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)

It has been proposed that autosomal dominant polycystic kidney disease (ADPKD)affected renal epithelial cells undergo a phenotypic transition from a highly differentiated absorptive state to a much less differentiated secretory state during cystogenesis and that this transition is accompanied by loss of epithelial cell polarity and mistargeting of specific membrane proteins. We conducted a detailed evaluation of this hypothesis in the Pkd2WS25/- mouse model of ADPKD. Ultrastructural analysis of Pkd2WS25/- cysts by electron microscopy confirmed that cystic epithelial cells progressively dedifferentiate with cyst enlargement. Immunocytochemical analysis of both early- and late-stage cysts with antibodies directed against Na+-K+-ATPase, Ksp-cadherin, and E-cadherin failed to detect evidence of altered cyst cell polarity. Na+-K+-ATPase and Ksp-cadherin were expressed exclusively on the basolateral membranes (BLM) of epithelial cells in all early cysts. Expression levels of both Na+-K+-ATPase and Ksp-cadherin decreased progressively with the degree of cyst cell dedifferentiation, but neither protein was ever mislocalized. Highly dedifferentiated cysts did not express immunodetectable levels of either Na+-K+-ATPase or Ksp-cadherin. E-cadherin was expressed prominently on the BLM of all cysts. Cysts were subsequently stained with an antibody directed against the secretory isoform of the Na+-K+-Cl- cotransporter NKCC1. NKCC1 expression was detected on the BLM of advanced cysts only. Our data are consistent with a model of progressive cystic epithelial cell dedifferentiation in which fluid accumulation in late-stage cysts is mediated by transepithelial secretion of chloride rather than secretion of sodium by apical Na+-K+-ATPase.
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PMID:Histopathological analysis of renal cystic epithelia in the Pkd2WS25/- mouse model of ADPKD. 1285 Dec 51

Na-K-ATPase, also known as the sodium pump, is a crucial enzyme that regulates intracellular sodium homeostasis in mammalian cells. In epithelial cells Na-K-ATPase function is also involved in the formation of tight junctions through RhoA GTPase and stress fibers. In this review, a new two-step model for the assembly of tight junctions is proposed: step 1, an E-cadherin-dependent formation of partial tight junction strands and of the circumferential actin ring; and step 2, active actin polymerization-dependent tethering of tight junction strands to form functional tight junctions, an event requiring normal function of Na-K-ATPase in epithelial cells. A new role for stress fibers in the assembly of tight junctions is proposed. Also, implications of Na-K-ATPase function on tight junction assembly in diseases such as cancer, ischemia, hypomagnesemia, and polycystic kidney disease are discussed.
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PMID:Role of Na-K-ATPase in the assembly of tight junctions. 1289 Jun 62

Pemphigus vulgaris (PV) is a life-threatening autoimmune disease of skin adhesion associated with IgG autoantibodies against keratinocytes (KC). Treatment of PV with systemic corticosteroids is life-saving, but the mechanism of the therapeutic action has not been fully understood. We have developed an animal model that demonstrates that methylprednisolone (MP) can block PV IgG-induced acantholysis, decreasing the extent of keratinocyte detachment in the epidermis of 3-5-day-old nude mice from 77.5 +/- 0.6 to 24.1 +/- 1.5% (p < 0.05). We hypothesized that in addition to immunosuppression, MP may exhibit direct anti-acantholytic effects in epidermis, and we compared the effects of PV IgG and MP on KC. The use of DNA microarray showed that PV IgG down-regulated and MP up-regulated expression of the genes encoding keratinocyte adhesion molecules, antigen-processing proteins, regulators of cell cycle and apoptosis, differentiation markers, Na+,K+-ATPase, protein kinases and phosphatases, and serine proteases and their inhibitors. Overall, PV IgG decreased transcription of 198 genes and increased transcription of 31 genes. MP decreased transcription of 14 genes and increased transcription of 818 genes. Specific effects of PV IgG and MP on keratinocyte adhesion molecules were further investigated by Western blot and immunofluorescence assays. By immunoblotting, MP increased the protein levels of E-cadherin and desmogleins 1 and 3 by 300, 180, and 40%, respectively. Specific staining of KC for E-cadherin and desmogleins 1 and 3 increased by 235, 228, and 148%, respectively. In addition, PV IgG increased the level of phosphorylation of E-cadherin by 42%, beta-catenin by 37%, gamma-catenin by 136%, and desmoglein 3 by 300%, whereas pretreatment with 0.25 mm MP abolished phosphorylation of these adhesion molecules. These results suggested that therapeutic effects of MP in PV include both the up-regulated synthesis and post-translational modification of the keratinocyte adhesion molecules.
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PMID:Pemphigus vulgaris IgG and methylprednisolone exhibit reciprocal effects on keratinocytes. 1460 Jan 50

