Ferric ions inhibit proteolytic processing of progastrin

Bramante, Gianni; Patel, Oneel; Shulkes, Arthur; Baldwin, Graham S.

doi:10.1016/j.bbrc.2010.12.117

Cited by 3 publications

(2 citation statements)

References 27 publications

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“…No significant change in circulating Ggly concentration was observed in the hGas mice, although in bismuth-treated wild-type mice the circulating Ggly concentration was significantly decreased. These observations suggest that, as previously reported for ferric ions [35], the binding of bismuth ions to progastrin inhibits processing during passage through the secretory pathway. Unfortunately due to the lack of a mouse-specific progastrin antibody we were unable to measure the circulating progastrin concentrations in wildtype or MTI-Ggly mice.…”

Section: Discussionsupporting

confidence: 85%

Bismuth ions inhibit the biological activity of non-amidated gastrins in vivo

Kovac

Loh

Lachal

et al. 2012

Biochemical Pharmacology

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The peptide hormone gastrin binds two ferric ions with high affinity, and iron binding is essential for the biological activity of non-amidated gastrins in vitro and in vivo. Bi3+ ions also bind to glycine-extended gastrin17 (Ggly), but inhibit Ggly-induced cell proliferation and migration in gastrointestinal cell lines in vitro. The aims of the present study were firstly, to establish the mechanism by which Bi3+ ions inhibit the binding of Fe3+ ions to Ggly, and secondly, to test the effect of Bi3+ ions on the activity of non-amidated gastrins in vivo. The interaction between Bi3+ ions, Fe3+ ions and Ggly was investigated by ultraviolet spectroscopy. The effect of Bi3+ ions on colorectal mucosal proliferation was measured in three animal models. In vitro in the presence of Bi3+ ions the affinity of Fe3+ ions for Ggly was substantially reduced; the data was better fitted by a mixed, rather than a competitive, inhibition model. In rats treated with Ggly alone proliferation in the rectal mucosa was increased by 318%, but was reduced to control values (p < 0.001) in animals receiving oral bismuth plus Ggly. Proliferation in the colonic mucosa of mice overexpressing Ggly or progastrin was significantly greater than in wild-type mice, but was no greater than control (p < 0.01) in animals receiving oral bismuth. Thus a reduction in the binding of Fe3+ ions to Ggly and progastrin in the presence of Bi3+ ions is a likely explanation for the ability of oral bismuth to block the biological activity of non-amidated gastrins in vivo.

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Section: Discussionsupporting

confidence: 85%

Bismuth ions inhibit the biological activity of non-amidated gastrins in vivo

Kovac

Loh

Lachal

et al. 2012

Biochemical Pharmacology

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“…Recently, it was proposed that in addition, ferric ions can inhibit proteolytic processing of progastrin by inhibiting prohormone convertase 1 (Bramante et al . ).…”

Section: Introductionmentioning

confidence: 97%

Novel roles of gastrin

Dimaline

Varró

2014

The Journal of Physiology

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The existence of the hormone gastrin in the distal stomach (antrum) has been known for almost 110 years, and the physiological function of this amidated peptide in regulating gastric acid secretion via the CCK2 receptor is now well established. In this brief review we consider important additional roles of gastrin, including regulation of genes encoding proteins such as plasminogen activator inhibitors and matrix metalloproteinases that have important actions on extracellular matrix remodelling. These actions are, at least in part, effected by paracrine signalling pathways and make important contributions to maintaining functional integrity of the gastric epithelium. Recent studies also provide support for the idea that gastrin, in concert with other hormones, could potentially contribute a post-prandial incretin effect. We also review recent developments in the biology of other gastrin gene products, including the precursor progastrin, which causes proliferation of the colonic epithelium and in certain circumstances may induce cancer formation. Glycine-extended biosynthetic processing intermediates also have proliferative effects in colonic mucosa and in some oesophageal cancer cell lines. Whether these additional gene products exert their effects through the CCK2 receptor or a separate entity is currently a matter of debate.

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Increased gastrin gene expression provides a physiological advantage to mice under hypoxic conditions

Laval

Baldwin

Shulkes

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Hypoxia, or a low concentration of O2, is encountered in humans undertaking activities such as mountain climbing and scuba diving and is important pathophysiologically as a limiting factor in tumor growth. Although data on the interplay between hypoxia and gastrins are limited, gastrin expression is upregulated by hypoxia in gastrointestinal cancer cell lines, and gastrins counterbalance hypoxia by stimulating angiogenesis in vitro and in vivo. The aim of this study was to determine if higher concentrations of the gastrin precursor progastrin are protective against hypoxia in vivo. hGAS mice, which overexpress progastrin in the liver, and mice of the corresponding wild-type FVB/N strain were exposed to normoxia or hypoxia. Iron status was assessed by measurement of serum iron parameters, real-time PCR for mRNAs encoding critical iron regulatory proteins, and Perls' stain and atomic absorption spectrometry for tissue iron concentrations. FVB/N mice lost weight at a faster rate and had higher sickness scores than hGAS mice exposed to hypoxia. Serum iron levels were lower in hGAS than FVB/N mice and decreased further when the animals were exposed to hypoxia. The concentration of iron in the liver was strikingly lower in hGAS than FVB/N mice. We conclude that increased circulating concentrations of progastrin provide a physiological advantage against systemic hypoxia in mice, possibly by increasing the availability of iron stores. This is the first report of an association between progastrin overexpression, hypoxia, and iron homeostasis.

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Ferric ions inhibit proteolytic processing of progastrin

Cited by 3 publications

References 27 publications

Bismuth ions inhibit the biological activity of non-amidated gastrins in vivo

Bismuth ions inhibit the biological activity of non-amidated gastrins in vivo

Novel roles of gastrin

Increased gastrin gene expression provides a physiological advantage to mice under hypoxic conditions

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