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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mouse neuroblastoma cells (clone N1E-115) differentiate in culture upon withdrawal of serum growth factors and acquire the characteristics of neurons. We have shown tht exponentially growing N1E-115 cells possess functional epidermal growth factor (EGF) receptors but that the capacity for binding EGF and for stimulation of DNA synthesis is lost as the cells differentiate. Furthermore, in exponentially growing cells, EGF induces a rapid increase in amiloride-sensitive Na+ influx, followed by stimulation of the (Na+-K+)ATPase, indicating that activation of the Na+/H+ exchange mechanism in N1E-115 cells [1] may be induced by EGF. The ionic response is also lost during differentiation, but we have shown that the stimulation of both Na+ and K+ influx is directly proportional to the number of occupied receptors in all cells whether exponentially growing or differentiating, thus only indirectly dependent on the external EGF concentration. The linearity of the relationships indicates that there is no rate-limiting step between EGF binding and the ionic response. Our data would suggest that as neuroblastoma cells differentiate and acquire neuronal properties, their ability to respond to mitogens, both biologically and in the activation of cation transport processes, progressively decreases owing to the loss of the appropriate receptors.
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PMID:Loss of EGF binding and cation transport response during differentiation of mouse neuroblastoma cells. 630 14

Recent studies have established that polypeptide growth factors cause an elevation of the cytoplasmic pH (pHi) in cultured mammalian cells by stimulating Na+/H+ exchange. We show that vanadate, previously found to act as a mitogen for a number of cells, reversibly activates Na+/H+ exchange at micromolar concentrations in A431 cells, leading to a large increase of pHi. The stimulation of Na+/H+ exchange by vanadate is not due to inhibition of the Na+/K+ ATPase and is unrelated to possible effects of vanadate on cAMP levels. Elevation of pHi by vanadate and by epidermal growth factor (EGF) both display similar kinetics, and both EGF and vanadate stimulate the rate of pHi recovery following an acute acid load, suggesting that vanadate stimulates Na+/H+ exchange by a mechanism similar to that of polypeptide growth factor stimulation. Thus, stimulation of Na+/H+ exchange may be a common property not only of polypeptide growth factors but also of other, chemically unrelated mitogens.
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PMID:Vanadate stimulates Na+/H+ exchange activity in A431 cells. 632 60

Cultured chicken heart mesenchymal cells are proliferatively quiescent at low densities in medium containing plasma at 10%. Mitogenic hormones like epidermal growth factor and insulin-like growth factors cause these cells to proliferate very actively, as does infection with avian sarcoma viruses, erythroblastosis virus, or myelocytomatosis virus. We have found that the combination of phorbol 12-myristate 13-acetate (PMA), ionomycin or ouabain, and raised extracellular magnesium, likewise, causes these cells to proliferate very actively. Although these agents have no significant effect when acting singly, the combination of PMA at 100 ng/ml and 0.5 microM ionomycin induces a 6-fold increase in cell number at 4 days, and the combination of PMA, ionomycin, and 5.6 mM magnesium induces 12-fold multiplication. Likewise, PMA plus 1 microM ouabain induces 3-fold multiplication, whereas the combination of PMA, ouabain, and magnesium induces 6-fold multiplication. The tumor promoter PMA, like diacylglycerol released by breakdown of plasma membrane phosphatidylinositol diphosphate, is known to activate the serine- and threonine-specific intracellular enzyme kinase C. The divalent cation ionophore ionomycin is known to carry calcium into cells down an electrochemical gradient, and the Na+,K+-ATPase inhibitor ouabain appears to elevate intracellular calcium by means of a sodium-mediated exchange mechanism. Magnesium, like calcium, is known to enter cells passively down an electrochemical gradient and to be involved in the regulation of many key intracellular reactions. Our findings with PMA, ionotropes, and magnesium support a hypothesis that diacylglycerol-mediated activation of kinase C plus cellular divalent cation influx and/or mobilization, caused by the action of mitogenic hormones or the protein products of onc genes, are key events in the initiation of cell replication.
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PMID:Phorbol 12-myristate 13-acetate, ionomycin or ouabain, and raised extracellular magnesium induce proliferation of chicken heart mesenchymal cells. 633 83

