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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that the highly reactive aldehyde 4-hydroxynonenal (HNE), a mediator of oxidative stress, can either stimulate or inhibit cell proliferation, depending on the concentration of the aldehyde and the presence of serum. HNE can also induce differentiation of tumour cells in vitro and inhibit the tumour development in vivo. The aim of the study presented was to find out more details about the basic mechanisms by which HNE influences cell growth behaviour. Therefore we analysed the effect of HNE on the transcription of the c-fos gene in HeLa cells, to clarify the pathway by which the aldehyde modulates gene transcription and growth behaviour of the cells. At a supraphysiological concentration (50 microM) the aldehyde caused an enhanced c-fos transcription (as measured by the reverse transcriptase/polymerase chain reaction assay), while it inhibited cell proliferation markedly. Therefore, we assume that among the "early" effects of HNE on cellular growth regulation might be an altered expression of the "early response" genes (c-fos), while a "late" effect might be an altered autocrine/paracrine growth regulation of the cells. This finding on the possible basic mechanisms of the biological effects of HNE together with the already described high toxicity of the aldehyde for cancer cells give support for the further evaluation of the possible use of HNE in cancer biotherapy.
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PMID:Inhibition of HeLa cell proliferation by 4-hydroxynonenal is associated with enhanced expression of the c-fos oncogene. 1085 57

This study aimed to elucidate the inhibitory effects of chlorophyllin (CHL) at different promotion stages in a DMBA-TPA-induced mouse skin carcinogenesis model. TPA promotion was undertaken for 6, 18 and 24 weeks, respectively. Proliferating activity was observed immunohistochemically and the ornithine decarboxylase (ODC) mRNA level was analyzed by reverse transcriptase-polymerase chain reaction. Messenger RNAs for c-fos, c-jun and jun-B were also observed. CHL treatment clearly reduced proliferating activity and the level of ODC mRNA at the 18-week-promotion stage. When promoted for 24 weeks, CHL was not effective in reducing proliferating activity and ODC mRNA expression. These results indicate that the promotion stage of each target tissue should be considered in a chemopreventive program.
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PMID:Anti-promotion effect of chlorophyllin in DMBA-TPA-induced mouse skin carcinogenesis. 1092 61

Chronic hypertension is associated with remodeling of small arteries. There is evidence that the high pressure itself may cause these structural changes, but the responsible mechanisms are not clearly defined. Previously we showed that pressure-induced c-fos expression in intact cannulated rat mesenteric small arteries was inhibited by genistein, a general tyrosine kinase inhibitor. The purpose of this study was to further unravel the underlying signal transduction mechanisms, and we particularly tested the involvement of src tyrosine kinases and extracellular signal-regulated kinase (ERK). Rat mesenteric small arteries were cannulated in a dual-vessel chamber. After a 60-minute equilibration period, the pressure in 1 artery was increased to 140 mm Hg, while the other artery remained at 90 mm Hg. Semiquantitative reverse transcriptase-polymerase chain reaction was used to determine c-fos expression, and Western blotting was used to examine levels of ERK phosphorylation. The involvement of src and ERK was tested with the inhibitors herbimycin A (1 micromol/L), PP1 (10 micromol/L), PP2 (10 micromol/L), and PD98059 (30 micromol/L). One-hour exposure to 140 mm Hg increased the c-fos/cyclophilin ratio 3.6-fold, from 0.29+/-0.07 to 1.06+/-0.25. All the tested inhibitors suppressed the pressure-induced increase of c-fos expression. A 5-minute exposure period to 140 mm Hg increased ERK phosphorylation, and this was abolished in the presence of PP1. The results suggest that pressure-induced c-fos expression in intact cannulated rat mesenteric small arteries may be mediated, at least in part, by src tyrosine kinases and ERK.
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PMID:Src tyrosine kinases and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases mediate pressure-induced c-fos expression in cannulated rat mesenteric small arteries. 1124 24

Long-term in vivo studies have highlighted smoking as a risk factor in postmenopausal osteoporosis, bone fracture incidence, and increased nonunion rates. In contrast, there are few data postulating the effects of smoking at the cellular level in human skeletal tissue. In this study, we present novel evidence demonstrating that the nicotinic receptor alpha4 subunit is present in human primary bone cells by using reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, we demonstrate direct cellular effects of nicotine on primary human bone cells and blockage of these effects with a nicotinic receptor antagonist, D-tubocurarine. Nicotine effects on cell proliferation were biphasic with toxic, antiproliferative effects at high levels of nicotine (>1 mmol/L) and stimulatory effects at very low levels (0.01-10 micromol/L) after 72 h. This nicotine-induced increase in cell proliferation was inhibited in a dose-dependent manner by the addition of D-tubocurarine. In addition, proliferation effects from low-level treatment correlated with an upregulation of expression of the AP-1 transcription factor, c-fos, within 1 h, which was blocked by incubation with D-tubocurarine. To determine in situ bone cell responses within their trabecular matrix, cores of human bone isolated from biopsies were perfused with 0.1 micromol/L nicotine for 24 h. Western analysis of proteins isolated from the cores highlighted an increase in osteopontin, a bone matrix protein implicated in regulating resorption, which was partially inhibited by the addition of D-tubocurarine. To conclude, our results suggest that nicotine has a direct effect on human bone cells in modulating proliferation, upregulation of the c-fos transcription factor, and the synthesis of the bone matrix protein, osteopontin.
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PMID:Nicotinic regulation of c-fos and osteopontin expression in human-derived osteoblast-like cells and human trabecular bone organ culture. 1142 48

