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)

Human blood monocytes can differentiate into osteoclast-like cells when they are cultured in the presence of anti-FRP-1. Messenger (mRNA) expression of markers related to osteoclasts was analyzed during differentiation of osteoclasts from monocytes. As markers related to osteoclasts, we selected cathepsin-K, carbonic anhydrase (CA) II, vacuolar H(+)-ATPase (v-ATPase), vitronectin receptor (VNR), tartrate-resistant acid phosphatase (TRAP), osteopontin (OPN), galectin-3, c-src, c-fos, and c-fms. The mRNAs other than c-src mRNA were expressed in freshly isolated monocytes or monocytes incubated with control antibody or anti-FRP-1 monoclonal antibody (MAb) for 14 days. Of these mRNAs, cathepsin-K, CA II, v-ATPase, VNR, TRAP, OPN, and c-fms mRNAs were expressed at higher levels in the osteoclast-like cells than those in monocytes cultured with control antibody. On the other hand, galectin-3 mRNA was expressed at lower levels in the osteoclast-like cells, and there was no significant difference in c-fos mRNA expression between the monocytes cultured with control antibody and anti-FRP-1 MAb. c-src mRNA could not be detected in monocytes freshly isolated or incubated with control antibody. Surprisingly, expression of c-src mRNA was induced in monocytes by anti-FRP-1 MAb and was detectable as early as 3 h after anti-FRP-1 MAb treatment, indicating that c-src is selectively induced by anti-FRP-1 MAb treatment. Furthermore, the osteoclast-like cells expressed calcitonin receptor. Receptor activator of NF-kappaB (RANK) mRNA was detectable in freshly isolated monocytes or monocytes cultured with control antibody or anti-FRP-1 MAbs. Maximal expression of RANK was observed in osteoclast-like cells. On the other hand, no receptor activator of NF-KB ligand (RANKL) mRNA was detectable in any of the samples, suggesting that anti-FRP-1 mAb can induce osteoclast-like cells from blood monocytes without RANKL.
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PMID:Gene expression during osteoclast-like cell formation induced by antifusion regulatory protein-1/CD98/4F2 monoclonal antibodies (MAbs): c-src is selectively induced by anti-FRP-1 MAb. 1067 16

Treatment of human leukemia THP-1 cells with bufalin, a specific inhibitor of Na(+)-K(+)-ATPase, sequentially induces c-fos and inflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) gene expressions before the appearance of mature phenotypes of monocytic cells. In this study we examined the signal transduction leading to bufalin-induced gene expressions. Bufalin selectively activated extracellular signal-regulated kinase (ERK), compared with other mitogen-activated protein (MAP) kinase family members. Pretreatment of THP-1 cells with PD-98059, an inhibitor of the ERK-kinase cascade, abolished bufalin-induced c-fos and IL-1 beta gene expressions, indicating that the ERK-kinase cascade mediates the induction of inflammatory cytokines by bufalin. Inhibition of the Na(+)/Ca(2+) exchanger by KB-R7943 and of protein kinase C (PKC) by Ro-31-8220 suppressed ERK activation and gene expressions of c-fos and IL-1 beta. These findings suggest that Na(+)-K(+)-ATPase inhibition by bufalin induces calcium influx and thereby activates PKC and ERK. In cells treated with an inhibitor of p38 MAP kinases, SB-203580, bufalin-mediated ERK activation became persistent and the induction of IL-1 beta and TNF-alpha expressions was significantly augmented. These results suggest that cross talk in bufalin-mediated ERK activation is negatively regulated by endogenous p38 MAP kinase activations.
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PMID:ERK signaling mediates the induction of inflammatory cytokines by bufalin in human monocytic cells. 1071 38