1. The contractile actions of vanadate (VO4) and pervanadate (PV, peroxide(s) of vanadate) were studied in rat gastric longitudinal muscle strips and in aortic rings. The roles of extracellular sodium and calcium were evaluated and the potential effects of nerve-released agonists were considered. The possibility that these responses were due to the potentiation of tyrosine kinase activity, as a result of PV-mediated tyrosine phosphatase inhibition was explored with the use of tyrosine kinase inhibitors (genistein, tyrphostin) and by Western blot analysis of phosphotyrosyl proteins in PV-treated tissues. The ability of PV to mimic the action of the tyrosine kinase receptor-associated agonist, epidermal growth factor-urogastrone (EGF-Uro), in the gastric preparation was also studied. 2. PV caused concentration-dependent contractions in both gastric and aorta-derived tissues, with a potency that was 1 to 2 orders of magnitude greater than that of VO4. 3. Although repeated exposure of gastric and aortic tissues to a fixed concentration of VO4 caused reproducible contractions in both tissues, repeated exposure of gastric tissue to PV caused an increased contractile response plateauing after 3 exposures. In contrast, a single exposure of aortic tissue to PV (20 microM) caused a prolonged desensitization of the tissue to the subsequent contractile actions of PV or other agonists. 4. The contractile responses to PV were unaffected in both preparations by tetrodotoxin, atropine, yohimbine and phenoxybenzamine; and in the aortic preparation, the responses to VO4 and PV were the same in the presence or absence of a functional endothelium. 5. PV-induced contractions in both tissues were observed in the absence of extracellular sodium but required extracellular calcium and were attenuated by 1 micro M nifedipine.6. In the gastric preparation, the characteristics of the contractile actions of PV paralleled those of EGF-Uro in terms of (1) inhibition by genistein, (2) inhibition by indomethacin and (3) a requirement for extracellular calcium. These response characteristics differed from those of other contractile agonists such as carbachol.7. In both the gastric and aortic preparations genistein was able to inhibit PV-induced contractions selectively without causing comparable inhibition of KCI-induced contractions. Tyrphostin (AG18) also selectively blocked PV-induced contractions in the gastric, but not in the aortic preparation.8. In both the gastric and aortic tissue, in step with an increased contractile response, PV caused increases in tissue phosphotyrosyl protein content, as detected by Western blot analysis using a monoclonal antiphosphotyrosine antibody; the increases in phosphotyrosyl protein content were reduced when tissues were treated with PV at the same time as a tyrosine kinase inhibitor.9 PV, at sub-contractile concentrations, potentiated the contractile action of angiotensin II in both the gastric and aorta tissue.10 We conclude that the growth factor-mimetic agent, PV, is a much more potent contractile agonist than V04 in both vascular and gastric smooth muscle tissue. PV can cause enhanced tissue phosphotyrosyl protein content most likely via the inhibition of tissue protein tyrosine phosphatases. The contractile actions of PV, which require extracelullar calcium and are independent of extracellular sodium, would appear not to be due either to Na+/Ca2" exchange, promoted by Na+/K+-ATPase inhibition or to the inhibition of Ca2+-ATPase and might be best explained by the ability of PV, via tyrosine phosphatase inhibition, to potentiate a tyrosine kinase pathway linked to calcium entry and to the contractile process.
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PMID:Regulation of vascular and gastric smooth muscle contractility by pervanadate. 753 May 69