The Na,K-ATPase consists of two essential alpha- and beta-subunits and regulates the intracellular Na+ and K+ homeostasis. Although the alpha-subunit contains the catalytic activity, it is not active without functional beta-subunit. Here, we report that poorly differentiated carcinoma cell lines derived from colon, breast, kidney, and pancreas show reduced expression of the Na,K-ATPase beta1-subunit. Decreased expression of beta1-subunit in poorly differentiated carcinoma cell lines correlated with increased expression of the transcription factor Snail known to down-regulate E-cadherin. Ectopic expression of Snail in well-differentiated epithelial cell lines reduced the protein levels of E-cadherin and beta1-subunit and induced a mesenchymal phenotype. Reduction of Snail expression in a poorly differentiated carcinoma cell line by RNA interference increased the levels of Na,K-ATPase beta1-subunit. Furthermore, Snail binds to a noncanonical E-box in the Na,K-ATPase beta1-subunit promoter and suppresses its promoter activity. These results suggest that down-regulation of Na,K-ATPase beta1-subunit and E-cadherin by Snail are associated with events leading to epithelial to mesenchymal transition.
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PMID:Repression of Na,K-ATPase beta1-subunit by the transcription factor snail in carcinoma. 1469 59

The small guanosine triphosphatase Rac1 is activated by E-cadherin-mediated cell-cell adhesion and is required for the accumulation of actin filaments, E-cadherin, and beta-catenin at sites of cell-cell contact. However, the modes of activation and action of Rac1 remain to be clarified. We here found that suppression of IQGAP1, an actin-binding protein and an effector of Rac1, by small interfering RNA apparently reduced the accumulation of actin filaments, E-cadherin, and beta-catenin at sites of cell-cell contact in Madin-Darby canine kidney II epithelial cells under the conditions in which knockdown of Rac1 reduced them. Knockdown of Rac1 did not affect the localization of these junctional components in cells expressing a constitutively active IQGAP1 mutant defective in Rac1/Cdc42 binding. Knockdown of either Rac1 or IQGAP1 accelerated the 12-O-tetradecanoylphorbol-13-acetate-induced cell-cell dissociation. The basal Rac1 activity, which was maintained by E-cadherin-mediated cell-cell adhesion, was inhibited in the IQGAP1-knocked down cells, whereas the Rac1 activity was increased in the cells overexpressing IQGAP1. Together, these results indicate that Rac1 enhances the accumulation of actin filaments, E-cadherin, and beta-catenin by acting on IQGAP1 and suggest that there exists a positive feedback loop comprised of "E-cadherin-mediated cell-cell adhesion --> Rac1 activation --> actin-meshwork formation by IQGAP1 --> increasing E-cadherin-mediated cell-cell adhesion."
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PMID:Positive role of IQGAP1, an effector of Rac1, in actin-meshwork formation at sites of cell-cell contact. 1469 63

