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:4.2.3.23 (GAS)
957 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The gastrin gene is expressed in fetal pancreatic islet cells, but in the adult is expressed mainly in the gastric antrum. To study the regulation of the gastrin promoter, we created several transgenes containing the human and rat gastrin 5' flanking regions joined to the coding sequences of the human gastrin gene. The human gastrin transgene contained 1,300 bp of 5' flanking DNA, while the rat gastrin transgene contained 450 bp of 5' flanking DNA. The human gastrin transgene was expressed in fetal islets, but was not expressed in adult gastric antrum. In contrast, the rat gastrin transgene was expressed in adult antral G cells, but no expression was observed in fetal islets. To study the possible role of gastrin as an islet growth factor, a chimeric insulin-gastrin (INS-GAS) transgene was created, in which the expression of the human gastrin gene is driven from the rat insulin I promoter. These INS-GAS mice were mated with mice overexpressing TGF alpha, transcribed from a mouse metallothionein-transforming growth factor alpha (MT-TGF alpha) transgene. While overexpression of gastrin or TGF alpha alone had no effect on islet mass, overexpression of both transgenes resulted in a twofold increase in islet mass. In conclusion, these data indicate that (1) gastrin can interact synergistically with TGF alpha to stimulate islet growth; (2) the human gastrin transgene contains the islet specific enhancer; (3) the rat gastrin transgene contains the antral specific enhancer.
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PMID:Function and regulation of gastrin in transgenic mice: a review. 134 Oct 73

Incompletely processed gastrins have been postulated to play a role in growth of the gastrointestinal tract, but few studies have examined the effects of progastrin on mucosal proliferation in vivo. Human gastrin gene expression and progastrin processing were therefore studied in transgenic mice containing a human gastrin (hGAS) minigene, and compared to processing in mice bearing an insulin gastrin (INS-GAS) transgene that overexpresses amidated gastrin. Progastrin processing was studied using region-specific antisera and radioimmunoassays, biosynthetic labeling, immunoprecipitation, and HPLC. Proliferative effects due to overexpression of processed and unprocessed gastrin in INS-GAS and hGAS mice, respectively, were determined using routine histology and BrdU incorporation. The pancreatic islets of INS-GAS mice were able to produce carboxyamidated G-17, resulting in a twofold elevation of serum amidated gastrin, marked thickening of the oxyntic mucosa, and an increased BrdU labeling index (LI) of the gastric body. In contrast, livers of adult hGAS mice expressed abundant human gastrin mRNA and human progastrin but were unable to process this peptide to the mature amidated form, resulting in markedly elevated serum progastrin levels and normal amidated gastrin levels. Nevertheless, there was a marked increase in the BrdU labeling index of the colon in hGAS mice (LI 7.46+/-1.90%), as well as in INS-GAS mice (LI 6.16+/-1.17%), compared to age-matched, wild type control mice (LI 4.01+/-0.98%, P < 0.05). These studies suggest that incompletely processed gastrin precursors may contribute to colonic mucosal proliferation in vivo.
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PMID:Processing and proliferative effects of human progastrin in transgenic mice. 887 44

STAT proteins are important transcription factors that regulate cell growth and differentiation. To elucidate the molecular mechanisms of insulin actions, we have studied how insulin activates STAT proteins in Hep3B cells. Insulin rapidly phosphorylated Stat1alpha at tyrosine residues and increased its specific binding activities to a GAS/ISRE consensus oligonucleotide. IL-4 also phosphorylated Stat1alpha and increased DNA binding activities to the same Stat1alpha responsive element. There was no increase in tyrosine phosphorylation of JAK family of kinases following insulin stimulation. In contrast, IL-4 stimulated tyrosine phosphorylation of JAK1, JAK2 and tyk2 in this cell line. These data indicate that insulin receptor signaling can activate the transcriptional regulatory function of STAT protein, and that insulin actions on Stat1alpha are mediated through signaling pathways independent of JAK family of kinases.
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PMID:Novel pathway of insulin signaling involving Stat1alpha in Hep3B cells. 919 89

