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)

The immunosuppressants cyclosporin A (CyA), FK-506, and rapamycin (RAP) have multiple actions on target cells that appear to be mediated by interaction of drug-binding protein complexes. Both FK-506 and CyA, but not RAP, inhibit the Ca2(+)-dependent phosphatase, calcineurin, and in so doing have been found to inhibit Na(+)-K(+)-ATPase activity in various nephron segments. Of interest, FK-506 and RAP, but not CyA, are bound by the steroid receptor-associated FK-506-binding heat shock protein of 56 kDa, HSP56. To determine the physiological effect of this interaction on a steroid-mediated phenomenon, the effect of these agents on steroid-mediated Na+ transport in A6 cells was investigated. Aldosterone stimulation of Na+ transport and Na(+)-K(+)-ATPase activity are significantly inhibited by prolonged incubation with FK-506 and RAP. Although CyA inhibits basal Na(+)-K(+)-ATPase activity, it has no effect on aldosterone-induced Na+ transport or the aldosterone-induced increase in Na(+)-K(+)-ATPase activity. FK-506 inhibits the aldosterone-induced synthesis of G alpha i-3 protein but has no effect on glucocorticoid receptor number as quantified by Western blotting. The results suggest that FK-506 and RAP inhibit steroid-mediated Na+ transport at some pretranslational site. The common interaction of these agents with the steroid receptor-associated HSP56 might account for these findings.
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PMID:FK-506 and rapamycin but not cyclosporin inhibit aldosterone-stimulated sodium transport in A6 cells. 876 46

We have previously reported that the Wistar/Furth (W/Fu) rat strain is resistant to mineralocorticoid hypertension. In the current study, we have examined renal mRNA levels for mineralocorticoid receptor (MR), glucocorticoid receptor (GR), renin and Na+, K(+)-ATPase in response to treatment with mineralocorticoids. Uninephrectomized male Wistar (WI) and W/Fu rats were treated with aldosterone or deoxycorticosterone acetate (DOCA) and were given 1% NaCl to drink. Rats were sacrificed after 1, 3 or 7 days of treatment. Renal MR and ATPase mRNA levels were significantly reduced in aldosterone and DOCA-treated WI rats (e.g. MR was 30% on day 3 and ATPase was 50% of control on day 7 of aldosterone treatment). Unexpectedly, GR mRNA levels paralleled the changes in MR. In W/Fu rats the level of message was either unchanged or only moderately altered by this treatment. In vivo administration of the MR antagonist RU28318 or the GR antagonist RU38486 to WI rats for 4 days reduced renal mRNA levels for both subunits of ATPase. In the W/Fu rat, this treatment resulted in no change in the alpha subunit and an increase in the beta subunit of ATPase. In preliminary studies, we have determined that the W/Fu rat is also resistant to dexamethasone-induced hypertension. These studies suggest that altered MR- and GR-mediated mechanisms may contribute to the resistance of the W/Fu rat strain to steroid-induced hypertension.
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PMID:The resistance of the Wistar/Furth rat strain to steroid hypertension. 896 28

This study was performed in order to test the hypothesis that the glucocorticoid hormone stimulates the formation of Na,K-ATPase in the inner ear of the mouse. An immunohistochemical study with respect to the presence and distribution of glucocorticoid receptors (GR) and Na,K-ATPase in the vestibular and cochlear regions of the inner ear was performed on a C57BL mouse with a null mutation of the glucocorticoid receptor (GR mutant mouse). The wild type C57BL mouse and the CBA mouse served as normal controls. As expected, the homozygous GR mutant mouse showed no specific staining for GR in the inner ear. The heterozygous GR mutant mouse showed faint staining of GR in the spiral limbus, the spiral ganglion, the organ of Corti and the utricle. This staining was markedly less than in the wild type C57BL mouse. Antibody labelling of Na,K-ATPase in the inner ear showed no significant difference between the homozygous and the heterozygous GR mutant mouse as compared to the control wild type C57BL mouse or the CBA mouse. Although earlier studies have shown a positive correlation between levels of glucocorticoid hormone in serum and the concentration of Na,K-ATPase in the inner ear, the hypothesis that glucocorticoid hormones alone stimulate the formation of Na,K-ATPase in the inner ear could not be confirmed by this study. Thus other regulating substances must be considered.
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PMID:Distribution of Na,K-ATPase is normal in the inner ear of a mouse with a null mutation of the glucocorticoid receptor. 982 12

