Binding sites for progastrin‐derived peptides in colonic crypts

Karelina, Yulia; Baldwin, Graham S.

doi:10.1046/j.1440-1746.2001.02429.x

Cited by 6 publications

(7 citation statements)

References 34 publications

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“…Previous studies have shown that recombinant human progastrin bound competitively to the colonic crypts [42]. In this study, we were able to localize GPR56 positive cells to the colonic crypts in GPR56-EGFP mice, and found that the number of GPR56 cells was increased in mice that overexpressed progastrin.…”

Section: Discussionsupporting

confidence: 52%

The G-protein coupled receptor 56, expressed in colonic stem and cancer cells, binds progastrin to promote proliferation and carcinogenesis

et al. 2017

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Overexpression of human progastrin increases colonic mucosal proliferation and colorectal cancer progression in mice. The G-protein coupled receptor 56 (GPR56) is known to regulate cell adhesion, migration, proliferation and stem cell biology, but its expression in the gut has not been studied. We hypothesized that the promotion of colorectal cancer by progastrin may be mediated in part through GPR56. Here, we found that GPR56 expresses in rare colonic crypt cells that lineage trace colonic glands consistent with GPR56 marking long-lived colonic stem-progenitor cells. GPR56 was upregulated in transgenic mice overexpressing human progastrin. While recombinant human progastrin promoted the growth and survival of wild-type colonic organoids in vitro, colonic organoids cultured from GPR56−/− mice were resistant to progastrin. We found that progastrin directly bound to, and increased the proliferation of, GPR56-expressing colon cancer cells in vitro, and proliferation was increased in cells that expressed both GPR56 and the cholecystokinin-2 receptor (CCK2R). In vivo, deletion of GPR56 in the mouse germline abrogated progastrin-dependent colonic mucosal proliferation and increased apoptosis. Loss of GPR56 also inhibited progastrin-dependent colonic crypt fission and colorectal carcinogenesis in the azoxymethane (AOM) mouse model of colorectal cancer. Overall, we found that progastrin binds to GPR56 expressing colonic stem cells, which in turn promotes their expansion, and that this GPR56-dependent pathway is an important driver and potential new target in colorectal carcinogenesis.

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Section: Discussionsupporting

confidence: 52%

The G-protein coupled receptor 56, expressed in colonic stem and cancer cells, binds progastrin to promote proliferation and carcinogenesis

et al. 2017

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“…A number of potential intestinal stem cell markers have been described, some of which appear to characterize active stem cells and others that characterize quiescent (position 4) stem cells (56,57). Previous studies have shown that progastrin-derived peptides bind preferentially to the colonic crypts (58). In the current study, we were able to localize CCK2R to the colonic crypts of WT mice, and showed that CCK2R cells were expanded in mice overexpressing progastrin.…”

Section: Figuresupporting

confidence: 55%

Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice

Jin

Ramanathan²,

Quante³

et al. 2009

J. Clin. Invest.

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Hyperproliferation of the colonic epithelium, leading to expansion of colonic crypt progenitors, is a recognized risk factor for colorectal cancer. Overexpression of progastrin, a nonamidated and incompletely processed product of the gastrin gene, has been shown to induce colonic hyperproliferation and promote colorectal cancer in mice, but the mechanism of pathogenesis has not been defined. Cholecystokinin-2 receptor (CCK2R) is the primary receptor for cholecystokinin (CCK) and amidated gastrin. Here, we show that Cck2r was expressed in murine colonic crypts and upregulated in the transgenic mice that overexpress human progastrin. Murine deletion of Cck2r abrogated progastrin-dependent increases in colonic proliferation, mucosal thickness, and β-catenin and CD44 expression in the colon tumor. In addition, either deletion or antagonism of Cck2r resulted in the inhibition of progastrin-dependent increases in progenitors expressing doublecortin and CaM kinase-like-1 (DCAMKL1), stem cells expressing leucine rich repeat-containing G protein-coupled receptor 5 (LgR5), and colonic crypt fission. Furthermore, in the azoxymethane mouse model of colorectal carcinogenesis, Cck2r deletion in human progastrin-overexpressing mice resulted in markedly decreased aberrant crypt foci formation and substantially reduced tumor size and multiplicity. Taken together, these observations indicate that progastrin induces proliferative effects, primarily in colonic progenitor cells, through a CCK2R-dependent pathway. Moreover, our data suggest that CCK2R may be a potential target in the treatment or prevention of colorectal cancer.

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“…This distinction has previously been demonstrated by the inability of selective CCK-2 receptor antagonists to block Ggly binding to cell lines (15,16,18) and to isolated colonic crypts (38), or to inhibit Ggly-induced cell proliferation (15,16,18). The absolute requirement for ferric ions for Ggly biological activity (26), when compared with the absence of any such requirement for ferric ions for the biological activity of Gamide, 2 provides additional support for the conclusion that none of the effects of Ggly are mediated via binding to the CCK-2 receptor.…”

Section: Fig 6 Bismuth Ions Inhibit Ggly-induced Cell Migrationmentioning

confidence: 93%

“…Ggly Receptor Binding Assay-Ggly was iodinated using the IODO-GEN method and purified by reversed phase high performance liquid chromatography (38). Binding assays with mono-[…”

Section: Methodsmentioning

confidence: 99%

A Novel Effect of Bismuth Ions

Pannequin

Kovac

Tantiongco

et al. 2004

Journal of Biological Chemistry

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Although bismuth salts have been used for over two centuries for the treatment of various gastrointestinal disorders, the mechanism of their therapeutic action remains controversial. Because gastrins bind two trivalent ferric ions with high affinity, and because ferric ions are essential for the biological activity of glycineextended gastrin 17, we have investigated the hypothesis that trivalent bismuth ions influence the biological activity of gastrins. Binding of bismuth ions to gastrins was measured by fluorescence quenching and NMR spectroscopy. The effects of bismuth ions on gastrinstimulated biological activities were measured in inositol phosphate, cell proliferation, and cell migration assays. Fluorescence quenching experiments indicated that both glycine-extended and amidated gastrin 17 bound two bismuth ions. The NMR spectral changes observed on addition of bismuth ions revealed that Glu-7 acted as a ligand at the first bismuth ion binding site. In the presence of bismuth ions the ability of glycine-extended gastrin 17 to stimulate inositol phosphate production, cell proliferation, and cell migration was markedly reduced. In contrast, bismuth ions had little effect on the affinity of the CCK-2 receptor for amidated gastrin 17, or on the stimulation of inositol phosphate production by amidated gastrin 17. We conclude that bismuth ions may act, at least in part, by blocking the effects of glycine-extended gastrin 17 on cell proliferation and cell migration in the gastrointestinal tract. This is the first report of a specific inhibitory effect of bismuth ions on the action of a gastrointestinal hormone.

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Binding sites for progastrin‐derived peptides in colonic crypts

Abstract: We conclude that the gastrin17gly binding site on normal colonic crypts has properties consistent with the gastrin/CCK-C receptor.

Cited by 6 publications

References 34 publications

The G-protein coupled receptor 56, expressed in colonic stem and cancer cells, binds progastrin to promote proliferation and carcinogenesis

The G-protein coupled receptor 56, expressed in colonic stem and cancer cells, binds progastrin to promote proliferation and carcinogenesis

Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice

A Novel Effect of Bismuth Ions

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