Gaseous CO2 was used as an antisolvent to induce the fractional precipitation of alkaline phosphatase, insulin, lysozyme, ribonuclease, trypsin, and their mixtures from dimethylsulfoxide (DMSO). Compressed CO2 was added continuously and isothermally to stationary DMSO solutions (gaseous antisolvent, GAS). Dissolution of CO2 was accompanied by a pronounced, pressure-dependent volumetric expansion of DMSO and a consequent reduction in solvent strength of DMSO towards dissolved proteins. View cell experiments were conducted to determine the pressures at which various proteins precipitate from DMSO. The solubility of each protein in CO2-expanded DMSO was different, illustrating the potential to separate and purify proteins using gaseous antisolvents. Polyacrylamide gel electrophoresis in sodium dodecyl sulfate (SDS-PAGE) was used to quantify the separation of lysozyme from ribonuclease, alkaline phosphatase from insulin, and trypsin from catalase. Lysozyme biological activity assays were also performed to determine the composition of precipitates from DMSO initially containing lysozyme and ribonuclease. SDS-PAGE characterizations suggest that the composition and purity of solid-phase precipitated from a solution containing multiple proteins may be accurately controlled through the antisolvent's pressure. Insulin, lysozyme, ribonuclease, and trypsin precipitates recovered substantial amounts of biological activity upon redissolution in aqueous media. Alkaline phosphatase, however, was irreversibly denaturated. Vapor-phase antisolvents, which are easily separated and recovered from proteins and liquid solvents upon depressurization, appear to be a reliable and effective means of selectively precipitating proteins.
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PMID:Protein purification with vapor-phase carbon dioxide. 1009 36

Recent studies show that nonamidated gastrins (Gly-gastrin and progastrin) stimulate colonic proliferation. However, the role of nonamidated vs. amidated gastrins in colon carcinogenesis has not been defined. We measured intermediate markers of carcinogenesis in transgenic mice overexpressing either progastrin (hGAS) or amidated gastrin (INS-GAS) in response to azoxymethane (AOM). The hGAS mice showed significantly higher numbers of aberrant crypt foci (140-200% increase) compared with that in wild-type (WT) and INS-GAS mice (P < 0.05) after AOM treatment. The bromodeoxyuridine-labeling index of colonic crypts also was significantly elevated in hGAS mice vs. that in WT and INS-GAS mice. The results therefore provide evidence for a mitogenic and cocarcinogenic role of nonamidated gastrins (progastrin), which is apparently not shared by the amidated gastrins. Although nonamidated gastrins are now believed to mediate mitogenic effects via novel receptors, amidated gastrins mediate biological effects via different receptor subtypes, which may explain the difference in the cocarcinogenic potential of nonamidated vs. amidated gastrins. In conclusion, our results provide strong support for a cocarcinogenic role for nonamidated gastrins in colon carcinogenesis.
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PMID:Mice overexpressing progastrin are predisposed for developing aberrant colonic crypt foci in response to AOM. 1071 58

Previous studies from our group have shown that hypergastrinemia in mice can synergize with Helicobacter felis infection to induce gastric carcinoma. In addition, epidemiological evidence and a recent study with C57BL/6 mice have strongly suggested a link between a high-salt diet during Helicobacter pylori infection and the development of hypergastrinemia and preneoplastic gastric lesions. To address the possible relationship between the two cofactors (gastrin and salt) and whether H. pylori can also lead to gastric cancer in this model, we undertook a longitudinal study involving 86 INS-GAS mice. The mice were fed either a high-salt (7.5%) or basal (0.25%) diet, and half were infected with H. pylori. Necropsies at 5 and 7 months postinfection included histopathological examination, quantitative culturing for bacterial colonization levels, and serology to estimate the magnitude of the Th1 and Th2 systemic inflammatory responses. Lesions consistent with in situ and intramucosal carcinoma were seen in H. pylori-infected male mice only. There was a highly significant main effect for Helicobacter infection status for all fundic and antral lesion parameters (P < 0.0001), as well as significant interactions of infection status with diet for all of the fundic parameters (all P < 0.03), except intestinal metaplasia. In subsequent ANOVAs in which the data were limited to that from infected animals, there was a highly significant main effect for time, diet, and gender (all P < 0.02) on all of the corpus lesion parameters scored (inflammation, atrophy, hyperplasia, metaplasia, and dysplasia/neoplasia). In addition, gender interacted significantly with time (all P < 0.03), and. H. pylori colonization increased quantitatively over the course of the experiment but were independent of either diet or gender. The Th1-associated serum IgG2a responses to H. pylori increased from the time of experimental infection to necropsy at 5 or 7 months and were similar among all experimentally infected mice with no influence of gender (P > 0.10) or dietary salt (P > 0.27). In contrast, the Th2-associated serum IgG1 response to H. pylori was significantly increased in infected male INS-GAS mice on the high-salt diet at 7 months postinfection (P < 0.012). These results show that H. pylori can also accelerate the development of gastric cancer in the INS-GAS mouse model, and the results suggest that salt has less of a procarcinogenic effect in the setting of endogenous hypergastrinemia. The increased Th2-associated humoral response of the infected male mice on the high-salt diet correlated with less severe gastric lesions. In the INS-GAS mouse model, male gastric tissue responded more rapidly and aggressively to H. pylori infection, high-salt diet, and the combination when compared with females; a finding that appears consistent with the greater incidence of gastric carcinoma in men. This study highlights the importance of using both genders to investigate the pathogenesis of H. pylori.
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PMID:Helicobacter pylori-associated gastric cancer in INS-GAS mice is gender specific. 1261 7

