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A Varro

Publications and source records attributed to A Varro.

At least 37 records · Page 2Linked to original sources
PubMed1999

Modulation of gastrin processing by vesicular monoamine transporter type 1 (VMAT1) in rat gastrin cells.

1. Gastrointestinal endocrine cells produce biogenic amines which are transported into secretory vesicles by one of two proton-amine exchangers, vesicular monoamine transporters type 1 and 2 (VMAT1 and 2). We report here the presence of VMAT1 in rat gastrin (G) cells and the relevance of VMAT1 function for the modulation of progastrin processing by biogenic and dietary amines. 2. In immunocytochemical studies VMAT1, but not VMAT2, was localized to subpopulations of G cells and enterochromaffin (EC) cells; neither was found in antral D cells. The expression of VMAT1 in antral mucosa was confirmed by Northern blot analysis, which revealed an mRNA band of approximately 3.2 kb, and by Western blot analysis, which revealed a major protein of 55 kDa. 3. In pulse-chase labelling experiments, the conversion of the amidated gastrin G34 to G17 was inhibited by biogenic amine precursors (L-DOPA and 5-hydroxytryptophan). This inhibition was stereospecific and sensitive to reserpine (50 nM), which blocks VMAT1 and VMAT2, but resistant to tetrabenazine, which is a selective inhibitor of VMAT2. 4. Dietary amines such as tyramine and tryptamine also inhibited G34 cleavage. This effect was associated with a loss of the electron-dense core of G cell secretory vesicles. It was not stereospecific or reserpine sensitive, but was correlated with hydrophobicity. 5. Thus rat antral G cells can express VMAT1; transport of biogenic amines into secretory vesicles by VMAT1 is associated with inhibition of G34 cleavage, perhaps by raising intravesicular pH. Dietary amines also modulate cleavage of progastrin-derived peptides, but do so by a VMAT1-independent mechanism; they may act as weak bases that passively permeate secretory vesicle membranes and raise intravesicular pH.

Amino Acids↗
PubMed1999

A comparison of an anti-gastrin antibody and cytotoxic drugs in the therapy of human gastric ascites in SCID mice.

The therapeutic effect of antibodies raised by the immunogen Gastrimmune was compared with both a CCKB/gastrin receptor antagonist, CI-988, and 5-Fluorouracil/leucovorin in a gastric cancer model. The human gastric ascites cell line, MGLVA1asc, produced and secreted progastrin and glycine-extended gastrin as determined by radioimmunoassay and immunocytochemistry. Cells were also stained with an antiserum directed against the human CCKB/gastrin receptor. MGLVAI asc cells were injected i.p. into SCID mice. Antibodies raised by Gastrimmune immunization of rabbits (affinity for G17 of 0.15 nM and GlyG17 of 0.47 nM) were passively infused i.p. and significantly enhanced survival by up to 5 days (p=0.0024 from vehicle controls). The enhancement in survival was not significantly different from that achieved by treatment with 5-Fluorouracil and leucovorin. A CCKB/gastrin receptor antagonist, CI-988, did not affect survival with cells injected at 7.5 x 10(5) cells/mouse but significantly increased the survival of mice injected with a lower cell innoculum of 5 x 10(5) cells/mouse from 30 to 35 days (p=0.0186). At this lower innoculum antibodies raised by Gastrimmune induced complete survival in 2 animals with the remaining dead by day 36 (p=0.0022). Thus, both endocrine and autocrine pathways mediated by precursor and mature gastrin molecules may be jointly operational in the gastric cancer scenario and may be important targets for therapeutic agents.

Animals↗
PubMed1999

Mutations of RegIalpha are associated with enterochromaffin-like cell tumor development in patients with hypergastrinemia.

