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)

KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A) is a metal complex with promising anticancer activity. Since chemoresistance is a major obstacle in chemotherapy, this study investigated the influence of several drug resistance mechanisms on the anticancer activity of KP1019. Here we demonstrate that the cytotoxic effects of KP1019 are neither substantially hampered by overexpression of the drug resistance proteins multidrug resistance-related protein 1, breast cancer resistance protein, and lung resistance protein nor the transferrin receptor and only marginally by the cellular p53 status. In contrast, P-glycoprotein overexpression weakly but significantly (up to 2-fold) reduced KP1019 activity. P-glycoprotein-related resistance was based on reduced intracellular KP1019 accumulation and reversible by known P-glycoprotein modulators. KP1019 dose dependently inhibited ATPase activity of P-glycoprotein with a K(i) of approximately 31 microM. Furthermore, it potently blocked P-glycoprotein-mediated rhodamine 123 efflux under serum-free conditions (EC(50), approximately 8 microM), however, with reduced activity at increased serum concentrations (EC(50) at 10% serum, approximately 35 microM). Moreover, P-glycoprotein-mediated daunomycin resistance could only be marginally restored by KP1019 in serum-containing medium, also indicating an influence of serum proteins on the interaction between KP1019 and P-glycoprotein. Acquired KP1019 resistance was investigated by selecting KB-3-1 cells against KP1019 for more than 1 year. Only an approximately 2-fold KP1019 resistance could be induced, which unexpectedly was not due to overexpression of P-glycoprotein or other efflux pumps. Accordingly, KP1019-resistant cells did not display reduced drug accumulation. Their unique cross-resistance pattern confirmed an ABC transporter-independent resistance phenotype. In summary, the likeliness of acquiring insensitivity to KP1019 during therapy is expected to be low, and resistance should not be based on overexpression of drug efflux transporters.
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PMID:Intrinsic and acquired forms of resistance against the anticancer ruthenium compound KP1019 [indazolium trans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A). 1533 56

Whether subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria contain monocarboxylate transporters (MCTs) is controversial. We have examined the presence of MCT1, 2, and 4 in highly purified SS and IMF mitochondria. These mitochondria were not contaminated with plasma membrane, sarcoplasmic reticulum or endosomal compartments, as the marker proteins for these sub-cellular compartments (Na+-K+-ATPase, Ca2+-ATPase, and the transferrin receptor) were not present in SS or IMF mitochondria. MCT1, MCT2, and MCT4 were all present at the plasma membrane. However, MCT1 and MCT4 were associated with SS mitochondria. In contrast, the IMF mitochondria were completely devoid of MCT1 and MCT4. However, MCT2 was associated with both SS and IMF mitochondria. These observations suggest that SS and IMF mitochondria have different capacities for metabolizing monocarboxylates. Thus, the controversy as to whether mitochondria can take up and oxidize lactate will need to take account of the different distribution of MCTs between SS and IMF mitochondria.
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PMID:Monocarboxylate transporters in subsarcolemmal and intermyofibrillar mitochondria. 1535 29

We sought to identify novel genes involved in intestinal iron absorption by inducing iron deficiency in rats during postnatal development from the suckling period through adulthood. We then performed comparative gene chip analyses (RAE230A and RAE230B chips; Affymetrix) with cRNA derived from duodenal mucosa. Real-time PCR was used to confirm changes in gene expression. Genes encoding the apical iron transport-related proteins [divalent metal transporter 1 (DMT1) and duodenal cytochrome b] were strongly induced at all ages studied, whereas increases in mRNA encoding the basolateral proteins iron-regulated gene 1 and hephaestin were observed only by real-time PCR. In addition, transferrin receptor 1 and heme oxygenase 1 were induced. We also identified induction of novel genes not previously associated with intestinal iron transport. The Menkes copper ATPase (ATP7a) and metallothionein were strongly induced at all ages studied, suggesting increased copper absorption by enterocytes during iron deficiency. We also found significantly increased liver copper levels in 7- to 12-wk-old iron-deficient rats. Also upregulated at most ages examined were the sodium-dependent vitamin C transporter, tripartite motif protein 27, aquaporin 4, lipocalin-interacting membrane receptor, and the breast cancer-resistance protein (ABCG2). Some genes also showed decreased expression with iron deprivation, including several membrane transporters, metabolic enzymes, and genes involved in the oxidative stress response. We speculate that dietary iron deprivation leads to increased intestinal copper absorption via DMT1 on the brush-border membrane and the Menkes copper ATPase on the basolateral membrane. These findings may thus explain copper loading in the iron-deficient state. We also demonstrate that many other novel genes may be differentially regulated in the setting of iron deprivation.
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PMID:Identification of differentially expressed genes in response to dietary iron deprivation in rat duodenum. 1563 78