Asbestos is a ubiquitous naturally occurring fiber causing multiple cancers and fibroproliferativedisease. The mechanisms of epithelial cell hyperplasia, a hallmark of the initiation of lung cancers by asbestos, have been unclear. We demonstrate here that mice expressing a dominant-negative mutant epidermal growth factor receptor (EGFR) under the control of the human lung surfactant protein-C promoter exhibit decreased pulmonary epithelial cell proliferation without alterations in asbestos-induced inflammation. In contrast to transgene-negative littermates, inhalation of asbestos by mice expressing the mutant EGFR does not result in early and elevated expression of early response proto-oncogenes (fos/jun or activator protein 1 family members). Additionally, quantitative reverse transcriptase-PCR analysis for levels of c-jun and c-fos in bronchiolar epithelium isolated by laser capture microdissection demonstrates increases in expression of these genes in asbestos-exposed epithelial cells. Results show that the EGFR mediates both asbestos-induced proto-oncogene expression and epithelial cell proliferation, providing a rationale for modification of its phosphorylation in preventive and therapeutic approaches to lung cancers and mesothelioma.
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PMID:A mutant epidermal growth factor receptor targeted to lung epithelium inhibits asbestos-induced proliferation and proto-oncogene expression. 1215 12

The arterial wall is composed of dynamically interacting cellular and acellular components that are necessary for the maintenance of vessel homeostasis. Two extracellular proteins in the vessel wall, elastin and laminin, play important structural roles. We recently established a role for the elastin-laminin receptor (ELR) in mechanotransduction of stretch in cultured vascular smooth muscle (VSM) (Am. J. Physiol.: Heart Circ. Physiol. 280(3) (2001) H1354). We found stretch-mediated signaling by the ELR decreased the expression of the proto-oncogene, c-fos, and subsequent cellular proliferation. However, the role for the ELR in mediating pressure-induced changes in gene expression in intact, isolated resistance vessels is unknown and the goal of this study was to ascertain this possibility. In this study, isolated rat cerebral (approximately 180 microm) and mesenteric (approximately 280 microm) arteries were pressurized to 65 mmHg (baseline) and this pressure was held for 2 h. After this equilibration, pressures were increased to either 80 mmHg (n=6) or 140 mmHg (n=6) for 30 min and transcript levels of c-fos and the housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA were assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). Elevation of pressure in the cerebral arteries decreased the c-fos/GAPDH ratio by 72% in the 140 mmHg group compared to the 80 mmHg control. Importantly, the decrease in c-fos expression was blocked by ELR peptide antagonists (VGVAPG or YIGSR, 10 microM, n=6). In contrast, the decrease in c-fos expression was not observed in the mesenteric resistance arteries. In these vessels, pressure (140 mmHg) increased the c-fos/GAPDH ratio (+68% compared to normotensive control, n=6). To account for the difference between the cerebral and mesenteric vessels, histological analysis of elastin fiber content was performed. Cerebral arteries have greater amounts of loose elastin fibers (fibers outside of the organized elastin laminae) in the tunica media compared to mesenteric arteries. This may explain the opposite stretch-induced responses of c-fos expression in these vessels. Stretch-induced ELR signaling may play a prominent role in vascular adaptations to hypertension in specific organ systems. Our data further suggest that ELR activation may represent a larger component of mechanosensitive signaling in the cerebral circulation than in the mesenteric circulation.
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PMID:Mechanotransduction via the elastin-laminin receptor (ELR) in resistance arteries. 1269 94