Parathyroid hormone-related protein (PTHrP) has been implicated in regulating tooth eruption and/or development. Formation of cementum, a mineralized tissue covering the tooth root surface, is a critical biological event for tooth root development. To test the hypothesis that PTHrP targets cementoblasts (CMs) and acts to regulate cementogenesis, CM cell lines were established and their responsiveness to PTHrP stimulation was determined, in vitro. First, subclones were derived from two immortalized murine cell populations that contained CMs; SV-CM/periodontal ligament (PDL) cells were obtained from the root surface of first mandibular molars of CD-1 mice and immortalized with SV40 T-antigen (TAg), and OC-CM cell population was established from OC-TAg transgenic mice in which their cells harbor an osteocalcin (OC and/or OCN) promoter-driving immortal gene SV40 TAg. Based on our previous in situ studies, CM subclones were identified as cells expressing bone sialoprotein (BSP) and OCN transcripts, while PDL cell lines were designated as cells lacking BSP and OCN messenger RNA (mRNA). CMs exhibited a cuboidal appearance and promoted biomineralization, both in vitro and in vivo. In contrast, PDL cells (PDL subclones) displayed a spindle-shaped morphology and lacked the ability to promote mineralized nodule formation, both in vitro and in vivo. Next, using these subclones, the effect of PTHrP on cementogenesis was studied. CMs, not PDL cells, expressed PTH/PTHrP receptor mRNA and exhibited PTHrP-mediated elevation in cyclic adenosine monophosphate (cAMP) levels and c-fos gene induction. PTHrP stimulation repressed mRNA expression of BSP and OCN in CMs and blocked CM-mediated mineralization, in vitro. Collectively, these data suggest that CMs possess PTH/PTHrP receptors and, thus, are direct targets for PTHrP action during cementogenesis and that PTHrP may serve as an important regulator of cementogenesis.
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PMID:Parathyroid hormone-related protein regulates extracellular matrix gene expression in cementoblasts and inhibits cementoblast-mediated mineralization in vitro. 1109 95

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

Adult cardiomyocytes are irreversibly postmitotic but respond to a variety of stimuli by hypertrophic growth, which is associated with an increase in cell size and protein content, organization of sarcomeres, and activation of a fetal gene program. Recently, we described a novel cardiac helicase activated by MEF2 protein (CHAMP), which is expressed specifically in the heart throughout prenatal and postnatal development. Here we show that CHAMP acts as an inhibitor of cell proliferation and cardiomyocyte hypertrophy. Ectopic expression of CHAMP inhibits proliferation of HeLa cells and blocks cell cycle entry of serum-stimulated NIH 3T3 cells. Overexpression of CHAMP in primary neonatal cardiomyocytes blocks hypertrophic growth and the induction of fetal genes in response to stimulation by serum and phenylephrine but does not prevent sarcomere organization or early mitogenic signaling events including activation of extracellular signal-regulated kinases or up-regulation of c-fos. Inhibition of cardiomyocyte hypertrophy by CHAMP requires the conserved ATPase domain and is accompanied by up-regulation of the cyclin-dependent protein kinase inhibitor p21(CIP1). These findings identify CHAMP as a cardiac-specific suppressor of cardiomyocyte hypertrophy and cell cycle progression and suggest that CHAMP may suppress these processes through the regulation of p21(CIP1).
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PMID:Suppression of proliferation and cardiomyocyte hypertrophy by CHAMP, a cardiac-specific RNA helicase. 1185

To study the mechanism of pulmonary edema after seawater drowning (PE-SWD), the indexes of blood-gas and acid-base in rabbits artery blood were measured by the blood-gas analyser. The activity of Na(+)-K(+)-ATPase, cytochrome oxidase(CYTO) and alkaline phospharase(ALP) in the lungs were measured and analysed by computer image system. C-fos mRNA and Fos protein in the lungs were respectively determined by situ hybrioization and immunohisto chemical techniques. The distribution of phospholipid and Ca2+ of rabbits lungs was quantitatively analysed by ultrastructural location method. The results showed that, five parameters of PaO2, oxygen saturation(SaO2), pH, actual bicarbonite(AB) and base excess(BE) and the activity of Na(+)-K(+)-ATPase and CYTO decreased remarkably in PE-SWD. Both c-fos mRNA and Fos protein expression in pulmonary epithelial cells in PE-SWD were significantly elevated compared with the normal controls(P < 0.01). The phospholipids products in the pulmonary alveolar type II epithelial cells were decreased, however, the Ca2+ precipitate pellets inside the lung capillary endothelial cells and the pulmonary alveolar type I and II epithelial cells increased obviously. The arthors suggest that the injuny action of the seawater, hypoxia and metabolic acidosis may be the mian three mechanisms of the pulmonary edema induced seawater drowning. The lowering activity of Na(+)-K(+)-ATPase and CYTO in the lungs and calcium overload in the cells are not only evil consequence resulted from above three factors, but also the importent causes leading to the worse of PE-SWD. The transmiting line of Ca(2+)-fos may be also a key link to bring about the worse of PE-SWD.
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PMID:[Study on the mechanism of pulmonary edema after seawater drowning in rabbit]. 1255 79