Induction of gene expression in response to calcium ionophores or thapsigargin, which inhibits the calcium-ATPase responsible for sequestering intracellular calcium, has frequently been attributed to direct stimulatory events subsequent to the elevation of intracellular free calcium. VL30 is a murine gene that is transcriptionally induced in response to a large array of mitogenic and transforming stimuli. We have shown previously that an enhancer element within the VL30 promoter region is dependent upon cotreatment with thapsigargin or calcium ionophore for a full-scale induction of gene expression. In this report, we demonstrate that both thapsigargin and calcium ionophores induce a transient inhibition of protein synthesis in Rat-1 cells transfected with a VL30 enhancer-driven reporter construct. Recovery of protein synthesis is facilitated by cotreatment with epidermal growth factor or phorbol esters. Furthermore, treatment with cycloheximide or DTT, which inhibit protein synthesis without altering intracellular calcium levels, can substitute for thapsigargin or ionophores in stimulating VL30 gene expression. These results suggest that the stimulatory effects of thapsigargin and calcium ionophores on VL30 expression may be mediated, at least in part, by the ability of these agents to initiate stress responses associated with inhibition of protein synthesis.
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PMID:Transient inhibition of protein synthesis induces the immediate early gene VL30: alternative mechanism for thapsigargin-induced gene expression. 754 11

E5 is the smallest transforming protein encoded by the human papillomaviruses (HPVs). It has been shown to promote anchorage-independent growth in established NIH 3T3 cells, an activity that is enhanced in the presence of epidermal growth factor (EGF). It is thought that this activity of E5 is brought about by an increase in the half-life of stimulated EGF receptors, possibly through the perturbation of receptor processing. Recent studies have also shown that E5 can co-operate with HPV-16 E7 to stimulate proliferation of primary rodent cells. Using haemagglutinin I epitope-tagged E5 proteins, we have compared the mitogenic activity of HPV-6 and HPV-16 E5. Both tagged proteins retain the ability to bind to the cellular 16 kDa H(+)-ATPase protein. In addition, both HPV-6 and HPV-16 E5 retain the ability to co-operate with E7 in primary rodent cells, although HPV-16 E5 is considerably more active than HPV-6 E5 in these mitogenic assays. Interestingly, transfection of a plasmid over-expressing c-Raf appears to be capable of functionally substituting for E5 in the co-mitogen assays. Polyclonal cell lines derived from baby rat kidney cells co-transfected with E7 and E5 genes continue to express both the E5 and E7 mRNA, although the level of E5 expression is very low and protein cannot be detected. These polyclonal lines appear to be immortal and in some cases demonstrate anchorage-independent growth, an activity which is enhanced by the addition of EGF.
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PMID:The human papillomavirus (HPV)-6 and HPV-16 E5 proteins co-operate with HPV-16 E7 in the transformation of primary rodent cells. 773 Aug 8

Previous studies have suggested that both cAMP-dependent signal transduction pathway and Ca2+/protein kinase C-dependent pathway are involved in GSH efflux from hepatocytes. In the present study, GSH efflux from Hep G2 cells, a human-derived hepatoma cell line, was further characterized. Both epidermal growth factor (0.1-10 ng/ml) and insulin (1 microgram/ml) significantly increased GSH efflux from Hep G2 cells. A fall in the membrane potential produced by the replacement of Na+ with equivalent K+ did not affect GSH efflux significantly. Neither ouabain, a Na+/K+ ATPase inhibitor, vanadate, a Ca2+ ATPase inhibitor, nor BaCl2, a K+ channel blocker, significantly affected the GSH efflux. Methionine (1mM) decreased GSH efflux from the cells, although total GSH content in the cells was not affected during the incubation time of 60 min. Signal transductions through tyrosine kinase-coupled receptors may also be involved in GSH efflux from hepatocytes.
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PMID:Characterization of glutathione efflux from Hep G2 cells. 782 1