The epidermal growth factor receptor ligands transforming growth factor alpha (TGF alpha) and amphiregulin are delivered to the basolateral surface of polarized epithelial cells where they are cleaved by TACE/ADAM17. Basolateral sorting information resides in their cytoplasmic tail domains, but tail-interacting proteins required for basolateral trafficking have not been identified. Naked (NKD)1 and NKD2 are mammalian homologs of Drosophila Naked Cuticle, which negatively regulates canonical Wnt signaling by binding Dishevelled. We present evidence that NKD2, but not NKD1, binds to basolateral sorting motifs in the cytoplasmic tail of TGF alpha. Processing and cell-surface delivery of TGF alpha are accelerated in NKD2-overexpressing Madin-Darby canine kidney cells. NKD2 is myristoylated on glycine, the second residue. On expression of myristoylation-defective (G2A) NKD2, neither NKD2 nor TGF alpha appears at the basolateral plasma membrane of polarized Madin-Darby canine kidney cells; however, membrane staining for TGF alpha is restored on silencing expression of this mutant NKD2. Amphiregulin does not interact with NKD2 and retains its basolateral localization in G2A-NKD2-expressing cells, as do Na(+), K(+) ATPase alpha 1 and E-cadherin. These data identify an unexpected function for NKD2, i.e., myristoylation-dependent escort of TGF alpha to the basolateral plasma membrane of polarized epithelial cells.
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PMID:Myristoylated Naked2 escorts transforming growth factor alpha to the basolateral plasma membrane of polarized epithelial cells. 1506 3

The cadherin/catenin complex is an essential regulator of intercellular adhesion and is critical for the establishment of epithelial cell polarity. The purpose of this study was to (1) determine the spatial pattern of cadherin and catenin expression, colocalization, and interaction along the mouse nephron, and (2) investigate the expression, localization, and interaction of proximal tubular cadherins and catenins during mercuric chloride-induced nephrotoxicity. Using a combination of Western blot analysis, colocalization studies, and coimmunoprecipitation, we conclude that two distinct cadherin/catenin complexes exist in adult mouse kidney proximal tubules: N-cadherin/beta-catenin/alpha-catenin and E-cadherin/beta-catenin/alpha-catenin/p120-catenin. In the distal tubule, E-cadherin/beta-catenin/alpha-catenin and E-cadherin/gamma-catenin/alpha-catenin complexes are present. Male C3H mice were challenged with 0-25 micromol/kg mercuric chloride i.p. (6-48 h) to assess the impact of nephrotoxicity on cadherin/catenin complexes. Plasma creatinine and blood urea nitrogen were increased between 6 and 48 h, indicating the onset of renal failure. In addition, histological evaluation demonstrated alterations in the proximal tubules. At 24 h, we observed decreases in Ksp- and N-cadherin, but not in E-cadherin. Additionally, alpha-catenin expression was decreased, in the absence of changes in beta-, gamma-, and p120-catenin. The early stages (6 h) of mercuric chloride-induced nephrotoxicity were associated with disruption of complex integrity. N-cadherin and alpha-catenin localizations were disrupted at 6 h. These changes in cadherin and catenin localization corresponded with a decrease in the coimmunoprecipitation of alpha-catenin with both beta-catenin and N-cadherin. Interestingly, these changes occurred at the same time that aberrant staining of Na+/K(+)-ATPase staining was seen. Taken together, these data suggest that alterations in cadherin and catenin expression, localization, and interaction are associated with nephrotoxicity.
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PMID:Disruption of cadherin/catenin expression, localization, and interactions during HgCl2-induced nephrotoxicity. 1508 54

Pretreatment with the nucleoside antibiotic tunicamycin was found to protect cultured renal epithelial cells in the face of ATP-depletion, in large part by preserving junctional and cellular architecture. Tunicamycin pretreatment of Madin-Darby canine kidney cells not only preserved E-cadherin staining at the plasma membrane, but also inhibited ATP-depletion-mediated E-cadherin degradation. Electron microscopic analysis, together with the preservation of the staining patterns of the tight junction marker ZO-1, the apical/microvillar marker gp135, and basolateral marker Na/K-ATPase suggested that tunicamycin preserved the junctional complex and the polarized epithelial cell phenotype. Tunicamycin pretreatment also prevented reductions in the filamentous actin content of the cells, as well as preserving Golgi architecture. Moreover, a quantitative measure of cell adhesion demonstrated that tunicamycin pretreatment resulted in a fivefold increase in attachment of cells to the substratum (77% versus 16%). Thus, pretreatment with tunicamycin protects polarized epithelial cells from ischemic injury through the preservation of epithelial cell architecture, intercellular junctions, and cell-substratum interactions in the setting of intracellular ATP-depletion.
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PMID:Tunicamycin preserves intercellular junctions, cytoarchitecture, and cell-substratum interactions in ATP-depleted epithelial cells. 1531 95