Our aim was to determine the molecular targets involved in the antiproliferative effects of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), in a normal murine mammary epithelial cell line, HC11. Among the early response genes analyzed, c-myc, junB, junD, c-jun, c-fos, fosB, fra, as well as max, mad1-4, sin3, only c-jun and fra-2 mRNAs were up-regulated after 1,25(OH)(2)D(3) exposure. Cyclin C was reduced and cyclin A2 and E were slightly enhanced; however, cyclins D1, D3, B1, B2, F, G1, G2, I and H, as well as TGF beta 1, TGF beta 3, T beta RI and T beta RII transcripts were not modulated by 1,25(OH)(2)D(3). Although p27(KIP1) protein content was unchanged, enhancement of p21(WAF1/CIP1) low basal levels in cell extracts and IGFBP-3 abundance on the culture medium was detected after 1,25(OH)(2)D(3) induction. Using differential display analysis, we identified eight down-modulated clones in exposed cells: 26S proteasome non-ATPase subunit Pad1, ubiquitin-conjugating enzyme Ube2i, extracellular proteinase inhibitor Expi or Wdnm1, cytochrome-c oxidase Cox7c, microtubule-associated protein-1 light chain-3 (Map1lc3), nascent-associated complex alpha Naca, transforming acidic coiled-coil Tacc3, stearoyl-CoA desaturase (Scd), keratin 6 alpha, and 1 up-regulated, fork head transcription factor Hfh-1L. Hence, the antiproliferative effect of 1,25(OH)(2)D(3) seems associated to enhancement of c-jun, Fra-2, IGFBP3 and p21(WAF1/CIP1). Decreased Pad1 and Ube2i might account for increased stability of cell cycle inhibitory proteins while reduced Wdnm1, Tacc3 and Scd might be secondary to accumulation of cells in G0/G1 phase.
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PMID:Molecular targets of 1,25(OH)2D3 in HC11 normal mouse mammary cell line. 1264 25

Some osteopetrotic mutations lead to low resorption, increased numbers of osteoclasts, and increased bone formation, whereas other osteopetrotic mutations lead to low resorption, low numbers of osteoclasts, and decreased bone formation. Elaborating on these findings, we discuss the possibility that osteoclasts are the source of anabolic signals for osteoblasts. In normal healthy individuals, bone formation is coupled to bone resorption in a tight equilibrium. When this delicate balance is disturbed, the net result is pathological situations, such as osteopetrosis or osteoporosis. Human osteopetrosis, caused by mutations in proteins involved in the acidification of the resorption lacuna (ClC-7 or the a3-V-ATPase), is characterized by decreased resorption in face of normal or even increased bone formation. Mouse mutations leading to ablation of osteoclasts (e.g., loss of macrophage-colony stimulating factor [M-CSF] or c-fos) lead to secondary negative effects on bone formation, in contrast to mutations where bone resorption is abrogated with sustained osteoclast numbers, such as the c-src mice. These data indicate a central role for osteoclasts, and not necessarily their resorptive activity, in the control of bone formation. In this review, we consider the balance between bone resorption and bone formation, reviewing novel data that have shown that this principle is more complex than originally thought. We highlight the distinct possibility that osteoclast function can be divided into two more or less separate functions, namely bone resorption and stimulation of bone formation. Finally, we describe the likely possibility that bone resorption can be attenuated pharmacologically without the undesirable reduction in bone formation.
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PMID:Are nonresorbing osteoclasts sources of bone anabolic activity? 1722 24

