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)

Exposure of neonatal rat cardiac myocytes to ouabain concentrations that caused partial inhibition of Na+/K+-ATPase but no loss of viability, increased c-fos and c-jun mRNAs and the transcription factor AP-1. The increased mRNAs were proportional to the extent of inhibition of Na+/K+-ATPase and the resulting rise in steady state intracellular Ca2+ concentration. The rapid and sustained increase of c-fos mRNA was shown to be due to increased transcriptional rate. Induction of c-fos by ouabain was prevented when either extracellular or intracellular Ca2+ was lowered and was attenuated by pretreatment of myocytes with a phorbol ester under conditions known to down-regulate protein kinase C. Exposure to ouabain for 24-48 h also increased total transcriptional activity and protein content of myocytes. The findings suggest that the same signal responsible for the positive inotropic action of ouabain, i.e. net influx of Ca2+ caused by partial inhibition of Na+/K+-ATPase, also initiates the rapid protein kinase C-dependent inductions of the early-response genes, the subsequent regulations of other cardiac genes by the resulting transcription factors, and stimulation of myocyte growth. Whether these hitherto unrecognized effects of cardiac glycosides are obtained in the intact heart and their relevance to the therapeutic uses of these drugs remain to be determined.
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PMID:Partial inhibition of Na+/K+-ATPase by ouabain induces the Ca2+-dependent expressions of early-response genes in cardiac myocytes. 862 9

Human monocytic leukemia THP-1 cells were induced to differentiate into macrophage-like cells by treatment with cardiotonic steroid bufalin, which was previously shown to interact with the Na+, K+-ATPase with similar kinetics to ouabain, a specific inhibitor of the enzyme. This induction of differentiation was characterized by loss of proliferation, cell adherence, increased ability to reduce Nitro Blue tetrazolium (NBT), and increased expression of interleukin 1 beta (IL-1 beta). During this process, bufalin downregulated c-myb and c-myc expressions and induced c-fos and Egr-1 transcripts. Ouabain also caused similar changes in proto- oncogene expression and induced phenotypic markers of differentiated cells at concentrations comparable to bufalin. The 12-O-tetradecanoyl phorbol-13-acetate resistant THP-1 cell variant, which was unresponsive to this agent as to growth inhibition and proto-oncogene expression, responded to bufalin. The finding that protein kinase inhibitor H7 failed to bufalin-mediated c-fos induction further supports the theory that the signal transduction machinery caused by bufalin is separable from the phorbol ester. The cytotoxic effect of high doses of bufalin apparently disappeared in the medium where Na+ was replaced with choline ions. Furthermore, bufalin failed to induce c-fos expression and to downregulate c-myb transcripts in the low-Na+ medium. These findings indicate that an increased intracellular Na+ concentration resulting from the Na+, K(+)-ATPase inhibition possibly triggers the change in proto-oncogene expression evoked by bufalin.
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PMID:A cardiotonic steroid bufalin-induced differentiation of THP-1 cells. Involvement of Na+, K(+)-ATPase inhibition in the early changes in proto-oncogene expression. 869 57

The isolated perfused rat kidney provides a model of selective hypoxia to the medullary thick ascending limb. To investigate the relationship between immediate early gene expression and the extent of hypoxic damage, we determined expression of the immediate early genes (IEG) c-fos and egr-1 in isolated perfused kidneys during standard perfusion and after various measures shown previously to be protective. mRNA levels of c-fos and egr-1 were markedly increased in kidneys after 90 minutes of standard perfusion with Krebs-Henseleit buffer containing albumin. Gene expression was most prominent in the outer medulla followed by papilla and cortex, a pattern reflected by the immunohistochemical demonstration of a prominent accumulation of both egr-1 and c-fos polypetides mainly in the medullary thick ascending limb (mTAL). Protective measures known to minimize morphological damage to the mTAL, including hyperoncotic perfusion, perfusion with glycine, or perfusion with a mixture of amino acids, decreased mRNA levels of c-fos and egr-1 in the outer medulla (by 50% and 35%, respectively) and the papilla (by 60 and 30%, respectively). Renal cortex showed only minor changes. In contrast, prevention of tubular transport by perfusion with 1 mM ouabain increased mRNA levels of c-fos and egr-1 in the outer medulla by 100% and 60%, respectively. Ouabain also dramatically increased mRNA levels of both IEGs in two lines of cultured renal epithelial cells. Changes in the level and distribution of the protein products of these IEGs were not detectable in perfused kidneys by immunohistochemistry. Hypoxic injury of the kidney stimulates IEG expression even in the absence of reperfusion. Protection against hypoxic injury in the mTAL correlates with suppression of IEG mRNA levels when protection is provided by amino acids or hyperoncotic perfusion, but not when provided by inhibition of Na,K-ATPase, which stimulates IEG expression. We conclude that diminished IEG expression is not a necessary concomitant of protection against hypoxic injury.
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PMID:Modulation of c-fos and egr-1 expression in the isolated perfused kidney by agents that alter tubular work. 921 55

