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)

In the present study we used LLC-PK1 cells, a porcine renal proximal tubular cell line, to investigate whether PI3 kinase activation was involved in the anti-apoptotic effect of ouabain, a specific inhibitor of Na,K-ATPase. Apoptosis was induced by actinomycin D (Act D, 5 microM) and assessed by appearance of hypodiploid nuclei and DNA fragmentation. Ouabain attenuated Act D-induced apoptotic response in a dose-dependent manner. Incubation in a low K(+) medium (0.1 mM) which is another way to decrease Na,K-ATPase activity also had anti-apoptotic effect. Both ouabain and low K(+) medium increased the PI3 kinase activity in p85 immunoprecipitates. Ouabain, as well as incubation in the low K(+) medium, also increased the phosphorylation of Akt. Inhibition of PI3 kinase by either wortmannin or LY294002 reversed the cytoprotective effect of ouabain. These data together indicate that inhibition of Na,K-ATPase activates PI3 kinase in LLC-PK1 cells which could then exert the cytoprotective effect.
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PMID:Inhibition of Na,K-ATPase activates PI3 kinase and inhibits apoptosis in LLC-PK1 cells. 1143 70

Interleukin-1alpha (IL-1alpha) and tumor necrosis factor-alpha (TNF-alpha) markedly stimulate glucose utilization in primary cultures of mouse cortical astrocytes. The mechanism that gives rise to this effect, which takes place several hours after application of cytokine, has remained unclear. Experiments were conducted to identify the major signaling cascades involved in the metabolic action of cytokine. First, the selective IL-1 receptor antagonist (IL-1ra) prevents the effect of IL-1alpha on glucose utilization in a concentration-dependent manner, whereas it has no effect on the action of TNF-alpha. Then, using inhibitors of three classical signaling cascades known to be activated by cytokines, it appears that the PI3 kinase is essential for the effect of both IL-1alpha and TNF-alpha, whereas the action of IL-1alpha also requires activation of the MAP kinase pathway. Participation of a phospholipase C-dependent pathway does not appear critical for both IL-1alpha and TNF-alpha. Inhibition of NO synthase by L-NAME did not prevent the metabolic response to both IL-1alpha and TNF-alpha, indicating that nitric oxide is probably not involved. In contrast, the Na(+)/K(+) ATPase inhibitor ouabain prevents the IL-1alpha- and TNF-alpha-stimulated 2-deoxyglucose (2DG) uptake. When treatment of astrocytes with a cytokine was followed 24 h later by an acute application of glutamate, a synergistic enhancement in glucose utilization was observed. This effect was greatly reduced by ouabain. These data suggest that Na(+) pump activity is a common target for both the long-term metabolic action of cytokines promoted by the activation of distinct signaling pathways and the enhanced metabolic response to glutamate.
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PMID:Long-term modulation of glucose utilization by IL-1 alpha and TNF-alpha in astrocytes: Na+ pump activity as a potential target via distinct signaling mechanisms. 1211 71

Recently, we have adapted IMCD3 cell cultures to survive under increasing hypertonic conditions (i.e., 600 and 900 mOsmol/kg H(2)O). In adapted cells, ATPase activity is increased by one order of magnitude, while the expression of the alpha and beta subunit is increased by a factor of 4 to 5 over controls (300 mOsmol/kg H(2)O). Corresponding increases in mRNAs were also detected. The gamma subunit has been described as being uniquely expressed in some areas of the kidney, but never in cell cultures (even those derived from kidney tissues). However, the gamma subunit was detected at the protein and mRNA levels in the adapted IMCD3 cells. In contrast to the alpha and beta subunits, the levels of gamma protein and mRNA expression continue to increase as a function of the media ion concentration. We have also demonstrated that signaling pathways that upregulate the alpha, beta, and gamma subunits are very different. Increasing concentrations of the PI3 kinase inhibitor, LY294002, resulted in a dose-dependent reduction in the expression of the gamma subunit, with total abolition at 10 micro M. However, LY294002 had no significant effect on the expression of the alpha subunit. Inhibition of the JNK2 (but not of the JNK1) pathways by dominant negative transfections abolished the upregulation of the gamma, but not the a subunit. Failure to upregulate the expression of the gamma subunit was associated with a marked decrease in cell viability upon stress.
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PMID:Adaptation of murine inner medullary collecting duct (IMCD3) cell cultures to hypertonicity. 1276 58