The SV40 T-antigen-transfected human thyroid cell line SGHTL-34 was used to investigate the effect of thyrotropin (TSH), insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF) on c-fos and c-erbB/EGF receptor (EGF-R) mRNA expression and their role in human thyroid cell proliferation. EGF caused a transient 8- and 4-fold increase in c-fos mRNA level after 30 min in serum/hormone-deprived and in logarithmically growing cells, respectively. EGF was only mitogenic in the presence of serum, as measured by 3H-thymidine incorporation and cell counting. TSH had no detectable effect on c-fos mRNA expression and no mitogenic effect on the SGHTL-34 cells. IGF-1 showed no effect alone or in combination with EGF or TSH on either proliferation or c-fos mRNA expression. Our data suggest that increased c-fos mRNA levels are part of the mitogenic pathway, but are insufficient to engender a mitogenic response. SGHTL-34 cells produced high levels of transforming growth factor-alpha (TGF-alpha) and c-erbB/EGF-R mRNA, also seen in thyroid papillary carcinomas. The TGF-alpha protein was detected in conditioned medium from the SGHTL-34 cells, indicating that TGF-alpha may function as an autocrine growth factor. Our data show that the c-erbB/EGF-R mRNA level is regulated by growth factors and hormones in the SGHTL-34 cell line. The SGHTL-34 cells may therefore represent a useful model system for studying the role of TGF-alpha and EGF-R in thyroid carcinogenesis.
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PMID:Growth requirements and oncogene expression in the human thyroid cell line SGHTL-34. 790 43

A transgenic mouse line (EGF/Tag) has been established in which expression of SV40 T-antigen is directed by a 5.5 kb fragment of the 5'-flanking region of the mouse epidermal growth factor (EGF) gene. Of the two principal sites of EGF expression in mice, submaxillary gland and kidney, T-antigen mRNA and protein were detected in the former but not in the latter tissue of the EGF/Tag animals. T-antigen expression in the submaxillary gland was restricted to the EGF-producing cells of the granular convoluted tubules, and the oncoprotein induced hyperplasia of these cells. T-antigen levels were markedly higher in the submaxillary glands of male compared with female transgenic mice, suggesting that expression of the transgene was androgen-regulated, like the endogenous EGF gene. These results indicate that the 5.5 kb fragment upstream of the mouse EGF gene contains the DNA enhancer elements required for hormonally regulated expression in the submaxillary gland. Since the hyperplastic submaxillary glands of the EGF/Tag mice continue to synthesize EGF, these glands provide a tissue source from which it may prove possible to establish EGF-secreting cell lines for further in vitro studies of the mechanisms regulating expression of the EGF gene.
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PMID:Directed expression of simian virus 40 T-antigen in transgenic mice using the epidermal growth factor gene promoter. 791 70

To investigate the signaling pathways to Na+/H+ exchanger activation with epidermal growth factor in hepatocytes, we measured changes in cytosolic free calcium and intracellular pH levels at the single-cell level using digital imaging fluorescence microscopy of fura-2- or BCECF-loaded hepatocytes in primary culture. Epidermal growth factor induced cytosolic free calcium oscillations consisting of periodic trains of spikes with a latency period of up to several minutes. These calcium responses were inhibited by tyrosine kinase inhibitor genistein (100 mumol/L) and abolished by emptying of intracellular Ca2+ pools with 3 mumol/L thapsigargin, an inhibitor of Ca(2+)-ATPase on the endoplasmic reticulum. Epidermal growth factor (1 nmol/L) induced an intracellular pH increase of 0.12 +/- 0.07 units from the basal level of 7.25 +/- 0.09 units after several minutes of latency. This effect was completely abolished by 1 mmol/L amiloride, an inhibitor of the Na+/H+ exchanger. The epidermal growth factor-induced intracellular pH increase was inhibited by pretreatment of hepatocytes with genistein (100 mumol/L), thapsigargin (3 mumol/L) or calmodulin inhibitor W-7 (25 mumol/L), but not with protein kinase C inhibitor H-7 (50 mumol/L) or with cyclic AMP-dependent kinase inhibitor H-8 (60 mumol/L). Phorbol ester PMA (phorbol 12-myristate 13-acetate), a potent activator of protein kinase C, induced a slight intracellular pH increase significantly smaller than that with epidermal growth factor, whereas this effect was completely blocked by pretreatment with H-7, indicating that PMA-induced intracellular pH increase is mediated by protein kinase C pathways, unlike epidermal growth factor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of signaling pathways to Na+/H+ exchanger activation with epidermal growth factor in hepatocytes. 792 39


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