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)

The trophic response of the gastrointestinal mucosa to treatment with the hormone gastrin includes a polyamine-dependent step. Because gastrin does not induce ornithine decarboxylase, experiments were designed to determine whether pentagastrin induced the polyamine interconverting enzyme, spermine/spermidine N1-acetyltransferase (SAT). Eight hours after intraperitoneal treatment of rats with either spermidine (0.8 mmol/kg) or pentagastrin (250 micrograms/kg) oxyntic gland mucosal SAT activity was increased from roughly 400 to 800 pmol [14C]acetate.mg protein-1.h-1. In contrast, colonic mucosa was not sensitive to pentagastrin even though spermidine treatment induced nearly a 400% increase in SAT activity. Measurement of both oxyntic gland and colonic mucosal polyamine concentrations showed that by 16 h after pentagastrin (250 micrograms/kg ip) putrescine, acetylspermidine, and spermidine levels all were increased to a level approximately 200% of that observed in NaCl-treated rats. By 24 h mucosal polyamine content of pentagastrin-treated rats was not different from control. Essentially the same results were found in animals treated with difluoromethylornithine, thus demonstrating that the increase in mucosal polyamine concentration was not related to the induction of ornithine decarboxylase. The results of these experiments demonstrate that unlike most hormones, the hormone gastrin induces the polyamine converting enzyme, SAT, rather than ornithine decarboxylase during stimulation of polyamine-dependent cell growth and/or division.
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PMID:Pentagastrin induction of spermine/spermidine N1-acetyltransferase and mucosal polyamines. 249 56

In most tissues increases in ornithine decarboxylase (ODC) are associated with growth. Refeeding fasted rats. a potent stimulus for mucosal growth, strongly increases ODC in both small and large intestinal mucosa. In the small bowel, almost all of this increase occurs in the mature villus cells rather than the proliferative crypt cells. Nevertheless, inhibition of ODC with difluoromethylornithine blocks the growth response. Using a highly specific, polyclonal antiserum to ODC, we have determined that in the fasted rat ODC is localized almost exclusively to the villus cells. Using antiserum dilution techniques, we have shown that, within 2 h, refeeding increases the amount of immunoreactive ODC in both villus and crypt cells. Furthermore, the trophic hormone gastrin also increases ODC, but only in the crypt cells. Epidermal growth factor increased ODC to a greater extent than gastrin, but stimulation was more general, including both crypt and villus cells. Perfusing an isolated segment of small bowel in situ with glycine for 2 h also increased immunoreactive ODC but only in the villus cells. Thus in the small intestine the effect of refeeding on ODC activity appears to be mediated by different types of stimuli: luminal nutrients increase enzyme levels in the absorbing villus cells, while trophic peptides stimulate ODC synthesis in the proliferative crypt cells.
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PMID:Mucosal ornithine decarboxylase in the small intestine: localization and stimulation. 264 50

Recent studies have demonstrated that cholecystokinin (CCK) receptors are heterologous in peripheral tissues and in the central nervous system and that CCK-gastrin (CCK-G) peptides are potent trophic factors for the gastrointestinal tract. In the present study we used 125I-labeled gastrin and 125I-labeled CCK to demonstrate the heterogeneity of CCK receptors on a rat pancreatic acinar cell line (AR4-2J) and analyze the role of these receptors in increasing the activity of ornithine decarboxylase. Pharmacological analysis of radioligand binding fit well with the presence of two different receptors: 1) a CCK-selective receptor having the characteristics of the CCK receptor present on normal pancreatic cells and 2) a high-affinity, low-selectivity CCK-G binding site that interacts with all CCK-G peptides sulfated and nonsulfated. CCK-G peptides stimulate ornithine decarboxylase activity with the following order of potencies (EC50): G-(2-17)-ds (0.1 nM) greater than or equal to CCK-9 (0.25 nM) greater than or equal to pentagastrin (0.4 nM) greater than CCK-4 (6 nM). This stimulation was not inhibited by CCK antagonist (asperlicin) at a concentration range that blocks the CCK receptor but does not compete with 125I-labeled gastrin binding to the CCK-G receptor. These results, obtained with CCK-G agonists and antagonists, demonstrate that ornithine decarboxylase stimulation in these cells is mediated via the CCK-G receptor.
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PMID:Cholecystokinin and gastrin peptides stimulate ODC activity in a rat pancreatic cell line. 271 9

