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)

An important goal of cancer immunology is the identification of antigens associated with tumor destruction. Vaccination with irradiated tumor cells engineered to secrete granulocyte/macrophage colony-stimulating factor (GM-CSF) generates potent, specific, and long-lasting antitumor immunity in multiple murine tumor models. A phase I clinical trial of this vaccination strategy in patients with advanced melanoma demonstrated the consistent induction of dense CD4(+) and CD8(+) T lymphocyte and plasma cell infiltrates in distant metastases, resulting in extensive tumor destruction, fibrosis, and edema. Antimelanoma antibody and cytotoxic T cell responses were associated with tumor cell death. To characterize the targets of these responses, we screened an autologous cDNA expression library prepared from a densely infiltrated metastasis with postvaccination sera from a long-term responding patient. High-titer IgG antibodies detected ATP6S1, a putative accessory unit of the vacuolar H(+)-ATPase complex. A longitudinal analysis of this patient revealed an association between the vaccine-induced increase in antibodies to ATP6S1 and tumor destruction. Three additional vaccinated melanoma patients and three metastatic non-small cell lung carcinoma patients vaccinated with autologous GM-CSF-secreting tumor cells similarly showed a correlation between humoral responses to ATP6S1 and tumor destruction. Moreover, a chronic myelogenous leukemia patient who experienced a complete remission after CD4(+) donor lymphocyte infusions also developed high-titer antibodies to ATP6S1. Lastly, vaccination with GM-CSF-secreting B16 melanoma cells stimulated high-titer antibodies to ATPS1 in a murine model. Taken together, these findings demonstrate that potent humoral responses to ATP6S1 are associated with immune-mediated destruction of diverse tumors.
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PMID:ATP6S1 elicits potent humoral responses associated with immune-mediated tumor destruction. 1198 66

Acidification of organelles of the eukaryotic vacuolar system is important for multiple intracellular processes including receptor-mediated endocytosis, proteolytic activity in lysosomes, and prohormone sorting and processing in secretory granules. Responsible for the generation of a proton gradient across a membrane is vacuolar H(+)-ATPase (V-ATPase). How the activity of this multisubunit enzyme is regulated remains to be established. Accessory subunits of the V-ATPase may be involved in the organelle-specific regulation, one candidate being the chromaffin granular V-ATPase-associated protein Ac45. To assess the function of Ac45, we disrupted its gene by gene targeting in male mouse embryonic stem cells. We have successfully generated Ac45 null mutant (-IY) embryonic stem cells and injected them into C57BL/6 recipient blastocysts. The blastocysts were replaced into pseudopregnant foster mothers, giving rise to 16 littermates. One of these appeared to be a low-chimeric female mouse that died 6 weeks after birth. No signs of late abortion were detected in the foster mothers. The results suggest that the injected Ac45 null mutant embryonic stem cells affect the normal development of the blastocyst and are in line with knockout studies on other V-ATPase subunits that point to an essential role for the V-ATPase in early embryonic development.
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PMID:Targeted disruption of the mouse gene encoding the V-ATPase accessory subunit Ac45. 1198 24

The vacuolar H+-ATPase (V-ATPase) is a multisubunit enzyme that couples ATP hydrolysis to proton pumping across membranes. The intracellular targeting and activity of the V-ATPase may be regulated via proteins that interact with the pump such as the accessory subunit Ac45. Here we report the isolation and characterization of the gene encoding Ac45. This single-copy gene is located in a gene-dense region of chromosome Xq and consists of 10 exons spanning approximately 8 kb in the mouse and human genomes. The gene structure is poorly conserved in that its invertebrate orthologs of Caenorhabditis elegans and Drosophila melanogaster encompass only six and four exons extending over 4.1 and 2.1 kb, respectively. Furthermore, the overall degree of amino acid sequence identity between the mammalian and invertebrate Ac45 proteins is very low (<18%), except for a surprisingly highly conserved putative targeting motif in the carboxy-terminal region. Primer extension analysis revealed that the mouse Ac45 gene contains two major transcription initiation sites. The start sites are not preceded by a clear CAAT-box and are located in a CpG island. The most downstream start site contains a TATA-box and transcriptional regulatory elements such as PEA-3, F2F, Maz and Sp1. The limited number of regulatory DNA elements common in the genes encoding Ac45 and V-ATPase subunits suggests a differential regulation of these genes. Together with the finding that Ac45 appears to occur only in multicellular organisms, these results indicate that this accessory subunit directs the V-ATPase to specialized and complex vacuolar systems.
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PMID:Structural gene organization and evolutionary aspects of the V-ATPase accessory subunit Ac45. 1199 89

