes, and TGF-beta 1 induced a marked increase in CNP secretion of chondrocytes. Therefore, we investigated the expression of CNP, B-type natriuretic peptide receptor (NPR-B or GC-B), and TGF-beta 1 in this process. Radioimmunoassay and RNase protection analyses revealed passage-associated increase in CNP-like immunoreactivity and in levels of NPR-B mRNA, respectively. Northern blot analyses showed that the level of TGF-beta 1 mRNA decreased with increasing passage number. These results suggest that the expression of CNP and NPR-B might be involved in in vitro dedifferentiation of chondrocytes and TGF-beta 1 does not affect the increasing level of CNP during in vitro dedifferentiation.
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PMID:Change in the expression of C-type natriuretic peptide and its receptor, B-type natriuretic peptide receptor, during dedifferentiation of chondrocytes into fibroblast-like cells. 888 16

Gossypol (GP), an antifertility agent in males, is also capable of inhibiting the proliferation of a wide range of cancer cells in vivo and in vitro. Thus, in this study we investigated the effect of GP on the growth of human androgen-independent prostate cancer cell line (PC3). The results showed that GP acts as a potent inhibitor of PC3 cells as determined by thymidine incorporation assay and flow cytometric analysis. Flow cytometry revealed that treatment of PC3 cells with GP resulted in a dose- and time-dependent accumulation of cells in the GO/GI phase with a concomitant decrease in cells progressing to the S and G2/M phase. These data support our thymidine incorporation results which indicated that GP is a potent inhibitor of PC3 cells. By ribonuclease protection assay, we also investigated the effect of GP on transforming growth factor-beta 1 (TGF-beta 1) gene expression in PC3 cells. Interestingly, the stimulatory effect of GP on TGF-beta 1 gene expression correlates well with its inhibitory effect on PC3 cell DNA synthesis and its ability to arrest cells in GO/G1 phase. Based on these data, it can be concluded that GP is a potent inhibitor of prostate cancer cell growth that acts by arresting cells in GO/G1 phase and that this inhibitory effect may be mediated by TGF-beta 1.
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PMID:Inhibition of human prostate cancer cells growth by gossypol is associated with stimulation of transforming growth factor-beta. 891 64

Glucocorticoids (CORT) have been shown to induce cleft palate in mice. Although the pathogenetic pathway of CORT-induced cleft palate has been investigated for several decades, the molecular details remain to be elucidated. Since growth factors have been shown to regulate palate morphogenesis, and the expression of several growth factors or their receptors, e.g. TGF-beta, EGF receptor (EGF-R), are known to be modulated by CORT, we postulate that CORT modulation of growth factor (or receptor) gene expression is a key mechanism involved in CORT-induced cleft palate. To test this hypothesis, we analyzed the steady-state levels (Northern and RNase protection) and developmental expression (in situ hybridization) of four CORT-responsive genes--TGF-Beta 1, TGF- beta 2, TGF-beta 3, and EGF receptor (EGF-R)--in developing mouse palates in the presence or absence of exogenous CORT. Pregnant B10.A dams were injected on day 12 of gestation with CORT or sham-injected and embryonic palates were collected at 1, 2, and 3 days postinjection (E13-E15). During mouse palate development, significant increases in TGF-beta 1 and TGF-beta 3 mRNA levels, as well as significant decrease in TGF-beta 2 mRNA levels, are detected; no significant difference in EGF-R transcript level is observed with progressive development. In CORT-exposed palates, we demonstrate no significant differences in the direction or magnitude of change with time in TGF-beta 1, TGF-beta 3, and EGF-R mRNA levels compared to controls. However, CORT delays by 1 day the down-regulation of palatal TGF-beta 2 transcript normally seen on day 14 of gestation. TGF-beta 2 is known to inhibit cell proliferation. The level of TGF-beta 2 mRNA, the only isoform primarily expressed in the palatal mesenchyme, significantly decreases with progressive palatal development; this down-regulation of TGF-beta 2 expression is associated with increased mesenchymal cell proliferation and palatal shelf growth. CORT, at a critical stage of palatogenesis, induces a delay in the normal down-regulation of TGF-beta 2 gene expression. Given that CORT is known to inhibit mesenchymal cell proliferation and palatal shelf growth, we conclude that the CORT-induced delay in the normal down-regulation of TGF-beta 2 gene expression is probably key event in the pathogenesis of CORT-induced cleft palate.
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PMID:Developmental expression and CORT-regulation of TGF-beta and EGF receptor mRNA during mouse palatal morphogenesis: correlation between CORT-induced cleft palate and TGF-beta 2 mRNA expression. 891 68