Intestinal epithelial cells (IEC) are located at a strategic position between the external environment and the most extended lymphoid tissue in the body. Besides their central role in the absorption of nutrients, IEC also provide antigenic information to the immune system and are involved in the balance tolerance/allergy to food antigens. Like professional antigen presenting cells, IEC have been shown to secrete 30- to 90-nm diameter vesicles named exosomes, in a polarized way, either from their apical or basolateral side. These vesicles carry molecules involved in adhesion and antigen presentation, comprising major histocompatibility complex (MHC) class I and class II molecules, tetraspan proteins, CD26/dipeptidyl-peptidase IV, and A33 antigen, a molecule essentially restricted to the intestinal epithelium. Invariant chain, transferrin receptor, and Na-K-ATPase are not expressed on epithelial exosomes. In vivo, in mice, epithelial exosomes carrying MHC/ovalbumin peptide complexes induce specific immune responses when injected intraperitoneally. A33 antigen, an Ig-like molecule highly specific for intestinal epithelial cells and enriched in epithelial exosomes, is found at the surface of cells entering mesenteric lymph nodes suggesting exosome migration from the epithelial layer to the gut associated lymphoid system. Taken together, intestinal epithelial exosomes released at the basolateral surface of enterocytes could be antigen-carrying structures constituting a link between luminal antigens and the local immune system and acting as sensors of the antigenic information present in the intestinal lumen.
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PMID:Phenotypic and functional characterization of intestinal epithelial exosomes. 1589 86

Previous studies revealed novel genetic changes in the duodenal mucosa of iron-deprived rats during postnatal development. These observations are now extended to compare the genetic response to iron deficiency in the duodenum versus jejunum of 12-wk-old rats. cRNA samples were prepared from the duodenal and jejunal mucosa of three groups each of control and iron-deficient rats and hybridized with RAE 230A and 230B gene chips (Affymetrix). Stringent data reduction strategies were employed. Results showed that several genes were similarly induced in both gut segments, including DMT1, Dcytb, transferrin receptor 1, heme oxygenase 1, metallothionein, the Menkes copper ATPase (ATP7A), tripartitie motif protein 27, and the sodium-dependent vitamin C transporter. However, a subset of genes showed regulation in only one or the other gut segment. In duodenum only, gastrokine 1, trefoil factor 1 and claudin 2 were induced by iron-deficiency. Other genes previously identified were only regulated in the duodenum. Overall, these studies demonstrate similarities and distinct differences in the genetic response to iron deprivation in the duodenum versus jejunum and provide evidence that more distal gut segments also may play a role in increasing iron absorption in iron-deficiency anemia.
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PMID:Gene chip analyses reveal differential genetic responses to iron deficiency in rat duodenum and jejunum. 1662 62

Cu and Fe metabolism are known to be linked, but the interactions during pregnancy are less well studied. In the present study we used rats to examine the effect of Cu deficiency during pregnancy on Fe and Cu levels in maternal and fetal tissue and on the gene expression profile of proteins involved in Cu and Fe metabolism in the placenta. Rats were fed diets with different Cu contents before and during pregnancy. Samples were collected on day 21 of gestation. Cu levels, ceruloplasmin activity and serum Fe all decreased in maternal serum of Cu-deficient animals. Maternal liver Fe inversely correlated with liver Cu. Placental Cu levels decreased with no change in Fe. Fe and Cu levels both decreased in the fetal liver. The drop in maternal liver Cu was significantly correlated with a decrease in organ weight of fetal liver, lung and kidney. No changes were observed in mRNA expression of Cu transporter 1, Menkes P-type Cu-ATPase 7A, Wilson P-type Cu-ATPase 7B, cytochrome-c oxidase, and Cu chaperone Atox1 in the placenta of Cu-deficient dams. Transferrin receptor 1 and the Fe-responsive element (IRE)-regulated divalent metal transporter 1 (DMT1) were up regulated; while ferroportin and non-IRE1-regulated DMT1 levels did not change. These data show that Cu deficiency during pregnancy not only has a direct effect on Fe levels but also regulates the expression of Fe transporters. The pattern closely mirrors that seen in Fe deficiency, suggesting that the changes are a consequence of the decrease in serum Fe, implying that the developing fetus not only suffers from Cu, but also from Fe deficiency.
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PMID:Effect of dietary copper deficiency on iron metabolism in the pregnant rat. 1729 91

For the application of microarray technology as an additional endpoint in toxicological studies, there is a need to understand associations between pathological processes and gene expression alterations. In the current study, we investigated gentamicin as a nephrotoxic model compound. Gene expression changes of the kidney in response to a dose of 80 mg/kg gentamicin were analyzed by using DNA microarray technology and alterations in gene expression were associated with results from conventional histopathological investigations and with the described pathomechanisms of gentamicin. Under the conditions of our experiment, the mRNA level of 211 genes were found to be deregulated by gentamicin. The gentamicin-induced affection of proximal convoluted tubules was associated with a strong up-regulation of mRNAs encoding for proteins which are used as nephrotoxicity markers in urine and plasma such as Kim-1, Osteopontin and TIMP1. Candidate marker genes for nephrotoxicity such as GATM were deregulated. Gentamicin-induced lysosomal phospholipidosis was indicated by deregulation of lysosomal located gene products such as ATP6V1D, a subunit of the lysosomal H+ transporting ATPase. Effects on glucose transport and metabolism were indicated by the down-regulation on SGLT-2 and glucose-6-phosphatase. Renal cell apoptosis was indicated by up-regulated genes as TP53 and BAX. The role of oxidative stress in gentamicin toxicity was reflected by deregulation of transferrin receptor and heme oxygenase. The results of the study show the potential of microarray technology to study a complex mechanism of toxicity in a single study.
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PMID:Identification of genes involved in gentamicin-induced nephrotoxicity in rats--a toxicogenomic investigation. 1966 12