Gastric cancer is the second most common cause of cancer-related mortality world-wide. In most cases, it develops via the pre-malignant stages of atrophic gastritis, intestinal metaplasia and dysplasia, following Helicobacter pylori infection of susceptible individuals. A number of rodent models have recently provided valuable insights into the host, bacterial and environmental factors involved in gastric carcinogenesis. Wild-type rodents do not develop gastric adenocarcinoma, but early studies showed that the disease could be induced in several rodent species by chemical carcinogens. More recently, it has been demonstrated that gastric adenocarcinoma can be induced in Mongolian gerbils by H. pylori infection and in C57BL/6 mice by long-term H. felis infection. These models have allowed the importance of Helicobacter virulence genes, host factors, such as gender, strain and immune response, and environmental factors, such as dietary salt, to be explored. A number of transgenic mice with alterations in various pathways, including the immune response, gastrin biosynthesis, parietal cell development, growth factors and tumour suppressors, have also provided models of various stages of gastric carcinogenesis. One model that has proved to be particularly valuable is the hypergastrinaemic INS-GAS mouse, in which gastric carcinoma develops spontaneously in old animals, but the process is greatly accelerated by Helicobacter infection.
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PMID:Review article: How useful are the rodent animal models of gastric adenocarcinoma? 1508 Aug 46

Recently we have reported synergistic effects between glycine-extended gastrin (G-gly) and amidated gastrin-17 on acid secretion in short-term infusion studies. In the present study, we examined the long-term effect of G-gly on the atrophy-promoting effects of amidated gastrin in the mouse stomach with or without Helicobacter infection. Transgenic mice overexpressing amidated gastrin (INS-GAS mice), G-gly (MTI/G-gly mice), and both peptides (INS-GAS/G-gly mice) were used for assessment of acid secretion and ulcer susceptibility and histologic examination and scoring of preneoplastic lesions in response to the 3 and 6 months Helicobacter felis (H. felis) infection. We found that MTI/G-gly mice had normal gastric histology and acid secretion. Double transgenic (INS-GAS/G-gly) mice showed 2-fold increases in acid secretion compared with INS-GAS mice. Acute peptic ulcers after pyloric ligation were noted in 50% of the INS-GAS/G-gly mice but in none of the INS-GAS mice at 6 months of age. Whereas male INS-GAS mice had a >50% decrease in the numbers of parietal cell and enterochromaffin-like cell at 6 months of age, the male double transgenic mice had no such decrease. Overexpression of G-gly reduced the scores of preneoplasia in the stomach; however, it did not prevent the development of amidated gastrin-dependent gastric cancer in both H. felis-infected mice and uninfected mice. We conclude that G-gly synergizes with amidated gastrin to stimulate acid secretion and inhibits parietal cell loss in INS-GAS/G-gly mice. The overexpression of G-gly seems to increase the susceptibility to peptic ulcer disease and delay the development of Helicobacter-mediated gastric preneoplasia in this model.
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PMID:Overexpression of glycine-extended gastrin inhibits parietal cell loss and atrophy in the mouse stomach. 1554 80

Hypergastrinemia in INS-GAS mice leads to accelerated carcinogenesis of the stomach, but the mechanisms have not been well defined. We investigated the possible role of gastrin-induced gastric cell apoptosis in the development of gastric cancer. We examined apoptosis and the expression of Bcl-2 family proteins in INS-GAS mice of different ages, as well as in gastrin-deficient (GAS-KO) mice after gastrin-17 (G-17) infusion. In addition, we studied the effects of the gastrin/cholecystokinin-2 (CCK-2) receptor antagonist YF476 and/or histamine H2 (H-2) receptor antagonist loxtidine on apoptosis and atrophy in INS-GAS mice with or without Helicobacter felis (H. felis) infection. INS-GAS mice had age-associated increases in Bax protein expression and decreases in Bcl-2 protein expression, along with increased glandular and epithelial cell apoptosis. At 8-week gastrin infusions in GAS-KO mice resulted in a similar pattern of altered Bax and Bcl-2 expression, followed by gastric cell apoptosis. H. felis infection of INS-GAS mice led to increased apoptosis and the development of atrophy, whereas treatment with either YF476 and/or loxtidine strongly inhibited both apoptosis and atrophy. In vitro studies with Fas-expressing RGM1 cells showed that gastrin stimulation alone directly induced apoptosis via gastrin/CCK-2 receptor and synergized with FasL stimulation. These results indicate that gastrin can induce apoptosis in gastric epithelial cells and contribute to the development of gastric carcinogenesis.
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PMID:Gastrin-induced apoptosis contributes to carcinogenesis in the stomach. 1689 54

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


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