Pathways of processing of the gastrin precursor in rat antral mucosa.

Varró, Andrea; Voronina, Svetlana; Dockray, Graham J.

doi:10.1172/jci117839

Cited by 61 publications

(56 citation statements)

References 35 publications

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“…Progastrin processing was examined using a pulse-chase experimental protocol as previously described (Varro et al 1994(Varro et al , 1995. In brief, antral mucosal explants (equivalent to one rat antrum per sample) were incubated at 22°C for 2 h in 3 ml modified Krebs-Ringer bicarbonate solution (composition (mÒ): 95 NaCl, 4·7 KCl, 2·6 CaClµ, 1·2 KHµPOÚ, 24·9 NaHCO×, 10 Hepes, 4·9 sodium pyruvate, 5·4 sodium fumarate, 4·9 sodium glutamate, 11·6 glucose) gassed with 95% Oµ-5% COµ containing 50 ìCi ml¢ [ÅH]Tyr and 100 ìCi ml¢ […”

Section: Progastrin Processingmentioning

confidence: 99%

“…Progastrin processing was initiated by raising the temperature to 37°C and replacing the medium with one containing 0·1 mÒ tyrosine and 1·2 mÒ MgSOÚ; in these conditions progastrin is rapidly translocated to secretory granules where further posttranslational processing takes place (Varro et al 1995;. Depending on the experiment, samples were taken after 20, 40, 80 and 160 min at 37°C.…”

Section: Progastrin Processingmentioning

confidence: 99%

“…In addition they may modulate the action of G34 and G17 on acid secretion, but they do not stimulate acid secretion on their own (Todisco, Takeuchi, Seva, Dickinson & Yamada, 1995;Higashide, Gomez, Greeley, Townsend & Thompson, 1996). The various forms of gastrin are generated during biosynthesis from a common precursor, progastrin (Varro, Henry, Vaillant & Dockray, 1994;Varro, Voronina & Dockray, 1995), which is itself also now recognized to be a putative growth factor (Wang et al 1996). The initial product of gastrin mRNA translation is the precursor preprogastrin, which is co-translationally converted to progastrin (Fig.…”

mentioning

confidence: 99%

“…1). The latter is sequestered in secretory granules and there converted to the Gly-gastrins and then amidated gastrins (Varro et al 1994(Varro et al , 1995. The results of pulse-chase labelling experiments in rat antral mucosa indicate that G34-Gly is the first major intermediate generated from progastrin.…”

mentioning

confidence: 99%

“…1). In principle the latter could be converted by PAM to G17, but this appears not to be a major route to G17, which instead is largely generated by cleavage of G34 (Varro et al 1995). The main enzymes involved in cleavage of progastrin and its derivatives are thought to be members of the prohormone convertase (PC) family.…”

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

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Varró

et al. 1997

The Journal of Physiology

185

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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. 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. 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 Gl7–Gly (G34 and G17 with COOH‐terminal glycine), was increased 3‐fold after treatment with omeprazole for either 1 or 5 days. 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. The amidating enzyme, peptidylglycine α‐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. 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.

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Section: Progastrin Processingmentioning

confidence: 99%

Section: Progastrin Processingmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

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Varró

et al. 1997

The Journal of Physiology

185

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Autocrine stimulation of AR4-2J rat pancreatic tumor cell growth by glycine-extended gastrin