The molecular mechanisms by which corticosteroids affect fluid and electrolyte balance are unclear. Though glucocorticoid-responsive genes have been identified, genes regulated by aldosterone have not. CHIF (channel-inducing factor gene) is a recently identified gene that is up-regulated in the distal colon by chronic corticosteroid exposure, is expressed in the kidney, and induces a K+-specific current in Xenopus oocytes. The predicted protein shows similarity to gammaNa.K-ATPase, phospholemman, and Mat-8; all seem to be involved in ion transport. CHIF thus presents as a potential aldosterone target gene. In this study, CHIF expression was examined in rats in the acute timeframe of 0.5-4 h after corticosteroid administration. CHIF messenger RNA showed up-regulation by both mineralocorticoid and glucocorticoid receptor agonists in the distal colon, which was not diminished by cycloheximide. Corticosteroid regulation was not observed in the kidney. Basal and induced expression was absent in the lung and in all gastrointestinal tissues except colon, with expression increasing proximal to distal. CHIF is the first gene to show acute regulation by aldosterone and thus encodes a candidate aldosterone-induced protein. In addition, gammaNa.K-ATPase gene expression was found to be very low in colon and significantly higher in kidney. Regulation by corticosteroids was not evident in either tissue.
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PMID:Acute regulation by corticosteroids of channel-inducing factor gene messenger ribonucleic acid in the distal colon. 1006 46

Yeast and mammalian SWI-SNF complexes regulate transcription through active modification of chromatin structure. Human SW-13 adenocarcinoma cells lack BRG1 protein, a component of SWI-SNF that has a DNA-dependent ATPase activity essential for SWI-SNF function. Expression of BRG1 in SW-13 cells potentiated transcriptional activation by the glucocorticoid receptor, which is known to require SWI-SNF function. BRG1 also specifically repressed transcription from a transfected c-fos promoter and correspondingly blocked transcriptional activation of the endogenous c-fos gene. Mutation of lysine residue 798 in the DNA-dependent ATPase domain of BRG1 significantly reduced its ability to repress c-fos transcription. Repression by BRG1 required the cyclic AMP response element of the c-fos promoter but not nearby binding sites for Sp1, YY1, or TFII-I. Using human C33A cervical carcinoma cells, which lack BRG1 and also express a nonfunctional Rb protein, transcriptional repression by BRG1 was weak unless wild-type Rb was also supplied. Interestingly, Rb-dependent repression by BRG1 was found to take place through a pathway that is independent of transcription factor E2F.
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PMID:Human SWI-SNF component BRG1 represses transcription of the c-fos gene. 1008 38

The mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) belong to the steroid/thyroid hormone superfamily of ligand-induced transcription factors. Both activate the human Na/K ATPase alpha1 and beta1 genes transcriptionally. To assess the role of the transcription factor Sp1 and the nuclear factor I (NF-I), in MR- and GR-mediated gene expression using the human Na/K ATPase beta1 full-length promoter, we have examined the functions of Sp-I and NF-I functions in two different cell lines, COS-1 and T-84. By transient transfections we have shown that Sp-I significantly enhances MR and GR expression, whereas NF-I had negligible effect. We propose that the transcriptional enhancement could be through a direct interaction physically between MR or GR with Sp1 that allows other factors to bind the responsive element resulting in synergistic upregulation of transcription.
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PMID:Upregulation of mineralocorticoid- and glucocorticoid-receptor gene expression by Sp-I. 1032 76

The heat shock protein hsp70/hsc70 is a required component of a five-protein (hsp90, hsp70, Hop, hsp40, and p23) minimal chaperone system reconstituted from reticulocyte lysate that forms glucocorticoid receptor (GR).hsp90 heterocomplexes. BAG-1 is a cofactor that binds to the ATPase domain of hsp70/hsc70 and that modulates its chaperone activity. Inasmuch as BAG-1 has been found in association with several members of the steroid receptor family, we have examined the effect of BAG-1 on GR folding and GR.hsp90 heterocomplex assembly. BAG-1 was present in reticulocyte lysate at a BAG-1:hsp70/hsc70 molar ratio of approximately 0.03, and its elimination by immunoadsorption did not affect GR folding and GR. hsp90 heterocomplex assembly. At low BAG-1:hsp70/hsc70 ratios, BAG-1 promoted the release of Hop from the hsp90-based chaperone system without inhibiting GR.hsp90 heterocomplex assembly. However, at molar ratios approaching stoichiometry with hsp70, BAG-1 produced a concentration-dependent inhibition of GR folding to the steroid-binding form with corresponding inhibition of GR.hsp90 heterocomplex assembly by the minimal five-protein chaperone system. Also, there was decreased steroid-binding activity in cells that were transiently or stably transfected with BAG-1. These observations suggest that, at physiological concentrations, BAG-1 modulates assembly by promoting Hop release from the assembly complex; but, at concentrations closer to those in transfected cells and some transformed cell lines, hsp70 is continuously bound by BAG-1, and heterocomplex assembly is blocked.
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PMID:Differential effects of the hsp70-binding protein BAG-1 on glucocorticoid receptor folding by the hsp90-based chaperone machinery. 1056 84