Recent evidence suggests that c-jun plays a pivotal role in macrophage differentiation induced by multiple agents and that cJun overexpression induces partial macrophage differentiation in the leukemic cell line U-937. The novel differentiating agent bufalin, a Na+/K+ ATPase inhibitor, has also been shown to induce macrophage differentiation in U-937. In order to further define the role of c-jun in macrophage differentiation, we examined the function of c-jun/AP-1 during bufalin induced differentiation in both c-jun transfected and parental U-937 cells. In contrast to phorbol esters, bufalin does not significantly stimulate c-jun or c-fos mRNA expression or AP-1 transactivation. However, bufalin treatment leads to markedly greater morphologic and functional changes indicative of more extensive differentiation in the cJun overexpressing cells compared to the non-transfected controls. Furthermore, cJun overexpressing cells maintain greater viability in the presence of bufalin and arrest in a different phase of the cell cycle than do control cell lines (G0/G1 versus S/G2M, respectively), although some apoptosis occurs in all cell lines treated with bufalin. These data suggest that while bufalin can induce some degree of differentiation in U-937 cells independent of c-jun/AP-1 controlled pathways, the involvement of these pathways by enforced cJun expression enhances the extent of differentiation and shifts the balance between differentiation and apoptosis.
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PMID:Alterations in differentiation and apoptosis induced by bufalin in cJun overexpressing U-937 cells. 945 68

Following myocardial Infarction (MI) the heart undergoes a process of remodeling characterized by considerable hypertrophy of the non-infarcted myocardium. We have recently characterized the molecular basis of key electrophysiologic alterations that may provide insight into the arrhythmogenecity of post-MI remodeled hypertrophied myocardium. To further characterize other key alterations in the pattern of cardiac gene expression in a time-dependent manner, we have measured mRNA and immunoreactive protein levels of selective cardiac genes in the remodeled hypertrophied left-ventricular (LV) myocardium of rats, 3 and 21 days after left-coronary ligation and compared the results with sham-operated rats. RNase protection assay was performed to assess the expression of c-fos, atrial natriuretic factor (ANF), brain natriuretic factor (BNF), alpha2/3 isoform of Na-K ATPase, cardiac alpha/beta isoform of myosin heavy chain (MHC). Compared to the sham group, the expression of c-fos was increased 10-fold (P<0.02) in the MI group on day 3, but unlike other overload hypertrophy models, the expression remained elevated by three-fold on day 21. Similar to other overload models, the ANF and BNF expression increased significantly. No alterations were observed in the expression of cardiac alpha-actin. There was reexpression of the fetal isogene form of MHC and Na-K ATPase after MI. The beta-MHC mRNA levels, the fetal isoform of MHC, returned to basal levels after 21 days. After an initial five-fold decrease the adult isoform of alphaNa-K ATPase, alpha2 Na-K ATPase mRNA, returned to control levels and similar changes were seen in the corresponding protein levels. These findings indicate that during LV remodeling and hypertrophy following MI, there is an upregulation of early response genes and fetal isogene expression. The pattern of activation, however, is distinct from that observed in other overload models, indicating the possible involvement of alternate signal transduction pathways.
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PMID:Alterations in cardiac gene expression during ventricular remodeling following experimental myocardial infarction. 951 38

