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 self-renewing epithelial populations present in the gastric units of the mouse stomach are descended from a multipotent stem cell and undergo an orderly migration-associated differentiation followed by apoptosis. The steady state census of the three principal cell types (acid-producing parietal cells, mucus-producing pit cells, and pepsinogen and intrinsic factor-producing zymogenic cells) is accurately controlled, despite marked differences in the rates of migration of each lineage. A transgenic mouse model has been created to define functional interrelationships between the proliferation, differentiation, and death programs of these lineages. Nucleotides -1035 to +24 of the noncatalytic beta subunit gene of mouse H+/K+-ATPase were used to direct expression of an attenuated diphtheria toxin A subunit in the parietal cell lineage. These transcriptional regulatory elements are not active in members of the pit and zymogenic lineages. Stomachs, prepared from postnatal day 28-80 transgenic mice and their normal littermates, were subjected to single- and multilabel immunohistochemical studies as well as qualitative and quantitative light and electron microscopic morphologic analyses. The toxin produced complete ablation of differentiated parietal cells. Loss of parietal cells was accompanied by a 5-fold increase in the number of undifferentiated granule-free cells located in the proliferative compartment of gastric units. This amplified population of granule-free cells included the multipotent stem cell as well as committed precursors of the pit and zymogenic lineages. Loss of mature parietal cells was also associated with (i) a block in the differentiation program of the zymogenic lineage with an accumulation of pre-neck cells and a depletion of their neck and mature zymogenic cell descendants, and (ii) an approximately 2-fold amplification of pit cells. These findings are consistent with the notion that epithelial homeostasis within gastric units is maintained by instructive interactions between their different cell lineages. Unlike pit and zymogenic cells, parietal cells complete their differentiation in the gastric unit's proliferative compartment before undergoing a bipolar migration along the unit. Thus, the mature parietal cell is in a strategic position to influence decision-making among gastric epithelial cell precursors and to modulate the migration-associated terminal differentiation programs of the pit and zymogenic lineages.
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PMID:Diphtheria toxin-mediated ablation of parietal cells in the stomach of transgenic mice. 863 79

Morphological and functional heterogeneity of parietal cells has been thought to be due to different maturation positions within the gastric gland. Morphodynamic studies have shown that 2% of parietal cells in mice derive from a pre-neck (chief) cell precursor. Intrinsic factor (IF) and pepsinogen, markers of rat chief cells, were used to determine if these proteins identified a subset of parietal cells that might reflect origin from the pre-neck cell lineage. The zymogenic region of the rat stomach and gradient-isolated fractions enriched in parietal and chief cells were fixed in 10% buffered Formalin or in Bouin's solution. Immunostaining was performed using indirect immunoperoxidase histochemistry and double-labeled immunofluorescence with antibodies raised against human IF, pepsinogen II, and H(+)-K(+)-adenosinetriphosphatase (H(+)-K(+)-ATPase). In intact tissue, parietal (H(+)-K(+)-ATPase-positive) cells were found starting at the upper edge of the isthmus, but parietal cells positive for IF and pepsinogen were only found from just below the isthmus and neck region to the base of the gastric gland. Three to four percent of isolated parietal cells were positive for these ectopic markers. This subset of cells was also positive for H(+)-K(+)-ATPase. Thus products of rat chief cells are expressed in a subset of parietal cells. The percentage of positive cells is similar to that predicted to be derived from the pre-neck (chief) precursor lineage in the mouse. The distribution of these cells to the lower neck and base of the gland suggests that the expression of chief cell products is consistent with either predetermination by lineage or parietal cell maturation or with both processes.
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PMID:Expression of intrinsic factor and pepsinogen in the rat stomach identifies a subset of parietal cells. 945 74

Selection of asymmetric cell fates can involve both intrinsic and extrinsic factors. Previously we have identified the bag-of-marbles (bam) gene as an intrinsic factor for cystoblast fate in Drosophila germline cells and shown that it requires active product from the benign gonial cell neoplasm (bgcn) gene. Here we present the cloning and characterization of bgcn. The predicted Bgcn protein is related to the DExH-box family of RNA-dependent helicases but lacks critical residues for ATPase and helicase functions. Expression of the bgcn gene is extremely limited in ovaries but, significantly, bgcn mRNA is expressed in a very limited number of germline cells, including the stem cells. Also, mutations in bgcn dominantly enhance a bam mutant phenotype, further corroborating the interdependence of these two genes' functions. On the basis of known functions of DExH-box proteins, we propose that Bgcn and Bam may be involved in regulating translational events that are necessary for activation of the cystoblast differentiation program.
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PMID:The Drosophila cystoblast differentiation factor, benign gonial cell neoplasm, is related to DExH-box proteins and interacts genetically with bag-of-marbles. 1092 76