Sodium-potassium ATPase (Na/K ATPase) is a major target of mineralocorticoids. Both aldosterone and glucocorticoids activate the human Na/K ATPase alpha1 and beta1 genes transcriptionally. The mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) have been shown to bind the glucocorticoid response element (GRE); however, a specific element responsible for the activation of the MR is not known. Sequence analysis of the putative regulatory region of the Na/K ATPase alpha1 gene revealed the presence of a hormone response element that allows the MR to interact with it, at least as well as if not better than the GR. This response element is designated MRE/GRE. In this investigation, we demonstrated the MR and GR induced gene expression in COS-1 cells by cotransfecting with respective expression plasmids (RshMR and RshGR) along with a luciferase reporter. The synthetic MRE/GRE linked to a neutral promoter was activated by MR (6-fold); however, the GR induced a lower level of expression (3.8-fold), suggesting that the element may be preferably MR responsive. Mutations in the synthetic MRE/GRE could not induce the expression with MR, whereas GR had a small effect. Electrophoretic mobility shift analyses demonstrated a direct interaction of MR and GR with the MRE/GRE that was supershifted by an antiMR antibody and the complex was partially cleared by an antiGR antibody, respectively, whereas nonimmune serum had no effect. Footprinting analyses of the promoter region showed that a portion of the DNA containing this element is protected by recombinant MR and GR. Thus these data confirm that this MRE/GRE interacts with both MR and GR but interaction with receptors may be more MR-responsive than response elements previously described.
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PMID:Identification of a mineralocorticoid/glucocorticoid response element in the human Na/K ATPase alpha1 gene promoter. 1058 Nov 56

The mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) are members of the steroid/thyroid hormone receptor superfamily of ligand inducible transcription factors and have been shown to bind the glucocorticoid response element (GRE). Sodium-potassium ATPase (Na/KATPase) is a major target of mineralocorticoids. Both aldosterone and glucocorticoids activate the human Na/K ATPase alpha1 subunit and beta1 subunit genes transcriptionally. However, the mechanisms of corticosteroid regulation of mammalian Na/K ATPase subunit gene expression are not known. In this investigation, we report for the first time that cell lines (T-84 and 293) express endogenous MR by RT-PCR message expression. However, the protein product was not expressed as determined by western blot analyses. In transactivation studies of MR with GRE31, we detected MR expression at low concentrations of aldosterone. We also performed Northern blot and nuclear run-off transcription assays to further confirm that the regulation is transcriptional. We conclude that the transcriptional regulation of the human Na/K ATPase alpha1 and beta1 subunits by aldosterone occurs via the involvement of the MR.
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PMID:Transcriptional regulation of the human Na/K ATPase via the human mineralocorticoid receptor. 1071 22

The effect of dexamethasone on cytosolic pH (pHc) in resident mouse peritoneal macrophages was investigated using the fluorescent probe 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein tetra-acetoxymethyl ester (BCECF-AM). Dexamethasone was found to significantly lower pHc and this reduction of pHc evolved gradually with time, was near maximal at 10 nM dexamethasone, and could be prevented by the glucocorticoid receptor antagonist RU-38486. The lower pHc of dexamethasone-treated cells was neither due to a reduction of cellular buffer capacity nor to an altered regulation of pHc by Na+/H+-exchange or by acidifying Na+-independent Cl-/HCO3- exchange, as assessed by studies of pH recovery after acute acid and alkali loads, respectively. Instead, an impaired pHc recovery by both the H+-ATPase and the alkalinizing Na+-dependent Cl-/HCO3- exchange was observed. This impairment was most likely not caused by an altered expression or localization of the 39-kDa subunit of the proton pump. Dexamethasone treatment caused a reduction of pHc also in a HCO3--containing solution, suggesting that acid extrusion by both the H+-ATPase and Na+-dependent Cl-/HCO3- exchange is important for maintenance and regulation of macrophage resting pHc. The lowering of macrophage pHc might be one mechanism whereby glucocorticoids exert their anti-inflammatory effects.
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PMID:Dexamethasone lowers cytosolic pH in macrophages by altering alkalinizing pH-regulatory mechanisms. 1085 62


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