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 human core COP9 signalosome consists of eight subunits which have been identified, cloned and sequenced. The components of COP9 signalosome possess homologies with eight non-ATPase regulatory subunits of the 26S proteasome. These polypeptides of the 19S regulator form a reversibly binding subcomplex called the 'lid'. We isolated the 'lid' from human red blood cells and compared it with the COP9 signalosome complex. In addition to the non-ATPase regulatory polypeptides, we found a high molecular mass ATPase copurifying with the human 'lid'. The COP9 signalosome-associated kinase activity is either not at all or only weakly affected by common kinase inhibitors such as 1-(5-Isoquinolinesulfonyl)-2-methyl-piperazine (H7), 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB) or Wortmannin. Curcumin, a tumor suppressor and effector of AP-1 activation, is a potent inhibitor of the COP9 signalosome kinase activity with a Ki of about 10 microM. Since curcumin is known as an inhibitor of the c-Jun N-terminal kinase (JNK) signaling pathway acting upstream of the MAP kinase kinase kinase level, one site of action of the COP9 signalosome might be proximal to regulators on that level.
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PMID:Comparison of human COP9 signalsome and 26S proteasome lid'. 1036 43

We showed before that in cardiac myocytes partial inhibition of Na+/K+-ATPase by nontoxic concentrations of ouabain causes hypertrophy and transcriptional regulations of growth-related marker genes through multiple Ca2+-dependent signal pathways many of which involve Ras and p42/44 mitogen-activated protein kinases. The aim of this work was to explore the roles of intracellular reactive oxygen species (ROS) in these ouabain-initiated pathways. Ouabain caused a rapid generation of ROS within the myocytes that was prevented by preexposure of cells to N-acetylcysteine (NAC) or vitamin E. These antioxidants also blocked or attenuated the following actions of ouabain: inductions of the genes of skeletal alpha-actin and atrial natriuretic factor, repression of the gene of the alpha3-subunit of Na+/K+-ATPase, activation of mitogen-activated protein kinases, activation of Ras-dependent protein synthesis, and activation of transcription factor NF-kappaB. Induction of c-fos and activation of AP-1 by ouabain were not sensitive to NAC. Ouabain-induced inhibition of active Rb+ uptake through Na+/K+-ATPase and the resulting rise in intracellular Ca2+ were also not prevented by NAC. A phorbol ester that also causes myocyte hypertrophy did not increase ROS generation, and its effects on marker genes and protein synthesis were not affected by NAC. We conclude the following: (a) ROS are essential second messengers within some but not all signal pathways that are activated by the effect of ouabain on Na+/K+-ATPase; (b) the ROS-dependent pathways are involved in ouabain-induced hypertrophy; (c) increased ROS generation is not a common response of the myocyte to all hypertrophic stimuli; and (d) it may be possible to dissociate the positive inotropic effect of ouabain from its growth-related effects by alteration of the redox state of the cardiac myocyte.
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PMID:Intracellular reactive oxygen species mediate the linkage of Na+/K+-ATPase to hypertrophy and its marker genes in cardiac myocytes. 1038 43

Hepatitis B virus (HBV) has a unique fourth open reading frame coding for a 16.5-kDa protein known as hepatitis B virus X protein (HBX). The importance of HBX in the life cycle of HBV has been well established, but the underlying molecular function of HBX remains controversial. We previously identified a proteasome subunit PSMA7 that interacts specifically with HBX in the Saccharomyces cerevisiae two-hybrid system. Here we demonstrate that PSMC1, an ATPase-like subunit of the 19 S proteasome component, also interacts with HBX and PSMA7. Analysis of the interacting domains among PSMA7, PSMC1, and HBX by deletion and site-directed mutagenesis suggested a mutually competitive structural relationship among these polypeptides. The competitive nature of these interactions is further demonstrated using a modified yeast two-hybrid dissociator system. The crucial HBX sequences involved in interaction with PSMA7 and PSMC1 are important for its function as a transcriptional coactivator. HBX, while functioning as a coactivator of AP-1 and acidic activator VP-16 in mammalian cells, had no effect on the transactivation function of their functional orthologs GCN4 and Gal4 in yeast. Overexpression of PSMC1 seemed to suppress the expression of various reporters in mammalian cells; this effect, however, was overcome by coexpression of HBX. In addition, HBX expression inhibited the cellular turnover of c-Jun and ubiquitin-Arg-beta-galactosidase, two well known substrates of the ubiquitin-proteasome pathway. Thus, interaction of HBX with the proteasome complex in metazoan cells may underlie the functional basis of proteasome as a cellular target of HBX.
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PMID:Structural and functional characterization of interaction between hepatitis B virus X protein and the proteasome complex. 1074 18