Endocytosis and trafficking of receptors and nutrient transporters are dependent on an acidic intra-endosomal pH that is maintained by the vacuolar H(+)-ATPase (V-ATPase) proton pump. V-ATPase activity has also been associated with cancer invasiveness. Here, we report on a new V-ATPase-associated protein, which we identified in insulin-like growth factor I (IGF-I) receptor-transformed cells, and which was separately identified in Caenorhabditis elegans as HRG-1, a member of a family of heme-regulated genes. We found that HRG-1 is present in endosomes but not in lysosomes, and it is trafficked to the plasma membrane upon nutrient withdrawal in mammalian cells. Suppression of HRG-1 with small interfering RNA causes impaired endocytosis of transferrin receptor, decreased cell motility, and decreased viability of HeLa cells. HRG-1 interacts with the c subunit of the V-ATPase and enhances V-ATPase activity in isolated yeast vacuoles. Endosomal acidity and V-ATPase assembly are decreased in cells with suppressed HRG-1, whereas transferrin receptor endocytosis is enhanced in cells that overexpress HRG-1. Cellular uptake of a fluorescent heme analogue is enhanced by HRG-1 in a V-ATPase-dependent manner. Our findings indicate that HRG-1 regulates V-ATPase activity, which is essential for endosomal acidification, heme binding, and receptor trafficking in mammalian cells. Thus, HRG-1 may facilitate tumor growth and cancer progression.
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PMID:Heme-binding protein HRG-1 is induced by insulin-like growth factor I and associates with the vacuolar H+-ATPase to control endosomal pH and receptor trafficking. 1987 48

Patients with Charcot-Marie-Tooth neuropathy and gene targeting in mice revealed an essential role for the SH3TC2 gene in peripheral nerve myelination. SH3TC2 expression is restricted to Schwann cells in the peripheral nervous system, and the gene product, SH3TC2, localizes to the perinuclear recycling compartment. Here, we show that SH3TC2 interacts with the small guanosine triphosphatase Rab11, which is known to regulate the recycling of internalized membranes and receptors back to the cell surface. Results of protein binding studies and transferrin receptor trafficking are in line with a role of SH3TC2 as a Rab11 effector molecule. Consistent with a function of Rab11 in Schwann cell myelination, SH3TC2 mutations that cause neuropathy disrupt the SH3TC2/Rab11 interaction, and forced expression of dominant negative Rab11 strongly impairs myelin formation in vitro. Our data indicate that the SH3TC2/Rab11 interaction is relevant for peripheral nerve pathophysiology and place endosomal recycling on the list of cellular mechanisms involved in Schwann cell myelination.
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PMID:SH3TC2, a protein mutant in Charcot-Marie-Tooth neuropathy, links peripheral nerve myelination to endosomal recycling. 2082 37

Vacuolar ATPases (V-ATPases) comprise specialized and ubiquitously distributed pumps that acidify intracellular compartments and energize membranes. To gain new insights into the roles of V-ATPases in prostate cancer (PCa), we studied the effects of inhibiting V-ATPase pumps in androgen-dependent (LNCaP) and androgen-independent (C4-2B) cells of a human PCa progression model. Treatment with nanomolar concentrations of the V-ATPase inhibitors bafilomycin A or concanamycin A reduced the in vitro invasion in both cell types by 80%, regardless that V-ATPase was prominent at the plasma membrane of C4-2B cells and only traces were detected in the low-metastatic LNCaP parental cells. In both cell types, intracellular V-ATPase was excessive and co-localized with prostate-specific antigen (PSA) in the Golgi compartment. V-ATPase inhibitors reversibly excluded PSA from the Golgi and led to the accumulation of largely dispersed PSA-loaded vesicles of lysosomal composition. Inhibition of acridine orange staining and transferrin receptor recycling suggested defective endosomal and lysosomal acidification. The inhibitors, additionally, interfered with the AR-PSA axis under conditions that reduced invasion. Bafilomycin A significantly reduced steady-state and R1881-induced PSA mRNA expression and secretion in the LNCaP cells which are androgen-dependent, but not in the C4-2B cells which are androgen ablation-resistant. In the C4-2B cells, an increased susceptibility to V-ATPase inhibitors was detected after longer treatments, as proliferation was reduced and reversibility of bafilomycin-induced responses impaired. These findings make V-ATPases attractive targets against early and advanced PCa tumors.
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PMID:Inhibitors of vacuolar ATPase proton pumps inhibit human prostate cancer cell invasion and prostate-specific antigen expression and secretion. 2294 74


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