The vacuolar (H(+))-ATPase (V-ATPase) is crucial for multiple processes within the eukaryotic cell, including membrane transport and neurotransmitter secretion. How the V-ATPase is regulated, e.g. by an accessory subunit, remains elusive. Here we explored the role of the neuroendocrine V-ATPase accessory subunit Ac45 via its transgenic expression specifically in the Xenopus intermediate pituitary melanotrope cell model. The Ac45-transgene product did not affect the levels of the prohormone proopiomelanocortin nor of V-ATPase subunits, but rather caused an accumulation of the V-ATPase at the plasma membrane. Furthermore, a higher abundance of secretory granules, protrusions of the plasma membrane and an increased Ca(2+)-dependent secretion efficiency were observed in the Ac45-transgenic cells. We conclude that in neuroendocrine cells Ac45 guides the V-ATPase through the secretory pathway, thereby regulating the V-ATPase-mediated process of Ca(2+)-dependent peptide secretion.
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PMID:Accessory subunit Ac45 controls the V-ATPase in the regulated secretory pathway. 1865 79

Furin is a proprotein convertase which activates a variety of regulatory proteins in the constitutive exocytic and endocytic pathway. The effect of genetic ablation of fur was studied in the endocrine pancreas to define its physiological function in the regulated secretory pathway. Pdx1-Cre/loxP furin KO mice show decreased secretion of insulin and impaired processing of known PC2 substrates like proPC2 and proinsulin II. Both secretion and PC2 activity depend on granule acidification, which was demonstrated to be significantly decreased in furin-deficient beta cells by using the acidotrophic agent 3-(2,4-dinitroanilino)-3'amino-N-methyldipropylamine (DAMP). Ac45, an accessory subunit of the proton pump V-ATPase, was investigated as a candidate substrate. Ac45 is highly expressed in islets of Langerhans and furin was able to cleave Ac45 ex vivo. Furthermore, the exact cleavage site was determined. In addition, reduced regulated secretion and proinsulin II processing could be obtained in the insulinoma cell line betaTC3 by downregulation of either furin or Ac45. Together, these data establish an important role for furin in regulated secretion, particularly in intragranular acidification most likely due to impaired processing of Ac45.
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PMID:Role of furin in granular acidification in the endocrine pancreas: identification of the V-ATPase subunit Ac45 as a candidate substrate. 1871 56

Perfluorododecanoic acid (PFDoA), a ubiquitous contaminant detected in environmental matrices, wildlife, and human blood, has been shown to produce adverse effects on male reproduction in rats. The mechanism of action of PFDoA in testis, however, is not well understood. In the present study, male rats were orally exposed to PFDoA (0.02, 0.2, and 0.5mg/kg/day for 110 days), and a two-dimensional gel electrophoresis (2-DE) approach was employed to investigate the alteration of protein expression in the testes. Decreased serum progesterone levels were observed. Matrix-assisted laser desorption/ionization (MALDI) tandem time of flight (TOF/TOF) mass spectrometry analysis allowed the unambiguous identification of 40 differentially expressed proteins. These proteins are mainly involved in mitochondrial respiration, oxidative stress, sperm activity, cytoskeleton and intracellular signal transduction. Furthermore, PFDoA led to decreases in activities of superoxide dismutase (SOD), mitochondrial H-ATPase, and cytochrome c oxidase as well as to an increase in lipid peroxidation in testes. Our results indicated that these proteins, which are involved in mitochondrial respiratory and antioxidative responses, play important roles in the inhibition of testicular steriodogenesis in response to PFDoA. Our data demonstrate that alterations of multiple pathways may be associated with the toxic effects of PFDoA on testes. SOD and H-ATPase subunit d may be sensitive to PFDoA exposure in testis.
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PMID:Proteomic analysis for testis of rats chronically exposed to perfluorododecanoic acid. 1985 47

The vacuolar (H(+))-ATPase (V-ATPase) is the main regulator of intraorganellar pH and in neuroendocrine cells is controlled by its accessory subunit, Ac45. Here, we report the discovery of the first isoform of a V-ATPase accessory subunit, namely an Ac45-like protein, denoted Ac45LP. Phylogenetic analysis revealed a lineage-dependent evolutionary history: Ac45 is absent in birds, and Ac45LP is absent in placental mammals, whereas all other tetrapod species contain both genes. In contrast to Ac45, Ac45LP is not proteolytically cleaved, a prerequisite for proper Ac45 routing. Intriguingly, Xenopus Ac45LP mRNA was expressed in developing neural tissue and in neural crest cells. In adult Xenopus, Ac45 mRNA is widely expressed mostly in neuroendocrine tissues, while Ac45LP mRNA expression was found to be restricted to the kidney and the lung. This novel Ac45LP may provide additional possibilities for V-ATPase regulation during neurodevelopment as well as in kidney and lung cells.
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PMID:An isoform of the vacuolar (H(+))-ATPase accessory subunit Ac45. 1994 30