The effects of inhibiting polyamine synthesis on the functional development of the gastric mucosa were studied in rats from 5 to 40 days old. They were treated from day 14 after birth with alpha-difluoromethylornithine (DFMO) at a concentration of 2% in the drinking water of mothers and pups. The rats were weaned on day 18. Basal acid and pepsin secretion, oxyntic gland mucosal pepsinogen content, and antral gastrin content followed similar developmental patterns in control animals. Levels of these parameters remained measurable but low until around the time of weaning, when dramatic log linear rises were observed. DFMO failed to delay the onset of the rises in any of these maturational indices. Ornithine decarboxylase (ODC) activity in the oxyntic gland mucosa was low but discernible in rats of every age studied. DFMO significantly reduced ODC activity at every age except 40 days, where there was no difference from control values. Our results suggest that ODC activity in the rat gastric mucosa does not change appreciably during neonatal development and that inhibiting putrescine synthesis from its precursor ornithine by DFMO treatment does not prevent or delay gastric mucosal maturation.
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PMID:Role of ornithine decarboxylase in functional development of rat gastric mucosa. 310 30

Trophic changes of the exocrine pancreas after in vivo gastrin (G)/CCK treatment are well documented but up to now the study of the mechanisms involved is restricted by the lack of a suitable in vitro model. Nevertheless the in vivo trophic effect induced by gastrin/CCK peptides has been associated with an increase of ornithine decarboxylase (ODC) activity. In the present work, using the AR42J cell line in which CCK receptors and stimulation of amylase release by CCK peptides has already been demonstrated, we investigated the presence of gastrin binding sites and the possible modulation of proliferation by an inhibitor of ODC activity. 125I-BH-G17ns binding is saturable, reversible and specific. Potencies of the different analogues tested are G17ns greater than CCK8 greater than CCK8ns greater than or equal to G6s greater than G/CCK4. Furthermore dBt cGMP, a non-peptide antagonist for CCK receptors, does not compete for gastrin binding. This indicates the existence of a subclass of gastrin binding sites. Difluoromethyl ornithine (DFMO) (1 mM), an irreversible inhibitor of ODC, inhibits cell growth from day 3 up to day 7. This growth inhibition is dose dependent and closely related to an intracellular polyamine modulation. Putrescine and spermidine levels fell under detectable values while spermine levels increased. All these data suggest that this cell line could be a useful in vitro model to study the mechanisms of gastrin induced growth control.
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PMID:Characterisation of gastrin receptors on a rat pancreatic acinar cell line (AR42J). A possible model for studying gastrin mediated cell growth and proliferation. 312 56

Gastrin injection and refeeding fasted rats are effective trophic stimuli for the oxyntic gland mucosa of the stomach. Neither stimulus increases detectable ornithine decarboxylase (ODC) activity in the tissue. Difluoromethylornithine (DFMO), a potent inhibitor of ODC, blocks the mucosal growth response, indicating that ODC activity is necessary for growth. Elevated levels of spermidine and spermine are detectable in the mucosa after gastrin administration. Using a highly specific, polyclonal antiserum to ODC, we determined that the enzyme is present in oxyntic gland mucosa confined to a narrow band of cells at the base of the gastric pits and openings of the glands. In antral mucosa, ODC is present throughout the lower 20% of the mucosa, which consists of the necks and pyloric glands. Using antiserum dilution techniques, we show that gastrin administration increases immunoreactive ODC in the oxyntic gland area but not in the antral mucosa, where it has no trophic effect. Elevated cellular content of ODC is apparent within 2 h after injection of gastrin, peaks at 4 h, and declines to basal levels by 12 h. Gastrin-stimulated increase in ODC is confined to the narrow band of cells in which low levels of the enzyme protein were detected in control animals. The decarboxylating activity detectable in oxyntic gland mucosal extracts is not inhibited by administration of DFMO or cycloheximide, each of which inhibits ODC activity in other tissues. Addition of unlabeled lysine to the decarboxylation assay reaction of oxyntic gland mucosa extract inhibits the decarboxylation of radiolabeled ornithine substrate. Thus it is likely that the stomach possesses nonspecific decarboxylase activity, which accounts for most of the measured activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Gastric mucosal ornithine decarboxylase: localization and stimulation by gastrin. 313 18

Either ethylamine or the diamine putrescine was infused at the rate of 1 mumol/h for 66 h into the ileal lumen of rats. Total mucosal RNA, DNA, and protein content was greater in amine-treated rats than in rats receiving 0.9% NaCl. Growth was greatest in the mucosa surrounding the tip of the infusion catheter but was also observed 9 cm proximal and distal to the catheter tip. Infusion of these amines induced the activity of the enzymes ornithine and S-adenosylmethionine decarboxylase. Ornithine decarboxylase activity was increased 2- and 6-fold and S-adenosylmethionine decarboxylase activity 10- and 5-fold by putrescine and ethylamine, respectively. Induction of the polyamine biosynthetic enzymes was not accompanied by increases in the tissue content of polyamines. Putrescine, spermidine, and spermine content of the ileal mucosa surrounding the catheter tip was the same in 0.9% NaCl-, ethylamine-, and putrescine-treated animals. Finally, ethylamine was without effect on serum gastrin concentration in these experiments. The results suggest that amines regulate mucosal growth and may do so by modulating the activity of the enzymes involved in the synthesis of the polyamines.
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PMID:Ileal mucosal growth during intraluminal infusion of ethylamine or putrescine. 405 Sep 94