Intrinsic factor is produced primarily by chief cells in rat and mouse, but 4 to 11% of isolated rat parietal cells also contain intrinsic factor. To test whether local conditions could alter the distribution of intrinsic factor expression, two rodent models of chronic lymphocytic gastric inflammation were examined. Immunocytochemistry was performed using antiserum against human intrinsic factor and H/K ATPase (a parietal cell marker), counting the percent of intrinsic factor-positive parietal cells. HLA-B27 transgenic rats develop chronic gastritis at age 3 months. Congenic controls expressed intrinsic factor in 8.9 +/- 3.8% (mean +/- SD) of parietal cells; in inflamed areas of transgenic rats 21 +/- 5.2% (P < 0.0001) of parietal cells were positive. In adjacent areas without inflammatory infiltrate 16 +/- 3.6% of parietal cells contained intrinsic factor. C57BL/6 mice inoculated with Helicobacter felis develop gastritis by 4 weeks. After 4 and 8 weeks of infection, intrinsic factor-positive parietal cells increased from 7.8 +/- 2.8% in the congenic controls to 17.6 +/- 4.1% in the inflamed gastric body (P < 0.0001). Isolated rat parietal cells incubated with interleukin-1beta demonstrated a twofold increase in intrinsic factor-positive parietal cells. These studies are consistent with the concept that intrinsic factor expression is both predetermined in chief cells and can be expressed in parietal cells in response to local inflammatory factors. The differences between inflamed and adjacent noninflamed areas in the rat model suggest a tissue gradient of soluble inducer(s), possibly cytokines.
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PMID:Expression of intrinsic factor in rat and murine gastric mucosal cell lineages is modified by inflammation. 1102 24

To study in vivo the cellular differentiation and secretion of human developing fetal stomach, ethically and technically impossible to perform in utero, 256 fetal stomachs were xenografted. Human stomachs from 6- to 10-week-old fetuses were grafted for 1-273 days into nude mice. Biopsies for immunohistochemistry, hybridization and electron microscopy were taken and a catheter introduced into the human stomach. Macroscopic growth was fast and cells in S phase were numerous during the first 9 weeks, then the stomach size was stable and the gastric mucosa, of adult type, remained normal. In situ hybridization detected only a minute mouse mesenchymal chimerism in the graft. Chromogranin A, intrinsic factor and H+/K+ adenosine triphosphatase were immunohistolocally detected in epithelial cells 20 days after grafting, gastrin was detected after 30 days and pepsinogen after 60 days. The pH in gastric juice, which was at 8.0 +/- 0.1 from days 10-25, dropped from 4.39 +/- 1.80 at 30 days to 1.58 +/- 0.29 at 90 days. Intrinsic factor was stable and pepsin ranged from 6.8 +/- 7.8 to 134 +/- 51 units at 90 days. The differentiation of the epithelial cells in xenografts was very accelerated in comparison to that in utero.
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PMID:Morphologic and functional development of whole human fetal stomachs grafted into nude mice. 1147 49

Human autoimmune gastritis is an organ-specific autoimmune disease of the stomach. It is characterized by the development of disease-specific autoantibodies and a pathology that specifically targets specialized cells within the gastric environment. The autoantigens associated with this disease have been defined as the gastric H+/K+ ATPase and intrinsic factor. The development of experimental disease models has been pivotal in our contemporary understanding of autoimmunity. Here we review mouse models of autoimmune gastritis and their relevance to human autoimmune gastritis associated with pernicious anemia. We appraise some historical as well as recent studies of experimental autoimmune gastritis (EAG), highlighting key findings that have formed the basis of our current understanding of the etiology and mechanism(s) associated with autoimmune gastritis. A precise understanding of the pathogenesis of autoimmune gastritis will permit the design of innovative and rational therapeutic strategies to prevent, arrest, ameliorate or reverse the disease.
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PMID:Animal models of human disease: experimental autoimmune gastritis--a model for autoimmune gastritis and pernicious anemia. 1178 Oct 67

The earliest recorded history of autoimmune gastritis can be traced to 1849 in London, when Thomas Addison described "a very remarkable form of anemia" later called pernicious (fatal) anemia (PA). This was followed by the recognition of a gastric mucosal defect suspected to have a nutritional basis, the discovery of the megaloblast that characterized the anemia, the insufficiency of a dietary extrinsic factor characterized as vitamin B12 (cobalamin), and a gastric-secreted intrinsic factor. Treatment with vitamin B12 proved curative. The link between PA and gastritis and atrophy was first confirmed histologically after immediate fixation of the stomach postmortem and later, in the 1940s, by peroral tube biopsy. The causes of gastritis remained enigmatic until the era of autoimmunity, when autoantibodies were detected first to gastric intrinsic factor and then to gastric parietal cells. Hints of a dichotomy in pathogenesis of gastritis were crystallized by the description in 1973 of Type A (Autoimmune) and Type B (later, Bacterial) gastritis. Clarification was enhanced by identification in Type A gastritis of the autoantigen of the parietal cell antibody, by the alpha and beta subunits of gastric H+/K+ ATPase, and by the highly informative experimental murine model of postneonatal thymectomy autoimmune gastritis, and in Type B of the causative role of gastric infection with Helicobacter pylori (H. pylori). A denouement will require a full understanding of (1) the origin and pathogenetic contribution of antibody to intrinsic factor; (2) the connection, if any, between H. pylori infection and Type A autoimmune gastritis; and (3) the genetic contributions to gastritis, whether due to autoimmunity or to H. pylori infection.
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PMID:Autoimmune gastritis: historical antecedents, outstanding discoveries, and unresolved problems. 1576 87