BACKGROUND & AIMS: The RegIalpha gene (Reg) encodes a secretory protein proposed to regulate islet beta-cell and gastric mucous cell growth. Reg is expressed in rat gastric enterochromaffin-like (ECL) cells. The aim of this study was to examine Reg expression in human corpus and to determine the identity of Reg in ECL cell carcinoid tumors in hypergastrinemic patients. METHODS: Reg messenger RNA (mRNA) abundance was quantified by Northern blot in extracts of gastric corpus from patients with and without ECL cell tumors and in AR4-2J cells stimulated by gastrin; cellular origins were determined by immunocytochemistry. Mutations of Reg were determined by reverse-transcription polymerase chain reaction, cloning, and sequencing, and the mutated protein was expressed in HIT-T15 cells. RESULTS: Reg mRNA abundance was increased approximately threefold in the corpus of hypergastrinemic patients compared with controls, and was enriched in 3 of 7 ECL cell carcinoid tumors but not in non-endocrine cell gastric polyps. In AR4-2J cells, gastrin stimulated Reg mRNA abundance; this was eliminated by the gastrin/cholecystokinin B antagonist L-740,093 (10(-9) mol/L). Immunocytochemistry indicated that Reg was located in both chief cells and ECL cells in human corpus. Mutations of Reg were identified in 3 of 5 patients with ECL cell carcinoid tumors; in 2 cases, mutation of the initiator methionine residue led to exclusion of the protein from the secretory pathway. CONCLUSIONS: Gastrin regulates Reg mRNA abundance in human corpus. Mutations of Reg that prevent secretion are associated with ECL cell carcinoids, suggesting a function as an autocrine or paracrine tumor suppressor.

Adult↗
PubMed1999

Expression and processing of gastrin in hepatocellular carcinoma, fibrolamellar carcinoma and cholangiocarcinoma.

BACKGROUND/AIMS: Gastrin is a trophic factor within the normal gastrointestinal tract and is also a mitogen for a number of gastrointestinal and non-gastrointestinal tumours. Precursor forms of gastrin including progastrin (proG) and glycine-extended gastrin (G-gly) as well as the fully processed amidated gastrin (G-NH2) are expressed by tumours. There has been little study of the role of gastrin in either normal liver or liver tumours. The aim of this study was to identify the expression of CCK-B/gastrin receptor (CCK-BR), proG, G-gly and G-NH2 in normal liver and liver tumours. METHODS: Tissue sections from patients with hepatocellular carcinoma, fibrolamellar carcinoma, cholangiocarcinoma as well as normal liver biopsies were assessed for expression of CCK-BR and gastrin isoforms. RESULTS: Most liver tumours express CCK-BR and are able to process gastrin as far as proG and G-gly, although not as far as the amidated form. There appears to be little expression of the receptor and no expression of precursor forms of gastrin in normal liver. CONCLUSIONS: Liver tumours express the CCK-BR and precursor forms of gastrin. This expression may be associated with tumour proliferation.

Bile Duct Neoplasms↗
PubMed1999

Antibodies raised by gastrimmune inhibit the spontaneous metastasis of a human colorectal tumour, AP5LV.

Both precursor forms of gastrin and mature amidated gastrin peptides can enhance proliferation of colorectal tumours and may regulate growth in an autocrine manner. The purpose of this study was to evaluate the effect of neutralization of precursor and amidated gastrin on primary and secondary in vivo growth of a human colorectal tumour. The human colorectal cell line, AP5LV, when injected into the muscle layer of the abdominal wall of severe combined immunodeficient (SCID) mice, grows as a well-vascularized primary tumour and metastasis to the lung. AP5LV expressed the precursor gastrin forms; progastrin and glycine-extended gastrin and gastrin/CCKB receptors, as assessed by immunocytochemistry. Gastrimmune is a gastrin immunogen in which the amino terminus of the gastrin-17 molecule is linked to diphtheria toxoid and induces antibodies which neutralise the amidated and glycine-extended forms of gastrin-17. Rabbit antiserum, raised against Gastrimmune, was administered intravenously into SCID mice bearing AP5LV tumours. Control animals were treated with antiserum raised against diphtheria toxoid only. Antibodies raised against Gastrimmune significantly limited the growth of primary AP5LV tumours, as assessed by median cross-sectional area (controls = 244 mm2; antibody-treated = 179 mm2; P = 0.033). In addition Gastrimmune-induced antiserum limited the growth of lung metastasis as assessed by nodule number (controls = 3.5; antibody-treated = 1.0; P = 0.0001) and nodule cross-sectional as assessed by image analysis (controls = 11.9 mm2; antibody-treated = 3.75 mm2; P = 0.0064). In conclusion in vivo neutralization of gastrin forms, which may potentially be fueling growth by an autocrine pathway, inhibited both primary growth and, to a greater degree, lung metastasis of a human colorectal tumour cell line. Immunization against tumour-associated gastrin forms may provide an effective therapy for advanced colorectal cancer.