We previously reported that hypertonicity-mediated upregulation of the gamma-subunit of Na-K-ATPase is dependent on both the JNK and the PI3 kinase pathways. The present experiments were undertaken to explore the mechanisms whereby these pathways regulate the expression of the gamma-subunit in inner medullary collecting duct cells (IMCD3). Inhibition of JNK with SP-600125 (20 muM), a concentration that causes an approximately 95% inhibition of hypertonicity-stimulated JNK activation, markedly decreased the amount of the gamma-subunit in response to 550 mosmol/kgH(2)O for 48 h. This was accompanied by a parallel decrease in the gamma-subunit mRNA. The rate at which the gamma-subunit mRNA decreased was unaffected by actinomycin D. In contrast, inhibition of PI3 kinase with LY-294002 results in a marked decrease in the amount of gamma-subunit protein but without alteration in gamma-subunit message. The rate at which the gamma-subunit protein decreased was unaffected by cyclohexamide. Transfection of IMCD3 cells with a gamma-subunit construct results in the expression of both gamma-subunit message and protein. However, in cortical collecting duct cells (M1 cells) such transfection resulted in expression of only the message and not the protein. We conclude that JNK regulates the gamma-subunit at the transcriptional level while PI3 kinase regulates gamma-subunit expression at the translational level. There is also posttranscriptional cell specificity in the expression of the gamma -subunit of Na-K-ATPase.
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PMID:Synthesis of the Na-K-ATPase gamma-subunit is regulated at both the transcriptional and translational levels in IMCD3 cells. 1538 96

The frequency of calcium oscillation reveals the platelet activation status, however, the biological significance of the periodic calcium responses and methods of communication with other integrin-mediated signals are not clear. RGD-containing disintegrin rhodostomin coated substrates were employed to enhance platelet spreading and calcium oscillation through direct binding and clustering of the receptor integrin alpha(IIb)beta3. The results showed that the activation of phosphatidylinositol 3-kinase (PI3-K) and internal calcium pathways were crucial for alpha(IIb)beta3 outside-in signaling. PI3-K antagonists wortmannin and LY294002 inhibited disintegrin substrates and induced platelet spreading and calcium oscillation. At the same time, pretreatment of platelets with the microsomal calcium-ATPase inhibitor thapsigargin to deplete internal calcium stores severely impaired the calcium oscillation as well as PI3-K activation and spreading on disintegrin substrates. Because inhibition of one pathway could inhibit the other, our data indicates that PI3-K and calcium oscillation are synergistically operated and form a positive-feedback regulation in integrin alpha(IIb)beta3-mediated outside-in signaling.
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PMID:Calcium oscillation and phosphatidylinositol 3-kinase positively regulate integrin alpha(IIb)beta3-mediated outside-in signaling. 1591 97

Myosins play essential roles in migration, cytokinesis, endocytosis, and adhesion. They are composed of a large N-terminal motor domain with ATPase and actin binding sites and C-terminal neck and tail regions, whose functional roles and structural context in the protein are less well characterized. The tail regions of myosins I, IV, VII, XII, and XV each contain a putative SH3 domain that may be involved in protein-protein interactions. SH3 domains are reported to bind proline-rich motifs, especially "PxxP" sequences, and such interactions serve regulatory functions. The activity of Src, PI3, and Itk kinases, for example, is regulated by intramolecular interactions between their SH3 domain and internal proline-rich sequences. Here, we use NMR spectroscopy to reveal the structure of a protein construct from Dictyostelium myosin VII (DdM7) spanning A1620-T1706, which contains its SH3 domain and adjacent proline-rich region. The SH3 domain forms the signature beta-barrel architecture found in other SH3 domains, with conserved tryptophan and tyrosine residues forming a hydrophobic pocket known to bind "PxxP" motifs. In addition, acidic residues in the RT or n-Src loops are available to interact with the basic anchoring residues that are typically found in ligands or proteins that bind SH3 domains. The DdM7 SH3 differs in the hydrophobicity of the second pocket formed by the 3(10) helix and following beta-strand, which contains polar rather than hydrophobic side chains. Most unusual, however, is that this domain binds its adjacent proline-rich region at a surface remote from the region previously identified to bind "PxxP" motifs. The interaction may affect the orientation of the tail without sacrificing the availability of the canonical "PxxP"-binding surface.
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PMID:The SH3 domain of a M7 interacts with its C-terminal proline-rich region. 1718 80

We have shown that repletion of Na,K-ATPase Beta1-subunit (Na,K-Beta) in Moloney Sarcoma virus transformed MDCK (MSV-Na,K-Beta) cells induced lamellipodia and suppressed motility in a PI3-Kinase dependent manner. In this study, we provide evidence that decreased cell motility is due to increased attachment of Na,K-Beta expressing cells to the substratum. Treatment of MSV-Beta-GFP cells with bisindolylmalemide, a general Protein Kinase C (PKC) inhibitor, abolished PI3-Kinase activation and its down stream effects of Rac1 activation, binding of Na,K-Beta to annexin II, and suppression of cell motility and attachment. Thus, these studies unraveled that a PKC is involved upstream of PI3-Kinase in the suppression of Na,K-Beta mediated cell motility in carcinoma cells.
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PMID:Identification of protein kinase C as an intermediate in Na,K-ATPase beta-subunit mediated lamellipodia formation and suppression of cell motility in carcinoma cells. 1753 35