Uncoating of clathrin-coated vesicles in neuronal cells requires hsc70 in concert with the cofactor auxilin which contains a J-domain as well as a domain with homology to dual specific phosphatases and tensin, known as PTEN. The question of whether an analogous factor operates in other cell types has until now remained unanswered. Here we show that it is the recently discovered and widely expressed cyclin G-associated protein kinase which fulfils the function of neuronal auxilin in hsc70-mediated clathrin coat dissociation. GAK possesses a J-domain, which stimulates the hsc70 ATPase, it competes with auxilin for clathrin binding and at sufficiently high concentrations acts as a clathrin assembly protein. Moreover, GAK binds to the gamma- and alpha-appendage domains of the adaptor proteins AP-1 and AP-2 in vitro and phosphorylates their medium chains. Cells that transiently overexpress GAK are impaired in respect of receptor-mediated endocytosis. In transfected cells clathrin is dislodged from coated pits/vesicles and co-localizes with GFP-GAK in the form of large aggregates. The cellular distribution of membrane-associated adaptors was unaffected by overexpression of GAK. Our results point to a hsc70/auxilin-based uncoating system as a ubiquitous feature of eukaryotic cells.
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PMID:Identification of the universal cofactor (auxilin 2) in clathrin coat dissociation. 1088 64

Although the gamma subunit of the Na,K-ATPase has only 66 or 68 amino acids, its human gene (FXYD2) was found to span 9.2 kb and have seven exons, including two alternatively spliced exons encoding different N-termini. Two candidate promoters with consensus sites for transcription factors Sp1, AP-1, and AP-2 are present, consistent with independent transcription of the splice variants. Multiple ESTs support the transcriptional competence of the identified gene elements. In the FXYD2 gene, there are two closely spaced polyadenylation signals, and both are used. A proposed third splice variant encoding a 31-residue N-terminal extension was not found in the gene, nor was the predicted larger protein found in human kidney Na,K-ATPase. Instead, evidence was found for the origin of the larger cDNA clone in homologous recombination with unrelated DNA from chromosome 2. FXYD2 is on chromosome 11q23 close to a site of tumorigenic chromosomal translocations, and has a number of repeat elements.
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PMID:Genomic organization of the human FXYD2 gene encoding the gamma subunit of the Na,K-ATPase. 1111 38

Release of calcium from the endoplasmic reticulum (ER) signals an increase in transcription of both the early response gene, c-fos, and the late response gene, grp78. We have used thapsigargin (TG), an ER calcium-ATPase pump inhibitor that induces calcium release from the ER, to investigate the possible involvement of c-Fos, a component of the AP-1 transcription factor, in grp78 induction. Two cell lines with markedly different responses to TG treatment were employed: the WEHI7.2 mouse lymphoma line in which TG fails to induce grp78, and the MDA-MB-468 mammary epithelial line in which TG induces grp78. In WEHI7.2 cells, TG-induced calcium release triggers a rapid increase in c-fos mRNA, but the level of c-Fos protein decreases due to degradation by the multicatalytic proteasome. C-FosdeltaC, a proteasome resistant c-Fos mutant with AP-1 activity similar to that of wild type c-Fos, restores grp78 induction in WEHI7.2 cells, detected by both Northern hybridization and a grp78 promoter-luciferase reporter assay. In MDA-MB-468 cells, TG-mediated calcium release induces a sustained elevation of c-Fos protein that precedes grp78 induction. A region of the grp78 promoter containing both ERSE and CORE regions, but missing TRE and CRE regions, is sufficient to mediate induction of reporter luciferase activity. Induction of this reporter was blocked by A-Fos, a dominant negative inhibitor of c-Fos. Also, the induction of grp78-luciferase reporter activity was inhibited by c-fos antisense mRNA. In summary, the findings indicate that c-Fos is involved in signaling grp78 induction following TG treatment, and that grp78 induction is inhibited by proteasome-mediated c-Fos degradation.
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PMID:Involvement of c-Fos in signaling grp78 induction following ER calcium release. 1112 25

The small GTP binding protein ARF has been implicated in budding clathrin-coated vesicles (CCVs) from Golgi and endosomal membranes. An arf1 synthetic lethal screen identified DRS2/SWA3 along with a clathrin heavy-chain conditional allele (chc1-5/swa5-1) and SWA2, encoding the yeast auxilin-like protein involved in uncoating CCVs. Drs2p/Swa3p is a P-type ATPase and a potential aminophospholipid translocase that localizes to the trans-Golgi network (TGN) in yeast. Genetic and phenotypic analyses of drs2Delta mutants suggested that Drs2p was required for clathrin function. To address a potential role for Drs2p in CCV formation from the TGN in vivo, we have performed epistasis analyses between drs2 and mutations that cause accumulation of distinct populations of post-Golgi vesicles. We find that Drs2p is required to form a specific class of secretory vesicles that accumulate when the actin cytoskeleton is disrupted. Accumulation of these vesicles also requires clathrin and is perturbed by mutation of AP-1, but not AP-2, AP-3, or GGA adaptins. Most of the accumulated vesicles are uncoated; however, clathrin coats can be partially stabilized on these vesicles by deletion of SWA2. These data provide the first in vivo evidence for an integral membrane protein requirement in forming CCVs.
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PMID:Drs2p-dependent formation of exocytic clathrin-coated vesicles in vivo. 1237 57