Animals↗
PubMed1999

A comparison of the therapeutic effectiveness of gastrin neutralisation in two human gastric cancer models: relation to endocrine and autocrine/paracrine gastrin mediated growth.

BACKGROUND: Gastrin is a growth factor for established tumours. AIMS: To investigate the therapeutic effect of antibodies, raised against the Gastrimmune immunogen, which neutralise the glycine extended and carboxy amidated forms of gastrin 17 in two human gastric cancer models. METHODS: MGLVA1 cells (which have a gastrin autocrine/paracrine phenotype) and ST16 cells (which have an endocrine phenotype) were injected into the peritoneal cavity of SCID mice. Peritoneal tumours, ascites, and cachexia formation occurred, with the monitored endpoint being morbidity. RESULTS: In MGLVA1 cells, intravenous administration of antibodies raised against Gastrimmune increased the 50% median survived by 25% at three different initial cell seeding concentrations (1 x 10(6)-5 x 10(5) per mouse). In ST16 cells, the effect of Gastrimmune induced antibodies on time to morbidity was greatest at the lowest cell seeding concentration (5 x 10(5) cells/mouse) with the 50% median survival increased by 74% and overall survival achieved in 38% of the mice. CONCLUSIONS: Gastrimmune may have potential therapeutic benefit on gastrin sensitive gastric tumours and may interact with both endocrine and autocrine mediated growth pathways.

Animals↗
PubMed1999

Overexpression of glycine-extended gastrin in transgenic mice results in increased colonic proliferation.

Gastrin is a peptide hormone involved in the growth of both normal and malignant gastrointestinal tissue. Recent studies suggest that the glycine-extended biosynthetic intermediates mediate many of these trophic effects, but the in vivo relevance of glycine-extended gastrin (G-Gly) has not been tested. We have generated mice (MTI/G-GLY) that overexpress progastrin truncated at glycine-72 to evaluate the trophic effects of G-Gly in an in vivo model. MTI/G-GLY mice have elevated serum and colonic mucosal levels of G-Gly compared with wild-type mice. MTI/G-GLY mice had a 43% increase in colonic mucosal thickness and a 41% increase in the percentage of goblet cells per crypt. MTI/G-GLY mice exhibited increased colonic proliferation compared with wild-type controls, with an expansion of the proliferative zone into the upper third of the colonic crypts. Continuous infusion of G-Gly into gastrin-deficient mice for two weeks also resulted in elevated G-Gly levels, a 10% increase in colonic mucosal thickness, and an 81% increase in colonic proliferation when compared with gastrin-deficient mice that received saline alone. To our knowledge, these studies demonstrate for the first time that G-Gly's contribute to colonic mucosal proliferation in vivo.

Animals↗
PubMed1998

Expression of CCKB/gastrin receptor isoforms in gastro-intestinal tumour cells.

Anti-serum raised against the human cholecystokinin B (CCKB)/gastrin receptor was used in Western blotting to differentiate the cellular locations of receptor isoforms expressed by human gastro-intestinal (GI) tumour cell lines. Using anti-serum directed against the amino-terminal extracellular tail of the CCKB/gastrin receptor, 8/9 cell lines were shown to express immunoreactive proteins of either m.w. 70 or 40 kDa, or both. Both isoforms were found to be associated with intracellular, non-nuclear membranes, whereas only the 70 kDa protein was expressed in the plasma membrane. Receptor expression was related to gastrin production and secretion. Both progastrin and glycine-extended gastrin-17 were produced and secreted by the tumour cell lines; however, carboxy amidated gastrin was not detected by radioimmunoassay. A CCKB/gastrin receptor transfectant NIH3T3 cell line did not produce detectable gastrin and showed exclusive expression of the 70 kDa receptor on the plasma membrane. One cell line had <50 pg/ml cell-associated progastrin and no detectable receptor form. Cell lines expressing 50-150 pg/ml had both 40 and 70 kDa receptor forms. Those expressing >150 pg/ml progastrin had only the 40 kDa isoform, which was shown to be exclusively expressed on intracellular, non-nuclear membranes, in one of the cell lines. Of the 4 cell lines exclusively expressing the lower m.w. receptor, 3 had gastrin present within the cell, which was not secreted. Thus, if cell-associated gastrin induces a proliferative effect, it may be by an intracrine pathway. Our study has identified the presence of CCKB/gastrin receptor isoforms in different cellular locations and may help toward understanding the complex autocrine and intracrine pathways mediated by gastrin peptides.