et al. 1996

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Glycine-extended gastrin (gastrin-Gly) stimulates proliferation of AR4-2) pancreatic tumor cell line through a specific receptor, different from the gastrin-cholecystokinin B receptor. Our purpose was to determine whether AR4-2) cells produced gastrin-Gly and then whether the peptide was involved in an autocrine loop. First, proliferation of AR4-2) cells in serum-free medium was inhibited by a gastrin anti-sense oligodeoxynucleotide phosphorothioate and by antibodies specific for gastrinGly. In contrast, antibodies specific for a-amidated gastrin were without effect. By using RT-PCR, we have shown that AR4-2J cells expressed gastrin mRNA. The presence of gastrin-Gly, but not a-amidated gastrin, in serum-free media was detected by radioimmunoanalysis. Gel chromatography revealed that the predominant molecular forms secreted were glycine-extended gastrin-34 and gastrin-17. Furthermore, epidermal growth factor (EGF), a stimulator of gastrin gene transcription, modulates gastrin-Gly secretion by AR4-2J. These data together suggest that gastrin-Gly is an autocrine growth factor for AR4-2) cells and that it participates with EGF in the regulation of AR4-2)-cell proliferation.o 1996 Wiley-Liss, Inc.The major physiological role of the gastrointestinal hormone, gastrin, is to stimulate gastric-acid secretion. Gastrin can also promote growth effects on normal gastric mucosa, on colorectal tumors in vivo (Winsett et al., 1986), and on colonic (Kuzyk et al., 1986), broncogenic (Sethi and Rozengurt, 1992) and pancreatic cell lines (Seva et al., 1990). Bioactivity of gastrin and several other regulatory peptides requires Cterminal a-amidation using glycine as amide donor (Hiked and Rehfeld, 1986). Carboxyamidation is the final step in the maturation to a bioactive gastrin, which is able to bind its CCK-B gastrin (RCCK-B) receptor with high affinity.Progastrin is expressed in several normal tissues, such as pituitary gland, cerebellum, antrum, vagal neurons and duodenum (Rehfeld, 1986(Rehfeld, , 1991Marino et al., 1994). The tissue concentration of progastrin and processing intermediates is in the same range as that of the mature a-amidated peptide (Sugano et al., 1987). It has been demonstrated that the immediate precursor of amidated gastrin, glycine-extended gastrin (gastrin-Gly), possesses specific biological functions. Thus, like a-amidated gastrin, gastrin-Gly stimulates proliferation of a tumor-derived pancreatic cell line (AR4-2J), through a specific receptor, different from the CCK-B receptor (Seva et al., 1994). Moreover, colorectal (Singh et al., 1994), gastric (Van Solinge and Rehfeld, 1992) and broncogenic tumors (Rehfeld et aL, 1989) contain glycine-extended gastrins, and occasionally at concentrations higher than that of amidated gastrin.A possible mechanism by which tumor cells show unrestricted growth is a response to the growth factors that they produce. An autocrine role for a "gastrin-like" peptide in human colonic tumor cells has already been suggested (Hoosein et al., 1990). More recently, immunologica...

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Vitamin C supplementation does not protect L‐gulono‐γ‐lactone oxidase‐deficient mice from Helicobacter pylori‐induced gastritis and gastric premalignancy

Lee

Wang

Chien

et al. 2007

Intl Journal of Cancer

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In human studies, low vitamin C intake has been associated with more severe Helicobacter pylori gastritis and a higher incidence of gastric cancer. However, vitamin C supplementation has not been definitively shown to protect against gastric cancer. Using vitamin C‐deficient B6.129P2‐Gulotm1Umc/mmcd (gulo−/−) mice lacking L‐gulono‐γ‐lactone oxidase, we compared gastric lesions and Th1 immune responses in H. pylori‐infected gulo−/− mice supplemented with low (33 mg/L) or high (3,300 mg/L) vitamin C in drinking water for 16 or 32 weeks. Vitamin C levels in plasma and gastric tissue correlated with the vitamin C supplementation levels in gulo−/− mice. H. pylori infection resulted in comparable gastritis and premalignant lesions in wildtype C57BL/6 and gulo−/− mice supplemented with high vitamin C, but lesions were less severe in gulo−/− mice supplemented with low vitamin C at 32 weeks post infection. The reduced gastric lesions in infected gulo−/− mice supplemented with low vitamin C correlated with reduced Th1‐associated IgG2c, gastric IFN‐γ and TNF‐α mRNA and higher H. pylori colonization levels. These results in the H. pylori‐infected gulo−/− mouse model suggest that although supplementation with a high level of vitamin C achieved physiologically normal vitamin C levels in plasma and gastric tissue, this dose of vitamin C did not protect gulo−/− mice from H. pylori‐induced premalignant gastric lesions. In addition, less severe gastric lesions in H.pylori infected gulo−/− mice supplemented with low vitamin C correlated with an attenuated Th1 inflammatory response. © 2007 Wiley‐Liss, Inc.

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Pathways of processing of the gastrin precursor in rat antral mucosa.

Cited by 61 publications

References 35 publications

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

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

Autocrine stimulation of AR4-2J rat pancreatic tumor cell growth by glycine-extended gastrin

Vitamin C supplementation does not protect L‐gulono‐γ‐lactone oxidase‐deficient mice from Helicobacter pylori‐induced gastritis and gastric premalignancy

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