Our recent work shows that in addition to pumping ions, Na/K-ATPase acts as a signal transducer. Binding of ouabain to Na/K-ATPase changes the interaction of the enzyme with neighboring membrane proteins and induces the formation of multiple signaling modules, resulting in activation of Src, transactivation of the EGF receptor (EGFR), and increased production of reactive oxygen species (ROS). Interaction of these signals leads to activation of several other cascades, including p42/44 and p38 MAPKs, phospholipase C, and protein kinase C isozymes, in a cell-specific manner. Ouabain also increases [Ca(2+)](i) and contractility, induces some of the early-response protooncogenes, and activates transcription factors AP-1 and NF-kappaB. Interplay among these pathways eventually results in changes in the expression of a number of growth-related genes and in cell growth. Significantly, inhibition of Src blocked many of the aforementioned ouabain-activated signaling pathways. Furthermore, Src binds to Na/K-ATPase directly and ouabain regulates the interaction between Src and the enzyme, resulting in Src activation. To address the possibility that the signaling Na/K-ATPase is concentrated in a separate pool on the plasma membrane, we have assessed interaction of the enzyme with caveolins. These studies indicated that Na/K-ATPase was concentrated in caveolae/rafts. In addition, caveolin-1 can be co-immunoprecipitated with Na/K-ATPase. Finally, we have shown that the signaling function of the enzyme is also pivotal to ouabain-induced nongenomic effects on cardiac myocytes.
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PMID:Molecular mechanisms of Na/K-ATPase-mediated signal transduction. 1276 70

Interleukin1-beta has been demonstrated previously to reduce the activity and expression of the Na(+)-K(+) pump in the rat jejunum and colon. This work attempts to elucidate the signal transduction pathway underlying its effect using Caco-2 cells. IL-1beta reduced, in these cells also, the activity and expression of ATPase, in a dose and time-dependent manner. The down-regulatory effect of the cytokine on the ATPase was not evident, when p38 MAP kinase was inhibited, but appeared in presence of inhibitors of MEK and NFkappaB, although activation of NF-kappaB was demonstrated by western blot analysis. The effect of IL-1beta on the pump disappeared in the presence of indomethacin, a COX inhibitor. Exogenous PGE2 reduced the expression of the pump within 15 minutes, and this effect was still apparent when p38MAPK was inhibited. Curcumin, a JNK/AP-1 inhibitor, partially abolished the effect of IL-1beta on ATPase expression but did not interfere with the effect of PGE2. These results indicate that IL-1beta reduces the expression of ATPase independently of NFkB but, through a major pathway involving p38 and COX-2/PGE2, and another pathway involving JNK/AP1.
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PMID:Mediators of interleukin-1 beta action Na(+)-K(+)ATPase in Caco-2 cells. 1295 88

There has been increasing evidence that tumor necrosis factor alpha (TNF-alpha) is synthesized by cardiomyoctes and contributes to their impaired function and to cardiac failure. Because the Na(+)-K(+) ATPase is a key player in the contraction of cardiomyocytes, this work was undertaken to study the effect of TNF-alpha on the Na(+)-K(+) ATPase in rat heart. Sprague Dawley rats (Rattus norvegicus) were injected with TNF-alpha (270 ng/100 g body weight) and 4 h later the ventricles were isolated, homogenized and assayed for their Na(+)-K(+) ATPase activity. The effect of TNF-alpha on the pump was studied also in isolated myocytes treated in suspension. The involvement of PGE2 was investigated by pre-treating animals or cells with indomethacin, an inhibitor of COX enzymes. The involvement of NF-kappaB and AP-1 was studied using their respective inhibitors PDTC and curcumin. A time response study showed an increase in the activity of the Na(+)-K(+) ATPase in the left and right ventricles of animals treated with the cytokine, with no change in its protein expression. This effect disappeared in the presence of indomethacin suggesting an involvement of PGE(2) in the action of TNF-alpha. Rats and cells treated directly with PGE(2) showed a dose-dependent response. A decrease in the activity of the Na(+)-K(+) ATPase was observed at a low dose and an increase at a high dose in both ventricles. Since PGE(2) is suspected to be the active mediator in TNF-alpha signaling, inhibiting its synthesis by inhibiting some suspected transcription factors was attempted. PDTC abrogated fully, and curcumin partially the effect of the cytokine. It was concluded that TNF-alpha activates NF-kappaB and AP-1 and induces PGE(2) release which alters dose-dependently the activity of the pump by activating different EP receptors with different affinities for PGE(2).
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PMID:Tumor necrosis factor alpha alters Na+-K+ ATPase activity in rat cardiac myocytes: involvement of NF-kappaB, AP-1 and PGE2. 1702 35


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