Cimetidine has been shown to inhibit normal and carcinoma cell growth but the mechanism of the antiproliferative action is incompletely understood. The current study determined the influence of cimetidine on ornithine decarboxylase (ODC) activity, which is the initial rate-limiting enzyme in polyamine biosynthesis, in rat duodenal mucosa and IEC-6 cells (a line of normal rat intestinal crypt cells). Rats were fasted 22 hr before the various treatments and ODC activity was measured in scraped duodenal mucosa. Administration of pentagastrin and epidermal growth factor (EGF) and refeeding fasted rats significantly increased ODC activity in duodenal mucosa. Cimetidine completely inhibited increases in ODC activity in the mucosa stimulated by pentagastrin and EGF, but not by refeeding. Ranitidine and H1-receptor antagonist chlorpheniramine had similar inhibitory effects on ODC activity induced by gastrin. In cultured IEC-6 cells, cimetidine caused a linear and significant inhibition of the stimulation of ODC activity in response to pentagastrin, EGF, 5% dialyzed fetal bovine serum (FBS) and asparagine. ODC messenger RNA (mRNA) levels in IEC-6 cells were significantly increased after exposure to 5% dialyzed FBS and asparagine. Although cimetidine almost completely prevented the induction of ODC activity in IEC-6 cells exposed to serum or asparagine, the increases in ODC mRNA levels were not inhibited by the compound.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of ornithine decarboxylase activity but not expression of the gene by cimetidine in intestinal mucosal cells. 761 40

Gastrin has been suggested to be involved in the promotion and progression of colon cancer. Mice colon cancers and colon-carcinoma cell lines are stimulated to grow by gastrin, and gastrin receptors have been found in the majority of human colon-tumor specimens. High serum gastrin levels have been reported in patients with colon polyps and cancers, together with increased ornithine decarboxylase (ODC) activity. Since gastrin stimulates ornithine decarboxylase in colon cancer cells in vitro it has been suggested that increased synthesis of intracellular polyamines is one of the mechanisms activated by the hormone. In order to confirm the presence of hypergastrinemia in colon cancer and to investigate the relationship between plasma gastrin and tumor growth, we used an animal model of colon carcinogenesis that minimizes the possible bias of human studies, related to varying diet, age and environmental factors. We evaluated blood gastrin levels in 35 rats with colon cancer induced by the carcinogen azoxymethane (AOM), and we correlated gastrinemia with tumor proliferation, assessed by thymidine-labeling index (TLI) and ODC activity; 6 animals constituted the control group. Gastrin levels in rats with AOM-induced tumors were significantly higher than in controls. Significantly higher TLI and ODC activity were found in the tumors of hypergastrinemic rats than in neoplasms of animals with normal gastrin levels. Our data provide additional evidence of a role for gastrin as trophic hormone for colon neoplastic cells.
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PMID:Hypergastrinemia in rats with azoxymethane-induced colon cancers. 770 52

Gastrin and cholecystokinin (CCK) have proven trophic effects on the gut. We have previously demonstrated that these peptides stimulate an early event in cellular proliferation, namely ornithine decarboxylase activity (ODC), in a rat exocrine pancreatic cell line AR4-2J. Furthermore, this effect is mediated through a G/CCKB receptor. Thus, in the present study we sought to examine the signal transduction mechanisms linked to the G/CCKB receptor occupancy. Both gastrin and CCK induced a rapid (maximum at 40 s) increase in inositol triphosphates (InsP3) and diacylglycerol (DAG) formation in a dose-dependent manner (EC50 = 5.6 nM) that quickly returned to baseline. Although InsP3 levels remained at baseline, DAG levels demonstrated a second gradual increase that was maximal at 15 min. CCK/gastrin efficiency to stimulate DAG and InsP3 formation (EC50 = 5.6 nM) could be correlated to the G/CCKB receptor occupancy, suggesting a coupling of this receptor to phospholipase C. To examine the involvement of protein kinase C (PKC) activation in the increase in ODC activity, we stimulated the AR4-2J cells with the phorbol ester TPA and observed an increase in ODC activity with a maximal effect at 100 nM. TPA stimulation of ODC activity was completely abolished by the PKC inhibitor staurosporine (50 nM). However, 50 nM staurosporine inhibited only 65% of the gastrin and CCK induced increase in ODC activity suggesting that a portion of the G/CCKB receptor-mediated increase in ODC activity is PKC independent.
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PMID:Coupling of pancreatic gastrin/cholecystokinin-B (G/CCKB) receptors to phospholipase C and protein kinase C in AR4-2J tumoral cells. 797 29


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