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)

Oxidant stress is thought to play a role in the pathogenesis of many gastric disorders. We have recently reported that histidine decarboxylase (HDC) promoter activity is stimulated by gastrin through a protein kinase C- and extracellular signal-regulating kinase (ERK)-dependent pathway in gastric cancer (AGS-B) cells, and this transcriptional response is mediated by a downstream cis-acting element, the gastrin response element (GAS-RE). To study the mechanism through which oxidant stress affects gastric cells, we examined the effects of hydrogen peroxide (H2O2) on HDC promoter activity and intracellular signaling in AGS-B cells. H2O2 (10 mM) specifically activated the HDC promoter 10-12-fold, and this activation was blocked by both mannitol and N-acetylcysteine. Hydrogen peroxide treatment of AGS-B cells increased the phosphorylation and kinase activity of ERK-1 and ERK-2, but did not affect Jun kinase tyrosine phosphorylation or kinase activity. In addition, treatment of AGS-B cells with H2O2 resulted in increased c-fos/c-jun mRNA expression and AP-1 activity, and also led to increased phosphorylation of epidermal growth factor receptor (EGFR) and Shc. H2O2-dependent stimulation of HDC promoter activity was completely inhibited by kinase-deficient ERKs, dominant-negative (N17 and N15) Ras, and dominant-negative Raf, and partially blocked by a dominant-negative EGFR mutant. In contrast, protein kinase C blockade did not inhibit H2O2-dependent induction of the HDC promoter. Finally, deletion analysis demonstrated that the H2O2 response element could be mapped to the GAS-RE (nucleotides 2 to 24) of the basal HDC promoter. Overall, these studies suggest that oxidant stress activates the HDC promoter through the GAS-RE, and through an Ras-, Raf-, and ERK-dependent pathway at least partially involving the EGFR.
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PMID:Oxidative stress activates the human histidine decarboxylase promoter in AGS gastric cancer cells. 972 30

The human histidine decarboxylase gene is regulated by gastrin through a cis-acting element known as the gastrin response element (GAS-RE) that was initially localized to a site (+2 to +24) downstream of the transcriptional start site. Electrophoretic mobility shift assays using sequentially deleted DNA probes and nuclear extracts from AGS-B gastric cancer cells showed that the GAS-RE is actually composed of two overlapping binding sites (GAS-RE1, +1 to +19; and GAS-RE2, +11 to +27) that bind distinct nuclear factors. Reporter gene assays demonstrated that each element alone could confer gastrin responsiveness, but the presence of both elements was required for complete gastrin response. Stimulation of AGS-B cells with gastrin for 10-20 min resulted in a >2-fold increase in factor binding. The binding was inhibited by pretreatment of AGS-B cells with cycloheximide and the MEK1 inhibitor PD98059, indicating a requirement for protein synthesis and also indicating that activation occurs through the MEK/mitogen-activated protein kinase pathway. UV cross-linking and Southwestern blot analysis showed that GAS-RE1 bound a 52-kDa protein, whereas GAS-RE2 bound a 35-kDa protein. Hence, activation of histidine decarboxylase gene promoter activity by gastrin is most likely mediated by two separate nuclear factors.
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PMID:Activation of human histidine decarboxylase gene promoter activity by gastrin is mediated by two distinct nuclear factors. 1040 43

In human gastric cancer cells the human histidine decarboxylase gene is regulated by gastrin through two overlapping cis-acting elements known as gastrin response elements 1&2 (GAS-RE1, GAS-RE2) [J. Biol. Chem. 274 (1999) 20961]. Here, we report the identification and characterization of a third element GAS-RE3 that was localized to a region +28 to +48 downstream of the transcriptional start site (+1). Gastrin stimulation induced a rapid increase in binding to the element of a novel nuclear factor named gastrin response element-binding protein 3 (GAS-REBP3). Block mutations in the GAS-RE3 sequence (+38GTGCG(+42) to +38TAAGT(+42)) led to reduced promoter activity and decreased binding in EMSA. UV cross-linking studies and Southwestern blot analysis with wildtype and mutant GAS-RE3 showed that GAS-REBP3 was a approximately 110kDa protein. Thus, gastrin-mediated regulation of HDC gene expression appears to be mediated by a complex cis-acting element, which binds at least three distinct nuclear factors.
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PMID:Identification and characterization of a third gastrin response element (GAS-RE3) in the human histidine decarboxylase gene promoter. 1237 97