3T3 Cells↗
PubMed1998

Modulation of the cleavage of the gastrin precursor by prohormone phosphorylation.

BACKGROUND & AIMS: Amidated gastrins are acid secretagogues and growth factors. Their precursor, progastrin, is a growth factor but not a secretagogue. Cleavage of progastrin at Arg94/95 determines the expression of these two alternative patterns of biological activity. We examined the hypothesis that cleavage at Arg94/95 is regulated by phosphorylation of the adjacent Ser96 residue. METHODS: Hamster insulinoma cells were stably transfected with wild-type rat preprogastrin and phosphorylation site mutants; biosynthesis was studied by a pulse-chase protocol. RESULTS: Rates of cleavage at Arg94/95 were increased in Ser96-->Ala compared with wild-type progastrin. Mutation of Glu98 to Ala inhibited incorporation of [32P]phosphate into progastrin and increased the rate of cleavage at Arg94/95. Conversely, mutation of Ser96 to Asp reduced rates of cleavage at Arg94/95. Depletion of calcium stores decreased phosphorylation of Ser96 and increased cleavage at Arg94/95. Modulation of Ser96 phosphorylation also directly influenced the ratio of progastrin-cleavage products (progastrin/CFP; G17Gly/G34Gly) secreted into the medium. CONCLUSIONS: Phosphorylation of progastrin is dependent on calcium stores, determines prohormone cleavage rates, and thereby controls the production of the alternative active products of preprogastrin translation.

Amino Acid Sequence↗
PubMed1998

Octreotide suppression test predicts beneficial outcome from antrectomy in a patient with gastric carcinoid tumor.

Multiple gastric carcinoids are a well-recognized complication of hypergastrinemia associated with chronic atrophic gastritis. However, the management of large tumors (>2 cm in diameter) remains uncertain, with the decision between antrectomy or total gastrectomy being empirical. This report describes the investigation of a patient with chronic atrophic gastritis and multiple large gastric carcinoid tumors. Before surgery, octreotide was infused for 72 hours to suppress enterochromaffin-like (ECL) cell and gastrin cell function. The infusion decreased plasma gastrin and gastrin synthesis; moreover, there were marked reductions in markers of ECL cell function, e.g., histidine decarboxylase and chromogranin A messenger RNA abundance, in carcinoid tumor tissue and macroscopically normal corpus mucosa. An antrectomy was performed, after which the patient made an uneventful recovery. Six months after surgery, a single residual polyp, enriched with smooth muscle cells but not ECL cells, was removed. One year after antrectomy, the remaining stomach was normal. The response of ECL cell markers in carcinoid tissue to octreotide suggested that these cells were under neuroendocrine control and, therefore, predicted a beneficial outcome for antrectomy. It is suggested that an octreotide supression test coupled with assay of histidine decarboxylase or chromogranin A gene expression is useful in the assessment of gastric carcinoid tumors.

Adult↗
PubMed1998

Gastric carcinoid expresses the gastrin autocrine pathway.

BACKGROUND: In gastric adenocarcinoma the gastrin autocrine-paracrine pathway is activated. As enterochromaffin-like (ECL) cells originate from the same stem as epithelial cells, the aim of this study was to determine if the gastrin autocrine pathway is present in gastric carcinoid. METHODS: Samples from ten patients with gastric carcinoid were assessed by immunocytochemistry using primary antibodies directed against gastrin precursors and the gastrin/cholecystokinin B receptor and detected using the avidin-biotin immunoperoxidase system. RESULTS: A high level of expression of precursor and mature gastrin peptides, together with the gastrin receptor, was seen in all carcinoids screened. CONCLUSION: In common with the glandular epithelium of the stomach the gastrin gene is activated during the neoplastic process in ECL cells. This finding may explain why some carcinoids do not regress after surgical procedures that lower serum gastrin. Antigastrin agents may be a useful treatment for carcinoid either in their own right or as an adjunct to surgery.

Adult↗
PubMed1997

Regulation by gastric acid of the processing of progastrin-derived peptides in rat antral mucosa.