Tissue anoxia occurs early in wound healing. This is accompanied by production of lactate followed by increased hyaluronan and CD44 expression, suggesting a cause and effect relationship. Fibroblasts increased hyaluronan and CD44 when lactate was added to cultures. Increased deposition of hyaluronan correlates with greater turnover. In current models of hyaluronan catabolism, it is tethered to cell surfaces by CD44 in caveolin-enriched invaginations. It is cleaved to 20-kDa fragments by Hyal-2 on the plasma membrane, endocytosed, and delivered ultimately to lysosomes, and further digested by Hyal-1. Sequence analyses of promoter regions of genes for CD44, caveolin-1, Hyal-1, and -2 revealed multiple AP-1 and ets-1 response elements. To test their relevance, RNA from lactate-treated fibroblasts was analyzed by reverse transcriptase-polymerase chain reaction. Increased transcripts of c-fos, c-jun, c-ets, Hyal-1, -2, CD44, and caveolin-1 mRNAs were observed. We have thus identified lactate-activated genes important in the wound healing responses. Similar responses facilitating tumor progression, the Warburg effect, may share such mechanisms.
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PMID:Lactate-sensitive response elements in genes involved in hyaluronan catabolism. 1273 17

Using the reverse transcriptase-polymerase chain reaction we examined the effect of basic calcium phosphate (BCP) crystals on the induction of the early growth response gene Egr2 transcription and the signal transduction pathway involved. The results showed that BCP crystals induced Egr2 transcription up to 8-fold, peaking at 24 h after treatment. The induction of Egr2 was confirmed by transient transfection assays using an Egr2 promoter/luciferase reporter construct and could be inhibited by the p44/42 mitogen-activated protein kinase (MAPK)-specific inhibitor U0126, or by calcium chelator TMB-8, but not by the SAPK2/p38 MAPK inhibitor SB202190 or by the protein kinase C inhibitor bisindolylmaleimide I (Bis-I). Using the Mercury Pathway Profiling System (Clontech, Palo Alto, Calif., USA) we further showed that induced Egr2 could stimulate the activities of several transcription factors that are associated with cell proliferation, such as c-fos, SRF and c-myc.
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PMID:Induction of early growth response gene Egr2 by basic calcium phosphate crystals through a calcium-dependent protein kinase C-independent p44/42 mitogen-activated protein kinase pathway. 1278 42

Mechanical strain plays a crucial role in bone remodeling during growth and development and healing of bone besides systemic and local factors. One of the major factors involves in remodeling process is matrix metalloproteinases (MMPs) such as MMP-13 that has been shown to degrade the native interstitial collagens in several tissues. To study how mechanical strain affects extracellular matrix degradation by MMP-13, a biaxial strain was applied to MC3T3-E1 osteoblastic cells plated onto a collagen-coated flexible elastic membrane. The MMP-13 protein and mRNA expression were determined by Western blotting and reverse transcriptase-PCR, respectively. The zymographic activities of MMP-13 increased dramatically at 30 min, reached a peak by 2-fold at 1 h, and maintained up to 4 h. Moreover, the MMP-13 and c-fos mRNA expressed at 5 min, increased to 2.8- and 3-fold at 1 h, respectively, and gradually declined thereafter. Cycloheximide and actinomycin D did not inhibit the MMP-13 and c-fos mRNA expression, suggesting that such expression does not require de novo protein synthesis and not change their stabilities. To investigate which of the mitogen-activated protein kinase (MAPK) pathways involves in the expression of MMP-13, inhibitors such as PD98059, SB203580, and SP600125 were used. However, only PD98059 (an inhibitor of MEK1/2 activation) inhibited MMP-13 and c-fos gene expression; the result was further substantiated by transfecting with the dominant negative mutants of MEK1/2 (MEK K97R) and ERK2. Taken together, our results showed that mechanical strain induces the MMP-13 expression through MEK-ERK signaling pathway to regulate mechanical adaptation.
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PMID:Mechanical strain induces collagenase-3 (MMP-13) expression in MC3T3-E1 osteoblastic cells. 1504 66

Immunohistochemical analysis revealed the presence of a gut-brain peptide, neuromedin U (NMU), in the suprachiasmatic nucleus (SCN), which is the site of the master circadian oscillator. The expression of NMU mRNA exhibited a circadian rhythm, with the peak expression in the SCN occurring at CT4-8h. The two NMU-binding receptors (NMU-R1 and NMU-R2) were also expressed in the SCN, but their phase angles were different. Intracerebroventricular injection (ICV) of NMU induced the expression of Fos protein in the SCN cells and caused a phase-dependent phase shift of the circadian locomotor activity rhythm. The magnitude of the phase shift was dose dependent. This NMU-induced phase shift was of the nonphotic type. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed increases in the expression in the SCN of immediate early genes, such as c-fos, NGFI-A, NGFI-B, and JunB. Furthermore, ICV injection of NMU increased the expression of Per1, but not Per2, in the SCN. These results indicate that NMU may play some important role in the circadian oscillator by exerting an autocrine or paracrine action in the SCN.
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PMID:The gut-brain peptide neuromedin U is involved in the mammalian circadian oscillator system. 1511 Jul 67


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