Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01350 (gastrin)
 9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycine (Gly)-extended gastrin has been described as the inactive precursor form of the biologically active amidated gastrin. The ratio of Gly-extended to amidated gastrin is higher in the circulation than in tissue, suggesting either differential secretion and/or metabolism. Although the distribution of the precursor form is similar in tissue and circulation to its amidated product, the significance of measurable levels of precursor peptide in the circulation is unknown. In this study, we have examined the pharmacokinetic properties and organ-specific metabolism of both the Gly-extended and the amidated forms of gastrin-17 (G-17-Gly and G-17-amide) in the conscious sheep. The metabolic clearance rate, half disappearance time, and production rates were similar for both G-17-Gly and G-17-amide. G-17-Gly was extracted across the head, kidney, and lung but not across the gut and liver. Similarly, G-17-amide was extracted across the head, gut, lung, and kidney but not across the liver. G-17-Gly had no biological activity as evidenced by its failure to stimulate somatostatin secretion nor was there any measurable conversion to amidated gastrin in the circulation. We conclude that the presence of G-17-Gly in the circulation is not the result of a slower clearance and that circulating G-17-Gly is not a precursor for circulating gastrin-amide. The results of this study provide important baseline data for understanding the dynamics of the precursor product relationship between G-Gly and G-amide.
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PMID:Pharmacokinetics and organ specific metabolism of glycine-extended and amidated gastrin in sheep. 135 96

Gastrin- 17 (G-17) and gastrin-34-like immunoreactivities of human gastrinoma cells were investigated at light and electron microscope level using N-terminally directed antisera. The procedure includes (a) the 24 hr/immunoperoxidase staining of Bouin-fixed paraffin embedded tissues, (b) the immunoelectron microscopic labelling of aldehyde-fixed Epon-embedded tissues according to the immunogold technique. On light microscopy, a variable number of tumor cells stained for G-34. In contrast, G-17 immunoreactivity was very low or undetectable in the tumor material, although it was easily detected in endocrine cells of similarly processed human pyloric mucosa. On electron microscopy, most of the tumor cell granules belonging to the round compact or dense-cored type exhibited a variable labelling for G-34, whereas the vacuolar/floccular type remained unlabelled. In contrast, the labelling for G-17 occurred over most of the tumor cell granules, whether compact or floccular. Dense granules of varying size and shape, previously shown to store C-terminal gastrin immunoreactivity, were only faintly labelled by the two antisera. When compared to the labelling pattern of human pyloric G-cells, the predominance of round dense granules with G-34 and G-17 immunoreactivity in gastrinoma cells suggests an incomplete or defective post-translational processing of the precursor peptide.
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PMID:Light and electron microscope localization of G-17- and G-34-like immunoreactivities of human gastrinomas. 408 98

Amidated forms of gastrin are derived by post-translational processing of a large precursor peptide and stimulate gastric acid secretion via the gastrin/CCK(B) receptor. Non-amidated biosynthetic intermediates may exert biological effects through other mechanisms, but their effect on gastric acid secretion is unclear. Amidated gastrins stimulate acid secretion mainly by releasing histamine from mucosal enterochromaffin-like cells. This study examines the effects on histamine release from the vascularly perfused rat stomach of amidated gastrin-17, COOH-terminal glycine-extended gastrin-17, gastrin-17 extended at the COOH-terminal including the remaining progastrin sequence, and carboxy-terminal progastrin fragments (SAEDEN and GRRSAEDEN). Carboxy-terminal extended gastrins induced histamine release which was inhibited by the gastrin/CCK(B) antagonist L-740,093, but had to be given in concentrations 100-fold higher than amidated gastrin-17 to produce comparable effects. These progastrin-derived peptides are found in high concentrations in some patients with the Zollinger-Ellison syndrome and may contribute to acid hypersecretion and other gastrin/CCK(B) receptor mediated responses.
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PMID:Biological activity of carboxy-terminal gastrin analogs. 993 24

Proliferation and carcinogenesis of the large intestinal epithelial cells (IEC) cells is significantly increased in transgenic mice that overexpress the precursor progastrin (PG) peptide. It is not known if the in vivo growth effects of PG on IEC cells are mediated directly or indirectly. Full-length recombinant human PG (rhPG(1-80)) was generated to examine possible direct effects of PG on IEC cells. Surprisingly, rhPG (0.1-1.0 nM) was more effective than the completely processed gastrin 17 (G17) peptide as a growth factor. Even though IEC cells did not express CCK(1) and CCK(2) receptors (-R), fluorescently labeled G17 and Gly-extended G17 (G-Gly) were specifically bound to the cells, suggesting the presence of binding proteins other than CCK(1)-R and CCK(2)-R on IEC cells. High-affinity (K(d) = 0.5-1.0 nM) binding sites for (125)I-rhPG were discovered on IEC cells that demonstrated relative binding affinity for gastrin-like peptides in the order PG >or= COOH-terminally extended G17 >or= G-Gly > G17 > *CCK-8 (* significant difference; P < 0.05). In conclusion, our studies demonstrate for the first time direct growth effects of the full-length precursor peptide on IEC cells in vitro that are apparently mediated by the high-affinity PG binding sites that were discovered on these cells.
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PMID:Progastrin1-80 stimulates growth of intestinal epithelial cells in vitro via high-affinity binding sites. 1238 91

Glycine-extended gastrin (G-Gly) is an end product of processing of the progastrin precursor peptide that has a different spectrum of activity to amidated gastrin. G-Gly promotes cell proliferation in normal and malignant colonic epithelium but the mechanisms responsible are poorly understood. Prostaglandins produced by the cyclo-oxygenase (COX) enzymes have been implicated as downstream mediators of several growth factors, and COX inhibitors such as non-steroidal anti-inflammatory drugs inhibit the proliferation and invasiveness of colonic cancer and reduce the incidence of colon cancer. We have examined the mechanisms of the actions of G-Gly in HT-29 colon cancer cells. G-Gly induced a dose-dependent increase in cell proliferation that was insensitive to inhibition of either COX-1 or COX-2, but was abolished by inhibition of the p38 MAP kinase, ERK and NF-kappaB pathways. G-Gly did not increase prostaglandin E2 production. Celecoxib induced apoptosis and reduced viable cell numbers in a COX-independent manner. G-Gly significantly reduced serum-starvation and celecoxib-induced apoptosis and this effect was also blocked by inhibition of the p38 MAP kinase, ERK and NF-kappaB pathways. Stimulation of HT-29 cells with G-Gly led to a rapid increase in ERK and p38 MAP kinase phosphorylation and increased nuclear translocation of active NF-kappaB. Activation of NF-kappaB was independent of ERK and p38 MAP kinase. G-Gly stimulates proliferation and inhibits apoptosis in colon cancer cells via COX-independent and ERK-, p38 MAP kinase-, and NF-kappaB-dependant pathways. Locally and systemically produced G-Gly may be important in reducing the beneficial effects of chemopreventative agents in colon cancer.
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PMID:Glycine-extended gastrin stimulates proliferation and inhibits apoptosis in colon cancer cells via cyclo-oxygenase-independent pathways. 1616 10