Excessive gastric acid secretion plays an important role in the pathogenesis of peptic ulcers. Dexamethasone, a widely used drug, is known to stimulate gastric acid secretion and increase the incidence of peptic ulcers. However little is known about the mechanism of the dexamethasone's effect on parietal cells. The present study was performed to investigate the contribution of the phosphatidylinositol-3-kinase (PI3 kinase) to dexamethasone induced stimulation of gastric acid secretion. In vivo pretreatment with dexamethasone injections (150 microg/100g for 3 days) or in vitro exposure to (10 microM for > 20 minutes) significantly increased acid secretion in isolated gastric glands approximately 2-3 fold. The dexamethasone induced stimulation of gastric acid secretion was concentration dependent and significantly blunted by the H+/K2+ ATPase inhibitor omeprazole (200 microM), the PI3 kinase inhibitor Wortmannin (500 nM), the protein kinase inhibitor staurosporine (2.5 microM) and the Cl(-) channel blocker NPPB (100 microM); but not by the H(2) antagonist cimetidine (100 microM). In conclusion, it was observed that dexamethasone's effect on proton extrusion requires the activity of a PI3 kinase pathway, an apical Cl(-) channel and the H2+/K2+ ATPase.
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PMID:PI3 kinase dependent stimulation of gastric acid secretion by dexamethasone. 1776 79

The kidney is important in the long-term regulation of blood pressure and sodium homeostasis. Stimulation of ETB receptors in the kidney increases sodium excretion, in part, by decreasing sodium transport in the medullary thick ascending limb of Henle and in collecting duct. However, the role of ETB receptor on Na(+)-K(+) ATPase activity in renal proximal tubule (RPT) cells is not well defined. The purpose of this study is to test the hypothesis that ETB receptor inhibits Na(+)-K(+) ATPase activity in rat RPT cells, and investigate the mechanism(s) by which such an action is produced. In RPT cells from Wistar-Kyoto rats, stimulation of ETB receptors by the ETB receptor agonist, BQ3020, decreased Na(+)-K(+) ATPase activity, determined by ATP hydrolysis (control=0.38+/-0.02, BQ3020=0.26+/-0.03, BQ788=0.40+/-0.06, BQ3020+BQ788=0.37+/-0.04, n=5, P<0.01). The ETB receptor-mediated inhibition of Na(+)-K(+) ATPase activity was dependent on an increase in intracellular calcium, because this effect was abrogated by a chelator of intracellular-free calcium (BAPTA-AM; 5 x 10(-3) M 15 min(-1)), Ca(2+) channel blocker (10(-6) M 15 min(-1) nicardipine) and PI3 kinase inhibitor (10(-7) M per wortmannin). An inositol 1,4,5-trisphosphate (IP3) receptor blocker (2-aminoethyl diphenyl borate; 10(-4) M 15 min(-1)) also blocked the inhibitory effect of the ETB receptor on Na(+)-K(+)ATPase activity (control=0.39+/-0.06, BQ3020=0.25+/-0.01, 2-APB=0.35+/-0.05, BQ3020+ 2-APB=0.35+/-0.06, n=4, P<0.01). The calcium channel agonist (BAY-K8644; 10(-6) M 15 min(-1)) inhibited Na(+)-K(+) ATPase activity, an effect that was blocked by a phosphatidylinositol-3 kinase inhibitor (10(-7) M 15 min(-1) wortmannin). In rat RPT cells, activation of the ETB receptor inhibits Na(+)-K(+) ATPase activity by facilitating extracellular Ca(2+) entry and Ca(2+) release from endoplasmic reticulum.
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PMID:Inhibitory effect of ETB receptor on Na(+)-K(+) ATPase activity by extracellular Ca(2+) entry and Ca(2+) release from the endoplasmic reticulum in renal proximal tubule cells. 1966 22

Up to one-third of human melanomas are characterized by an oncogenic mutation in the gene encoding the small guanosine triphosphatase (GTPase) NRAS. Ras proteins activate three primary classes of effectors, namely, Rafs, phosphatidyl-inositol-3-kinases (PI3Ks) and Ral guanine exchange factors (RalGEFs). In melanomas lacking NRAS mutations, the first two effectors can still be activated through an oncogenic BRAF mutation coupled with a loss of the PI3K negative regulator PTEN. This suggests that Ras effectors promote melanoma, regardless of whether they are activated by oncogenic NRas. The only major Ras effector pathway not explored for its role in melanoma is the RalGEF-Ral pathway, in which Ras activation of RalGEFs converts the small GTPases RalA and RalB to an active guanosine triphosphate-bound state. We report that RalA is activated in several human melanoma cancer cell lines harboring an oncogenic NRAS allele, an oncogenic BRAF allele or wild-type NRAS and BRAF alleles. Furthermore, short hairpin RNA (shRNA)-mediated knockdown of RalA, and to a lesser extent of RalB, variably inhibited the tumorigenic growth of melanoma cell lines having these three genotypes. Thus, as is the case for Raf and PI3 K signaling, Rals also contribute to melanoma tumorigenesis.
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PMID:Ral activation promotes melanomagenesis. 2056 21


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