1. Inhibition of gastric acid secretion by proton pump inhibitors like omeprazole increases the synthesis and secretion of the pyloric antral hormone gastrin. We report here how omeprazole influences the conversion of the gastrin precursor to its final products, and the abundance of mRNAs encoding proteins associated with progastrin processing in rat antral mucosa. 2. Progastrin processing was studied using a pulse-chase protocol in antral mucosa, incubated in vitro, from rats treated with omeprazole for up to 5 days. Labelled peptides were detected by on-line scintillation counting after immunoprecipitation and HPLC. The mRNAs encoding prohormone-processing enzymes were identified by Northern blot, polymerase chain reaction or ribonuclease protection assay, and their cellular origins identified by immunocytochemistry. 3. Cleavage of [3H]- and [35S]-labelled progastrins at Arg-94-95 or Arg-57-58, and amidation at Phe-92 were not influenced by pretreatment with omeprazole. In contrast, cleavage of G34 (the thirty-four amino acid amidated gastrin) at Lys-74-75 to give G17 (the seventeen amino acid amidated gastrin), and of G34-Gly to G17-Gly (G34 and G17 with COOH-terminal glycine), was increased 3-fold after treatment with omeprazole for either 1 or 5 days. 4. Approximately 20% of newly synthesized amidated and Gly-extended gastrins were secreted within 240 min of the labelling period in omeprazole-treated samples, but secretion of labelled gastrins from control tissue was undetectable over a comparable period. 5. The amidating enzyme, peptidyglycine alpha-amidating mono-oxygenase (PAM), the prohormone convertases PC1/3, PC2, PC5 and the PC2 chaperone 7B2 were localized to rat antral gastrin cells by immunocytochemistry. The relative abundance of mRNA species encoding 7B2, PC5 and PAM were unchanged after treatment with omeprazole for 5 days, whereas gastrin, PC1/3 and PC2 mRNAs are known to increase at this time. 6. The main consequence of increased cleavage at Lys-74-75 is the production of G17 and G17-Gly at the expense of G34 and G34-Gly, respectively. The latter have longer plasma half-lives, and so their increased cleavage may serve to limit the rise in plasma gastrin concentration after inhibition of acid secretion. Changes in the abundance of mRNAs encoding prohormone-processing enzymes cannot account for the rapidity of the changes in cleavage of progastrin at Lys residues after omeprazole.

Animals↗
PubMed1997

Amine precursor uptake and decarboxylation: significance for processing of the rat gastrin precursor.

1. Conversion of prohormone precursors to smaller active products occurs in secretory granules, which also have the capacity to concentrate biogenic amines. We have examined how processing of the gastrin precursor, progastrin, in rat antral mucosa is influenced by modulation of the biogenic amine content of secretory granules. 2. Newly synthesized progastrin-derived peptides in rat antral mucosa were labelled in vitro with 35SO4(2-) using a pulse-chase protocol and detected after immunoprecipitation by HPLC with on-line liquid scintillation counting. Secretory granule morphology was examined by electron microscopy. The effects of experimentally manipulating secretory granule pH and amine content were examined. 3. The dopamine precursor L-beta-3,4-dihydroxyphenylalanine (L-DOPA) inhibited cleavage of 35S-labelled thirty-four amino acid amidated gastrin, i.e. [35S]G34, and of [35S]G34 with COOH-terminal glycine, i.e. [35S]G34-Gly, at a pair of lysine residues, but did not influence cleavage of progastrin at pairs of arginine residues. The effect of L-DOPA was reversed by reserpine, which inhibits the amine-proton exchangers VMAT1 and VMAT2, and by carbidopa, which inhibits aromatic L-amino acid decarboxylase. 4. Treatments that raise intragranular pH, e.g. the weak base chloroquine, the ionophore monensin and the vacuolar proton pump inhibitor bafilomycin A1, had similar effects to L-DOPA. 5. Electron microscopical studies showed that the electron-dense aggregrates in gastrin cell secretory granules were lost after inhibition of the vacuolar proton pump. Treatment with L-DOPA produced reserpine-sensitive dissipation of the electron-dense aggregates, compatible with the idea that increased amine delivery raised intragranular pH. 6. The data suggest that the processes of amine precursor uptake, decarboxylation and sequestration in secretory granules are associated with selective modulation of progastrin cleavage, possibly by raising intragranular pH and thereby inhibiting pH-sensitive prohormone convertases.