The number of corticotrophs increases in the anterior pituitary (AP) gland in adrenalectomized (AdX) rats. In this study, aimed at identifying the growth factor implicated in this proliferation, we analyzed proteins secreted from a cDNA library of the AP of AdX rats, using the signal sequence trap method. A PCR analysis of several cDNAs that coded for insulin-like growth factor binding protein (IGFBP) 5, IGFBP7, and vacuolar H+-ATPase accessory subunit Ac45 revealed an increased and decreased expression level of IGFBP7 mRNA in the AP of AdX rats and AdX rats injected with dexamethasone, respectively. IGFBP7 mRNA was predominately expressed in the corticotrophs of the APs of both sham-operated and AdX rats. The AP of AdX rats contained an increased number of IGFBP7 mRNA-expressing cells and corticotrophs compared with that of sham-operated rats, but the ratio of IGFBP7 mRNA-positive corticotrophs per total number of corticotrophs did not significantly change in either group. Histochemical analysis of labeled proliferating cell nuclear antigen (PCNA) and sex-determining region Y box-2 (SOX2) revealed the presence of several PCNA-positive signals and the absence of SOX2 cells among the corticotrophs, suggesting that IGFBP7 mRNA-expressing corticotrophs are derived from in situ corticotrophs and that they increase in number as corticotrophs increase. The possible roles of IGFBP7 in the corticotrophs are also discussed.
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PMID:Expression of IGFBP7 mRNA in corticotrophs in the anterior pituitary of adrenalectomized rats. 2064 9

The vacuolar (H(+))-ATPase (V-ATPase) is an important proton pump, and multiple critical cell-biological processes depend on the proton gradient provided by the pump. Yet, the mechanism underlying the control of the V-ATPase is still elusive but has been hypothesized to involve an accessory subunit of the pump. Here we studied as a candidate V-ATPase regulator the neuroendocrine V-ATPase accessory subunit Ac45. We transgenically manipulated the expression levels of the Ac45 protein specifically in Xenopus intermediate pituitary melanotrope cells and analyzed in detail the functioning of the transgenic cells. We found in the transgenic melanotrope cells the following: i) significantly increased granular acidification; ii) reduced sensitivity for a V-ATPase-specific inhibitor; iii) enhanced early processing of proopiomelanocortin (POMC) by prohormone convertase PC1; iv) reduced, neutral pH-dependent cleavage of the PC2 chaperone 7B2; v) reduced 7B2-proPC2 dissociation and consequently reduced proPC2 maturation; vi) decreased levels of mature PC2 and consequently reduced late POMC processing. Together, our results show that the V-ATPase accessory subunit Ac45 represents the first regulator of the proton pump and controls V-ATPase-mediated granular acidification that is necessary for efficient prohormone processing.
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PMID:V-ATPase-mediated granular acidification is regulated by the V-ATPase accessory subunit Ac45 in POMC-producing cells. 2070 83

The vacuolar (H+)-ATPase (V-ATPase) is a universal proton pump and its activity is required for a variety of cell-biological processes such as membrane trafficking, receptor-mediated endocytosis, lysosomal protein degradation, osteoclastic bone resorption and maintenance of acid-base homeostasis by renal intercalated cells. In neuronal and neuroendocrine cells, the V-ATPase is the major regulator of intragranular acidification which is indispensable for correct prohormone processing and neurotransmitter uptake. In these specialized cells, the V-ATPase is equipped with the accessory subunits ATP6AP1/Ac45 and ATP6AP2/(pro) renin receptor. Recent studies have shown that Ac45 interacts with the V0- sector of the V-ATPase complex, thereby regulating the intragranular pH and Ca2+-dependent exocytotic membrane fusion. Thus, Ac45 can be considered as a V-ATPase regulator in the neuroendocrine secretory pathway. ATP6AP2 has recently been found to be identical to the (pro) renin receptor and has a dual role: (i) in the renin-angiotensin system that also regulates V-ATPase activity; (ii) acting as an adapter by binding to both the V-ATPase and the Wnt receptor complex, thereby recruiting the receptor complex into an acidic microenvironment. We here provide an overview of the two V-ATPase accessory subunits as novel key players in V-ATPase regulation. We argue that the accessory subunits are candidate genes for V-ATPase-related human disorders and promising targets for manipulating V-ATPase functioning in vivo.
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PMID:Novel insights into V-ATPase functioning: distinct roles for its accessory subunits ATP6AP1/Ac45 and ATP6AP2/(pro) renin receptor. 2204 56


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