We showed before that in neonatal rat cardiac myocytes partial inhibition of Na+/K+-ATPase by nontoxic concentrations of ouabain causes hypertrophic growth and transcriptional regulations of genes that are markers of cardiac hypertrophy. In view of the suggested roles of Ras and p42/44 mitogen-activated protein kinases (MAPKs) as key mediators of cardiac hypertrophy, the aim of this work was to explore their roles in ouabain-initiated signal pathways regulating four growth-related genes of these myocytes, i.e. those for c-Fos, skeletal alpha-actin, atrial natriuretic factor, and the alpha3-subunit of Na+/K+-ATPase. Ouabain caused rapid activations of Ras and p42/44 MAPKs; the latter was sustained longer than 90 min. Using high efficiency adenoviral-mediated expression of a dominant-negative Ras mutant, and a specific inhibitor of MAPK kinase (MEK), activation of Ras-Raf-MEK-p42/44 MAPK cascade by ouabain was shown. The effects of the mutant Ras, an inhibitor of Ras farnesylation, and the MEK inhibitor on ouabain-induced changes in mRNAs of the four genes indicated that (a) skeletal alpha-actin induction was dependent on Ras but not on p42/44 MAPKs, (b) alpha3 repression was dependent on the Ras-p42/44 MAPK cascade, and (c) induction of c-fos or atrial natriuretic factor gene occurred partly through the Ras-p42/44 MAPK cascade, and partly through pathways independent of Ras and p42/44 MAPKs. All ouabain effects required extracellular Ca2+, and were attenuated by a Ca2+/calmodulin antagonist or a protein kinase C inhibitor. The findings show that (a) signal pathways linked to sarcolemmal Na+/K+-ATPase share early segments involving Ca2+ and protein kinase C, but diverge into multiple branches only some of which involve Ras, or p42/44 MAPKs, or both; and (b) there are significant differences between this network and the related gene regulatory pathways activated by other hypertrophic stimuli, including those whose responses involve increases in intracellular free Ca2+ through different mechanisms.
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PMID:Multiple signal transduction pathways link Na+/K+-ATPase to growth-related genes in cardiac myocytes. The roles of Ras and mitogen-activated protein kinases. 961 40

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

Electrostimulations of cells by weak electric or electromagnetic LF and HF-fields are applied widely today; capacitively or inductively coupled, however, they are seldom applied for cell-free and membrane-free solutions of enzymes. First, the detection of a response of the cells ('electrical window') is a prerequisite for testing at least three parameters: frequency, amplitude and treatment time, besides reproducible biological conditions. The 'state-of-the-art' of this fast developing direction of bioelectrochemistry can be characterized in the following way: the results from several laboratories of (a) cell proliferation, (b) ion transport, (c) activation of several enzymes (Na,K-ATPase), (d) increase of certain protein concentrations (heat-shock protein hsp70) are more or less in agreement. Unfortunately, there are discrepancies between no less than 7 labs in the gene expression of c-myc, c-fos histone 2B, -actin, URA-3 and others, especially for low fields (< 0.05 mT), e.g., in HL60 cells! The reason why seems to be: (1) differences in the most suitable isolation procedure, (2) interferences in the case of too low magnetic flux and (3) too small ranges of parameters have been measured. Today, three open problems must be pointed out: (A) What is the physiological causality for specific 'electrical windows' and their positive or negative efficacy? (B) What are the biochemical targets for either magnetic or electric fields or both? (C) What is the influence of electrical and (or) thermal noise on field efficiency?
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PMID:Problems of weak electromagnetic field effects in cell biology. 1037 54

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

A single cerebroventricular injection of ethacrynic acid (EA), a Cl(-)-ATPase inhibitor, induces generalized tonic-clonic convulsions in mice. To clarify whether such convulsive stimulus triggers a long-lasting rearrangement of the neural circuitry culminating in seizure susceptibility, we examined molecular, cellular and behavioral changes following the EA-induced seizure. The expression of immediate early gene c-fos mRNA as an index for cellular activation increased biphasically, with an early transient increase at 60 min and a late prolonged increase on the 10th to 14th day post-EA administration, most remarkably in the hippocampus and pyriform cortex. On the 14th day post-EA seizure, subconvulsive dose of kainic acid (5-17.5 mg/kg) caused severe (stage 5) seizure in 77% of the mice, with 70% mortality. In addition, the expression of nerve growth factor (NGF) also showed biphasic increases with close spatiotemporal correlation with c-fos expression. Moreover, the number of cell somata and the density of axon fibers of parvalbumin (PARV)-positive cells, a subpopulation of GABAergic interneurons, decreased in area dentata, CA1 and CA3 on the 7th and 14th day post-EA seizure. In area dentata and CA1, the density of glutamic acid decarboxylase (GAD)-positive cells also decreased on the 14th day. Thus, the transient EA-induced seizures appear to develop seizure susceptibility by causing damage of a subpopulation of inhibitory interneurons along with increases in the expression of c-fos and NGF in limbic structures.
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PMID:Long-lasting c-fos and NGF mRNA expressions and loss of perikaryal parvalbumin immunoreactivity in the development of epileptogenesis after ethacrynic acid-induced seizure. 1040 97


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