Adrenergic Uptake Inhibitors↗
PubMed1997

Phosphorylation of gastrin-related peptides: physiological casein kinase like enzyme in Golgi membranes from bovine adrenal chromaffin cells and GH3 cells.

Prohormones such as the gastrin precursor can be phosphorylated at Ser residues, on passage along the secretory pathway. The phosphorylation site occurs in a sequence (-Ser-Ala-Glu-) that suggests these peptides are substrates for physiological casein kinase, but the presence of this enzyme in endocrine cells is unknown. We have examined the specificity of Golgi membrane kinases from lactating rat mammary gland, bovine adrenal medulla and the GH3 cell line, for phosphorylation of progastrin fragments and analogues. The kinetics of phosphorylation of peptides with the native sequence, -Arg-Arg-Ser-Ala-Glu- were similar to those of tryptic cleavage fragments (Ser-Ala-Glu-) in both mammary and endocrine cell preparations. The product of in vitro phosphorylation was chromatographically indistinguishable from native peptide. Peptides with the sequence Ser-Ala-Ala (i.e., substitution of Glu to Ala) were not phosphorylated. We conclude that a physiological casein kinase like enzyme can act on both the gastrin precursor and its COOH-terminal cleavage product, and occurs in the Golgi complex of both mammary gland and peptide-producing endocrine cells.

Adenosine Triphosphate↗
PubMed1997

Gastrin deficiency results in altered gastric differentiation and decreased colonic proliferation in mice.

BACKGROUND & AIMS: Gastrin is a peptide hormone important in the regulation of both acid secretion and differentiation of oxyntic mucosal cells of the stomach. To further elucidate the role of gastrin in the growth and development of the gastrointestinal tract, we have generated mice that are deficient in gastrin. METHODS: Gastrin-deficient mice were generated through targeted gene disruption. Gastric and colonic architecture were determined by routine histology and immunohistochemical techniques. Proliferation was assessed by 5-bromo-2'-deoxyuridine incorporation. RESULTS: Targeted disruption of the gastrin gene resulted in mice incapable of expressing gastrin messenger RNA (mRNA) or producing gastrin peptide. This deficiency led to a marked change in gastric architecture, with a decrease in number of parietal and enterochromaffin-like cells and an increase in number of mucous neck cells. There was no difference in the proliferation labeling index of the stomach in gastrin-deficient mice (3.04% +/- 0.33%) compared with wild-type littermates (3.15% +/- 0.18%). The colon of gastrin-deficient mice seemed normal histologically, although there was a decreased proliferation labeling index (2.97% +/- 0.52%) compared with wild-type littermates (4.71% +/- 0.44%; P < 0.01). CONCLUSIONS: Gastrin is important in regulating the differentiation of the gastric mucosa and is a trophic factor for the colonic mucosa.

Animals↗
PubMed1997

Gastrin biosynthesis in the antrum of patients with pernicious anemia.

BACKGROUND & AIMS: The gastrin precursor progastrin produces multiple alternative active products, but the pathways of posttranslational processing in human antral mucosa have not yet been studied directly. The aim of this study was to investigate the biosynthetic relationships and release kinetics of newly synthesized progastrin-derived peptides in the antrum of patients with pernicious anemia. METHODS: Antral mucosal explants were incubated with [35S]sulfate and [3H]tyrosine to label progastrin and its derivatives, which were detected by online scintillation counting after immunoprecipitation and high-performance liquid chromatography. RESULTS: [35S]- and [3H]progastrin were detected within 2.5 hours, and labeled G34Gly and G34 were readily detected after 5-hour incubation. Pulse-chase studies indicated conversion of progastrin to G17 via G34Gly and G34. Secretion of newly synthesized G34, but not G34Gly, was routinely detected; G17Gly was present only in trace quantities in cell extracts and media. In control samples, progastrin synthesis was about 10 times lower than in pernicious anemia samples, although the proportions of different labeled amidated gastrins after 5-hour incubation were similar. CONCLUSIONS: In the antrum of patients with pernicious anemia, Gly-gastrins, particularly G34Gly, are biosynthetic intermediates and not major secretory products. Some G34 is secreted preferentially under basal conditions.

Aged↗
PubMed1996

Processing and proliferative effects of human progastrin in transgenic mice.

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.

Animals↗