Transforming growth factor (TGF-beta) binds several discrete membrane proteins. Of these, a type 1 receptor appears indispensable for signal transduction. Previous examination of TGF-beta receptor expression has been limited to changes in cell surface protein, and more recently, mRNA abundance. In order to learn more about TGF-beta function and receptor expression during osteogenesis, we have now cloned a 4 kilobase (kb) DNA fragment 5' proximal to the coding region of the rat TGF-beta type I receptor gene. Sequence analysis revealed multiple elements compatible with transcription initiation, including a properly positioned and oriented CCAAT box, six Sp1 binding sites (three defining GC boxes), and two strong AP2 binding sites within a 0.7 kb span directly upstream of the coding region. The 3' terminal 0.3 kb span comprises a GC-enriched (77%) so-called CpG island that, like other similarly organized promoters, lacks a TATA box. Primer extension and RNase protection studies with cRNAs from this area show multiple initiation sites within 220 bp 5' proximal to the initial methionine codon. Transient transfections using nested, deleted, and inverted promoter sequences demonstrated maximal reporter expression by a 1 kb fragment encompassing all of these elements. Truncation of the 1 kb fragment from the 5' and 3' ends indicated the need for several elements for peak promoter activity. These results, and transfections in fetal rat bone and dermal cells, suggest that this promoter contains elements that specify basal and conditional expression of the TGF-beta type I receptor in bone.
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PMID:Cloning, characterization, and expression of the transforming growth factor-beta type I receptor promoter in fetal rat bone cells. 897 63

Long-term sensitization training, or procedures that mimic the training, produces long-term facilitation of sensory-motor neuron synapses in Aplysia. The long-term effects of these procedures require mRNA and protein synthesis (Montarolo et al., 1986; Castellucci et al., 1989). Using the techniques of differential display reverse transcription PCR (DDRT-PCR) and ribonuclease protection assays (RPA), we identified a cDNA whose mRNA level was increased significantly in sensory neurons by treatments of isolated pleural-pedal ganglia with serotonin for 1.5 hr or by long-term behavioral training of Aplysia. The effects of serotonin and behavioral training on this mRNA were mimicked by treatments that elevate cAMP. The aplysia mRNA increased by serotonin and behavioral training was 41-45% identical to a developmentally regulated gene family which includes Drosophila tolloid and human bone morphogenetic protein-1 (BMP-1). Both tolloid and BMP-1 encode metalloproteases that might activate TGF-beta (transforming growth factor beta)-like molecules or process procollagens. Aplysia tolloid/BMP-1-like protein (apTBL-1) might regulate the morphology and efficacy of synaptic connections between sensory and motor neurons, which are associated with long-term sensitization.
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PMID:A developmental gene (Tolloid/BMP-1) is regulated in Aplysia neurons by treatments that induce long-term sensitization. 898 97

Angiogenesis is a significant prognostic factor in breast cancer, but the factors that control angiogenesis in vivo are not well defined. Multiple angiogenic polypeptides are known, and we have determined the expression of seven of these in primary human breast cancers; the relationship of expression to estrogen receptor and vascular density was also examined. Vascular endothelial growth factor (VEGF) and its four isoforms (121, 165, 189, and 206 amino acids), transforming growth factor (TGF)-beta1, pleiotrophin, acidic and basic fibroblast growth factor (FGF), placental growth factor, and thymidine phosphorylase (platelet-derived endothelial cell growth factor) were quantitated by RNase protection analysis. beta-FGF was also measured by ELISA. The estrogen receptor (ER), epidermal growth factor receptor, and vascular density were analyzed in 64 primary breast cancers. All tumors expressed at least six different vascular growth factors. VEGF was most abundant, and the transcript for the 121-amino acid form predominated. Other angiogenic factors expressed at high levels were thymidine phosphorylase and TGF-beta1. Expression of most of the angiogenic factors did not correlate with that of ER or vascular density. However, thymidine phosphorylase did, with a correlation coefficient of 0.3 (P = 0.03). There were significant associations of pleiotrophin with acidic FGF expression (P = 0.001) and TGF-beta with platelet-derived endothelial cell growth factor expression (P = 0.001). Thus, angiogenesis may involve a coordinate regulation of some vascular growth factors. High VEGF expression correlated with poor prognosis in univariate analysis (P = 0.03), as did ER and epidermal growth factor receptor expression. Basic FGF was also assessed by ELISA and was more highly expressed in tumors than normal breast tissues (median, 346 microg/ml cytosol; range, 54-1323 versus median, 149; range, 32-509; P = 0.01). Implications for therapy are that broad spectrum agents that block features common to these factors may be useful (e.g., antagonism of heparin-binding activity agents), because so many angiogenic factors are expressed. Inhibiting endothelial migration or agents directly toxic to endothelium would be of value in a combined approach to therapy.
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PMID:Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. 904 Dec 2