Lysosomal trafficking and protease exocytosis in osteoclasts are essential for ruffled border formation and bone resorption. Yet the mechanism underlying lysosomal trafficking and the related process of exocytosis remains largely unknown. We found ATP6ap1 (Ac45), an accessory subunit of vacuolar-type H(+)-ATPases (V-ATPases), to be highly induced by receptor activator for nuclear factor kappa B ligand (RANKL) in osteoclast differentiation. Ac45 knockdown osteoclasts formed normal actin rings, but had severely impaired extracellular acidification and bone resorption. Ac45 knockdown significantly reduced osteoclast formation. The decrease in the number of osteoclasts does not result from abnormal apoptosis; rather, it results from decreased osteoclast precursor cell proliferation and fusion, which may be partially due to the downregulation of extracellular signal-regulated kinase (ERK) phosphorylation and FBJ osteosarcoma oncogene (c-fos), nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), and "transmembrane 7 superfamily member 4" (Tm7sf4) expression. Notably, Ac45 knockdown osteoclasts exhibited impaired lysosomal trafficking and exocytosis, as indicated by the absence of lysosomal trafficking to the ruffled border and a lack of cathepsin K exocytosis into the resorption lacuna. Our data revealed that the impaired exocytosis is specifically due to Ac45 deficiency, and not the general consequence of a defective V-ATPase. Together, our results demonstrate the essential role of Ac45 in osteoclast-mediated extracellular acidification and protease exocytosis, as well as the ability of Ac45 to guide lysosomal intracellular trafficking to the ruffled border, potentially through its interaction with the small guanosine-5'-triphosphatase (GTPase) Rab7. Our work indicates that Ac45 may be a novel therapeutic target for osteolytic disease.
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PMID:V-ATPase subunit ATP6AP1 (Ac45) regulates osteoclast differentiation, extracellular acidification, lysosomal trafficking, and protease exocytosis in osteoclast-mediated bone resorption. 2246 41

The goal of the current work is to study the molecular mechanisms underlay the action of 5- amino-exo-3-azatricyclo[5.2.1.0(2,6)]decan-4-one (P-11) with combined antiarrhythmic, nootropic, anti-inflammatory and anaesthetic activities. The aconitine-induced experimental rat model of cardiac arrhythmia has been used in our study. Aconitine was administered once intravenously in a dose 50 microg/kg whereas experimental animal group received P-11 in a dose 0.3 mg/kg (the compound was injected intravenously 2 min before acute aconitine treatment). Expression macroarray (Atlas Rat cDNA Expression Array, #7738-1; BD Biosciences) was used to identify the target genes for P-11 compound. Comparative analysis of changes in the status of expression of genes in the heart of rats induced by P-11 against the simulated in vivo arrhythmia identified 16 genes that reproducibly alter the level of expression.These genes encode the extracellular matrix proteins (glypican 1, Gpc1; tissue inhibitor of metalloproteinase 2, 3, Timp2, Timp 3); intracellular signaling molecules (rho GTPase activating protein 7, Dlc1; protein tyrosine phosphatase 4a1, Ptp4a1; phosphodiesterase 4D, PDE4D; PI3-kinase regulatory subunit alpha, PIK3R1; guanine nucleotide binding protein alpha 12, Gna12) and protein of intermediate junctions (junction plakoglobin, Jup), proteins involved in glycolysis (phosphofructokinase I, Pfk1) and hemostasis (tissue plasminogen activator, Plat), plasma membrane transporters (Solute carrier family 16, member 1, Slc16a1; ATPase, Na+/K+ transporting, Atp1a), and ets. (c-fos protooncogene, c-fos; telomerase protein component 1, tlp; Annexin 1, anxa 1). Thus, the data about the selective effect of P-11 on genes whose products are involved in the aritmogenesys mechanisms, allow us to consider this compound as a promising means of pathogenetically oriented pharmacotherapy of cardiac arrhythmias.
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PMID:[Animal in vivo model of arrhythmia for genes target identification for 5-amino-exo-3-azatricyclo[5.2.1.0(2,6)]decan-4-one]. 2249 81


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