The objective of this study was to compare the relative transcript abundance of several important candidate genes between ovine and bovine blastocysts. Blastocysts were produced by in vitro maturation, fertilization, and subsequent culture in one of two formulations of synthetic oviduct fluid medium (SOF1 and SOF2). From each IVF replicate groups of 10 bovine and 10 ovine blastocysts from each of the two media were used for analysis of mRNA relative abundance. Transcript levels for mitochondrial Mn-superoxide dismutase (MnSOD), survivin, and glucose transport 5 (Glut-5) were significantly higher in ovine blastocysts than bovine (P < 0.05), while transcripts for Connexin 31 (Cx31), interferon tau (IFN-tau), and sarcosine oxidase (SOX) were significantly more abundant in bovine blastocysts (P < 0.01). For the two remaining transcripts, E-cadherin (E-cad) and Na/K ATPase (Na/K), there was no difference. Culture of bovine embryos in SOF2 resulted in a significant increase in the level of expression of MnSOD and Glut-5 (P < 0.05) compared to those bovine embryos cultured in SOF1. For all the other transcripts, except survivin, there was a significant decrease in the relative abundance. Culture of sheep embryos in either SOF1 or SOF2 did not have a major influence on transcript abundance; of the eight transcripts examined, the relative abundance of only one, SOX, was significantly altered. Bovine blastocysts produced in SOF2 had significantly higher survival rates at 24, 48, and 72 hr and significantly higher hatching rates following vitrification and warming than those cultured in SOF1 (P < 0.001). In conclusion, we have quantified for the first time the mRNA expression of a set of important developmental genes in sheep blastocysts and we have demonstrated that these differences between species in their adaptability to culture conditions, manifested in differences in embryo morphology and cryotolerance, are related to differences in mRNA relative abundance. The results also highlight the usefulness of transcript analysis as a marker of embryo quality.
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PMID:Species-related differences in blastocyst quality are associated with differences in relative mRNA transcription. 1545 17

In secretory epithelia, activation of PKC by phorbol ester and carbachol negatively regulates Cl(-) secretion, the transport event of secretory diarrhea. Previous studies have implicated the basolateral Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) as a target of PKC-dependent inhibition of Cl(-) secretion. In the present study, we examined the regulation of surface expression of NKCC1 in response to the activation of PKC. Treatment of confluent T84 intestinal epithelial cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (PMA) reduced the amount of NKCC1 accessible to basolateral surface biotinylation. Loss of cell surface NKCC1 was due to internalization as shown by 1) the resistance of biotinylated NKCC1 to surface biotin stripping after incubation with PMA and 2) indirect immunofluorescent labeling. PMA-induced internalization of NKCC1 is dependent on the epsilon-isoform of PKC as determined on the basis of sensitivity to a panel of PKC inhibitors. The effect of PMA on surface expression of NKCC1 was specific because PMA did not significantly alter the amount of Na(+)-K(+)-ATPase or E-cadherin available for surface biotinylation. After extended PMA exposure (>2 h), NKCC1 became degraded in a proteasome-dependent fashion. Like PMA, carbachol reduced the amount of NKCC1 accessible to basolateral surface biotinylation in a PKC-epsilon-dependent manner. However, long-term exposure to carbachol did not result in degradation of NKCC1; rather, NKCC1 that was internalized after exposure to carbachol was recycled back to the cell membrane. PKC-epsilon-dependent alteration of NKCC1 surface expression represents a novel mechanism for regulating Cl(-) secretion.
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PMID:Dynamic regulation of Na(+)-K(+)-2Cl(-) cotransporter surface expression by PKC-{epsilon} in Cl(-)--secretory epithelia. 1600 Jun 38


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