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

Gastrin promotes gastric mucosal growth, and hypergastrinemia induces gastric mucosal hypertrophy. Recently, it has been reported that gastrin induces cyclooxygenase-2 (COX-2) in human gastric and colorectal cancer cell lines. However, whether COX-2 is involved in gastrin-induced gastric mucosal growth in vivo is unknown. We investigated the role of COX-2 in gastrin-induced gastric mucosal hypertrophy using gastrin transgenic mice. Hypergastrinemic mice [mice with mutated gastrin under the control of the beta-actin promoter (ACT-GAS mice)] received the COX-2 inhibitor celecoxib (0, 200, or 500 mg/kg of diet) from 5 wk of age and were killed at 16 or 24 wk. Some ACT-GAS mice received celecoxib from 16 wk and were killed at 24 wk. Eighty-week-old ACT-GAS mice without celecoxib treatment were also examined. The thickness of the gastric mucosa, cell populations, COX-2 expression, and PGE(2) levels were evaluated. All ACT-GAS mice showed gastric mucosal hypertrophy, and four of six 80-wk-old ACT-GAS mice developed gastric cancer. COX-2 was expressed in interstitial cells of the hypertrophic gastric mucosa and gastric cancers. Moreover, PGE(2) levels in the gastric mucosa of ACT-GAS mice were significantly higher than those of normal mice. With treatment with celecoxib, PGE(2) levels, the gastric mucosal thickness, and the number of total gastric cells per gastric gland of ACT-GAS mice were significantly decreased. The decrease in gastric mucosal thickness was caused by a reduction of foveolar hyperplasia. The thickness of glandules and the number of Ki67-positive cells were not significantly changed. In conclusion, COX-2 contributes to gastrin-induced mucosal hypertrophy of the stomach.
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PMID:Involvement of cyclooxygenase-2 in gastric mucosal hypertrophy in gastrin transgenic mice. 1625 46

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

The Swedish variant of moist oral smokeless tobacco (snus) is popular in Sweden and Norway, banned from sale within the European Union and is currently being introduced in USA. The aim of the present study was to determine if snus is carcinogenic to the stomach, particularly in Helicobacter pylori (H.P.)-infected hosts at increased risk for gastric cancer development. Snus (Generaltrade mark; Swedish Match, Sweden) was mixed with powdered standard mouse chow at a concentration of 5-9% (wt/wt) and given to wild-type (WT, FVB) and gastrin transgenic (INS-GAS, FVB) mice for 6 months with or without H.P. (strain 67:21, CagA+, VacA+) infection. At necropsy, pathological evaluation of stomachs from uninfected snus-treated WT mice showed mild morphological changes, whereas 50% snus-treated INS-GAS mice developed carcinoma in situ (CIS), compared with 25% not exposed to snus. When snus was given to H.P.-infected mice, 9 of 17 WT mice developed CIS with intramucosal invasion, and the remaining 8 of 17 WT mice developed high-grade dysplasia (score >1.5) that was associated with increased gastritis, epithelial defects, oxyntic atrophy, hyperplasia and intestinal metaplasia. Twelve of 12 H.P.-infected INS-GAS mice developed CIS with intramucosal invasion and submucosal herniation. We suggest that snus is a potential gastric carcinogen in mice. The development of CIS was associated with increased rates of the epithelial cell proliferation and apoptosis, common features of gastric carcinogenesis.
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PMID:Swedish moist snuff accelerates gastric cancer development in Helicobacter pylori-infected wild-type and gastrin transgenic mice. 1738 11

The gastric pathogen Helicobacter pylori accelerates the progression to gastric cancer but the precise mechanisms that mediate carcinogenesis remain unidentified. We now describe how Helicobacter and gastrin stimulate the expression of a putative growth factor, Reg1, in primary gastric epithelial cells. RT-PCR and Western immunoblotting of human gastric corpus and antrum showed significantly increased Reg1alpha in H. pylori-infected patients. Similarly, Reg1 was increased in the stomachs of H. felis-infected INS-GAS mice. To study transcriptional regulation of the Reg1 gene, we transfected primary mouse gastric glands with -2111 bp and -104 bp Reg1 promoter-luciferase reporter constructs. Expression of both constructs was detected in pepsinogen- and VMAT-2-expressing cells, which corresponds to the normal pattern of expression of human and mouse endogenous Reg1. The expression of both constructs was increased in response to gastrin and H. pylori, and there were potentiating interactions between them; in contrast, only the -2111 bp construct responded to H. felis. Mutation of a C-rich putative regulatory element within the -104 bp sequence abolished the response to gastrin but not to H. pylori whereas mutation of the proximal -98 to -93 region of the promoter reduced the response to H. pylori but not to gastrin. Stimulation of Reg1 by H. pylori required the virulence factor CagA. These data indicate that expression of the putative growth factor Reg1 is controlled through separate promoter elements by gastrin and Helicobacter.
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PMID:Helicobacter and gastrin stimulate Reg1 expression in gastric epithelial cells through distinct promoter elements. 1746 84


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