Researchers have developed murine lymphopenic, non-lymphopenic, transgenic, spontaneous and infectious agent based models to induce an experimental autoimmune gastritis (EAG) for the study of human organ-specific autoimmune disease. These models result in a chronic inflammatory mononuclear cell infiltrate in the gastric mucosa, destruction of parietal and zymogenic cells with autoantibodies reactive to the gastric parietal cells and the gastric H+/K+ ATPase (ATP4), arguably hallmarks of a human autoimmune gastritis (AIG). In the case of AIG, it is well documented that, in addition to parietal cell antibodies being detected in up to 90% of patients, up to 70% have intrinsic factor antibodies with the later antibodies considered highly specific to patients with pernicious anemia. This is the first report specifically investigating the occurrence of intrinsic factor antibodies, cobalamin deficiency and pernicious anemia in EAG models. We conclude, in contrast to AIG, that, in the three EAG models examined, intrinsic factor is not selected as a critical autoantigen.
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PMID:Murine experimental autoimmune gastritis models refractive to development of intrinsic factor autoantibodies, cobalamin deficiency and pernicious anemia. 1703 94

We have previously reported that a synergistic interaction between hypergastrinemia and Helicobacter felis (H. felis) infection accelerates gastric carcinogenesis in mice, but the precise mechanism for this interaction has not been clarified. Consequently, we undertook an oligonucleotide cDNA microarray study to investigate changes in gene expression in this model system. Male hypergastrinemic transgenic (INS-GAS) mice with 6-months H. felis infection were compared with three different age, strain and gender-matched control groups: (i) INS-GAS mice without H. felis infection; (ii) non-transgenic FVB/N mice with H. felis infection; and (iii) non-transgenic FVB/N mice without H. felis infection. Complementary RNA derived from whole stomach were hybridized to the Affymetrix GeneChip murine U74Av2 array. Among 12 000 cDNA spotted on each chip, 35 cDNA were upregulated and 41 cDNA were downregulated more than twofold in H. felis-infected INS-GAS mice compared with all three control groups. Expression changes were validated in 12 selected genes by northern hybridization and/or quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). Confirmed upregulated genes included Reg I, amphiregulin, MMP-10, MMP-13, claudin-7 and chitinase 3-like 1, while confirmed downregulated genes included H/K-ATPase alpha and beta subunits, intrinsic factor, somatostatin, galectin-2 and apolipoprotein A-I. Immunohistochemical analysis of MMP-10, amphiregulin, H/K-ATPase beta subunit and galectin-2 confirmed these expression changes at the protein level, and MMP-10 was mainly detected in stromal cells of submucosal region, while the other three genes were expressed in gastric epithelial cells. Taken together, gene expression profiling of this mouse model may provide novel insights into Helicobacter-induced gastric carcinogenesis.
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PMID:Gene expression profiling in a mouse model of Helicobacter-induced gastric cancer. 1727 17

Spasmolytic polypeptide (TFF2)-expressing metaplasia (SPEM) is observed in mucosa adjacent to human gastric cancer and in fundic glands showing oxyntic atrophy in Helicobacter felis-infected mice. Mongolian gerbils infected with Helicobacter pylori (Hp) develop goblet cell intestinal metaplasia and adenocarcinoma, but the presence of SPEM has not been studied in gerbils. We therefore have sought to examine the development of metaplastic mucosal changes in Hp-infected Mongolian gerbils. Mongolian gerbils were assigned to either uninfected controls or infected with Hp at 17 weeks of age. The animals were killed at 17, 20, 26, 31, 41 and 56 weeks of age. Stomach sections were stained using antibodies for TFF2, intrinsic factor, H/K-ATPase, BrdU and MUC2. Dual immunofluorescence staining for TFF2 with intrinsic factor and for TFF2 with MUC2 was performed. In uninfected animals, no SPEM or intestinal metaplasia was observed. Infected gerbils developed SPEM initially in the intermediate zone along the lesser curvature and subsequently spread out towards the greater curvature. In the earlier stages of infection, SPEM glands demonstrated TFF2 and intrinsic factor double staining cells. However, after 35 weeks of infection, the number of double staining SPEM cells decreased. While early in infection SPEM organized in straight glands, in the later stages of infections, SPEM glands became distorted or dilated along with the development of gastritis cystica profunda that was TFF2 positive. Goblet cell intestinal metaplasia developed only late in the infection. Dual staining for TFF2 and MUC2 showed glands containing both SPEM- and MUC2-positive goblet cell intestinal metaplasia. SPEM develops early in Hp infection in Mongolian gerbils, and alterations in gland morphology arise from SPEM glands during the course of gastric infection with goblet cell intestinal metaplasia developing subsequent to SPEM.
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PMID:Emergence of spasmolytic polypeptide-expressing metaplasia in Mongolian gerbils infected with Helicobacter pylori. 1800 96


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