The start sites for the major human TGF-beta 1 transcripts have been reexamined. A comparison of ribonuclease and S1 nuclease protection analyses on native TGF-beta 1 mRNA and in vitro transcribed human TGF-beta 1 transcripts of defined sizes places the most 5' start site for the native TGF-beta 1 message approx. 50 nucleotides upstream from the previously published start site at base +1. Furthermore, the same techniques indicate that the apparent downstream start site at base +271 is an artefact due to the presence of an A + T-rich island in the middle of an otherwise highly G + C-rich sequence. This is not apparent if S1 nuclease protection is used alone, which emphasizes the importance of using the two techniques in combination for this type of analysis. Thus the major 2.5 kb TGF-beta 1 band seen on Northern blots comprises only mRNA transcribed from the more upstream of the two previously characterized promoters. This has important implications both for the transcriptional and translational regulation of this growth factor.
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PMID:Recharacterization of the start sites for the major human transforming growth factor-beta 1 mRNA. 916 39

The success of coronary reconstructive procedures is limited by the high incidence of restenosis secondary to intimal hyperplasia (IH). Transforming growth factor-beta 1 (TGF-beta 1) is a growth factor which has been shown to be important in the early development of IH in arteries and peripheral vein grafts. To date, there is little information concerning the early remodeling in aortocoronary vein grafts (ACVG). The purpose of this study was to characterize the expression of TGF-beta 1 expression in early aortocoronary vein grafts. Eighteen mongrel dogs underwent aortocoronary vein bypass grafting. Vein grafts were excised at 2 hr, 4 hr, and 7 days after implantation, snap frozen, and processed for ribonuclease protection assays (RPA) using 32P-labeled riboprobes for TGF-beta 1 and 18 S rRNA. TGF-beta 1 expression was quantified by densitometric analysis of autoradiographs which were expressed as a ratio TGF-beta 1/rRNA. Representative vessel rings were also collected for histology. There was a significant rise in TGF-beta 1 expression in the 2-hr vein grafts (0.42 +/- 0.04 compared to control saphenous vein (0.21 +/- 0.05, P < 0.02). In addition, there was significant downregulation of TGF-beta 1 at 4 hr (0.28 +/- 0.05) and at 7 days (0.18 +/- 0.01) when compared to 2 hr (P < 0.05). Histological specimens showed minimal intimal hyperplasia at 7 days. These results show for the first time an acute rise in TGF-beta 1 expression in ACVG. This upregulation quickly subsides by 4 hr and gene expression approaches control values by 7 days. By understanding this temporal relationship of expression one could better target potential therapeutic modalities to attenuate IH.
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PMID:The temporal expression of transforming growth factor-beta 1 in early aortocoronary vein grafts. 922 5

Inhalation of fibrogenic particles causes injury to the bronchiolar-alveolar epithelium. Consequently, there is a rapid proliferative response as the epithelium recovers and interstitial mesenchymal cells divide and produce connective tissue. In our model of brief (5-hr) exposure to chrysotile asbestos (approximately 1000 fibers/cc) in rats and mice, these events result in focal scarring at the bronchiolar-alveolar duct junctions in a histopathologic pattern identical to that seen in asbestos-exposed individuals. After 3 consecutive days of exposure, these lesions persist for at least 6 months postexposure. We postulate that cell proliferation and production of extracellular matrix is mediated in large part by three peptide growth factors, transforming growth factors alpha and beta (TGF-alpha and -beta), and platelet-derived growth factor (PDGF) A- and B-chains. To test this hypothesis in part, we have asked whether the genes that code for these growth factor proteins are activated at sites of asbestos-induced lung injury. If these genes were not activated, it would be reasonable to suspect that other potent growth factors and cytokines released during lung injury could be the primary mediators of fibroproliferative lung disease. In the studies reported here, we show, by in situ hybridization (ISH) and immunohistochemistry, that the four genes and their concomitant proteins are expressed within 24 hr in the bronchiolar-alveolar epithelium and underlying mesenchymal cells. RNase protection assay and ISH showed that the PDGF gene was upregulated during the first 5 hr of exposure and all the gene products remained above control levels for at least 2 weeks postexposure. TGF-alpha is a potent mitogen for epithelial cells, whereas the PDGF isoforms are potent growth factors for mesenchymal cells. TGF-beta retards fibroblast growth but stimulates extracellular matrix synthesis. Further studies using gene knockouts, appropriate antibodies, or antisense technology will be necessary to prove whether any of the growth factors are playing a significant role in fibrogenic lung disease. In addition, we have carried out a series of studies using type II alveolar epithelial cells purified from adult mouse lungs and maintained for up to 8 weeks in serum-free culture. These cells exhibit high transepithelial resistance values and they release TGF-beta 1 and -beta 2. This cell type also has been cultured from TGF-alpha knockout mice, resulting in monolayers with increased transepithelial resistance. This combination of studies in vivo and in vitro will allow us to pursue the mechanisms through which growth factors mediate lung fibrosis.
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PMID:Analyzing the genes and peptide growth factors expressed in lung cells in vivo consequent to asbestos exposure and in vitro. 940 Jul 18


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