Antiproliferative gastrin/cholecystokinin receptor antagonists target the 78-kDa gastrin-binding protein.

Baldwin, Graham S.

doi:10.1073/pnas.91.16.7593

Cited by 53 publications

(26 citation statements)

References 30 publications

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“…Another group reported a 45-kD gastrin preferring receptor on Swiss 3T3 cells that does not discriminate between amidated and glycine extended gastrin and apparently mediates mitogenic effects of gastrin-like peptides on these cells (19). Finally, Baldwin reported a 78-kD gastrin binding protein (GBP), purified from extracts of porcine gastric mucosal membrances, which binds glycine-extended forms of gastrin with similar affinity to mature amidated gastrin (20,56). At present, it is unclear which, if any, of the above candidate receptors may be the colonic receptor mediating the growth effects of progastrin.…”

Section: Discussionmentioning

confidence: 99%

Processing and proliferative effects of human progastrin in transgenic mice.

Wang¹,

Koh²,

Varró³

et al. 1996

J. Clin. Invest.

276

219

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Incompletely processed gastrins have been postulated to play a role in growth of the gastrointestinal tract, but few studies have examined the effects of progastrin on mucosal proliferation in vivo. Human gastrin gene expression and progastrin processing were therefore studied in transgenic mice containing a human gastrin (hGAS) minigene, and compared to processing in mice bearing an insulin gastrin (INS-GAS) transgene that overexpresses amidated gastrin. Progastrin processing was studied using region-specific antisera and radioimmunoassays, biosynthetic labeling, immunoprecipitation, and HPLC. Proliferative effects due to overexpression of processed and unprocessed gastrin in INS-GAS and hGAS mice, respectively, were determined using routine histology and BrdU incorporation. The pancreatic islets of INS-GAS mice were able to produce carboxyamidated G-17, resulting in a twofold elevation of serum amidated gastrin, marked thickening of the oxyntic mucosa, and an increased BrdU labeling index (LI) of the gastric body. In contrast, livers of adult hGAS mice expressed abundant human gastrin mRNA and human progastrin but were unable to process this peptide to the mature amidated form, resulting in markedly elevated serum progastrin levels and normal amidated gastrin levels. Nevertheless, there was a marked increase in the BrdU labeling index of the colon in hGAS mice (LI 7.46 Ϯ 1.90%), as well as in INS-GAS mice (LI 6.16 Ϯ 1.17%), compared to agematched, wild type control mice (LI 4.01 Ϯ 0.98%, P Ͻ 0.05). These studies suggest that incompletely processed gastrin precursors may contribute to colonic mucosal proliferation in vivo. ( J. Clin. Invest. 1996Invest. . 98:1918Invest. -1929

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Section: Discussionmentioning

confidence: 99%

Processing and proliferative effects of human progastrin in transgenic mice.

Wang¹,

Koh²,

Varró³

et al. 1996

J. Clin. Invest.

276

219

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“…Many human colon carcinoma cell lines and colorectal carcinomas have been shown to express mRNA for this gastrin-binding protein as well as for progastrin [19,201. The structural requirements for the binding of gastrin and gastrin-Gly to the gastrin-binding protein have been established [19,37,381. To test the hypothesis that gastrin and gastrin-Gly stimulate tumor growth by interacting with the gastrinbinding protein (sometimes referred to as the cholecystokinin-C receptor), 102 human colorectal adenocarcinomas were screened by means of radioligand binding and a RNase protection assay [20].…”

Section: Discussionmentioning

confidence: 99%

Widespread Tissue Expression of Gastrin‐Binding‐Protein Mrna

Monstein

Nylander

Håkanson

1997

European Journal of Biochemistry

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Glycine-extended forms of gastrin (gastrin-Gly) are thought to be involved in the autocrine growth control of colorectal carcinomas. The recently described gastrin-binding protein has been suggested to be a gastrin-Gly accepting receptor. Northern blot analysis demonstrated the expression of gastrin-bindingprotein mRNA in many tissues of mouse, rat, and man. The gastrin-binding-protein mRNA expression was confirmed by reverse-transcribed PCR analysis. Analysis of the cDNA and the deduced amino acid sequence of the PCR-amplified rat gastrin-binding-protein DNA fragments revealed sequence identity (except in a single position) with the corresponding human and pig gastrin-binding protein and with the a-subunit of a rat and human mitochondria1 trifunctional enzyme, involved in fatty acid oxidation. The widespread and abundant tissue expression of gastrin-binding-protein mRNA and its sequence identity with a fatty-acid-oxidizing enzyme do not support the view that it represents a genuine gastrin receptor.Keywords: gastrin-binding protein; cholecystokinin-C receptor; gastrin-Gly ; trifunctional enzyme ; autocrine loop.Gastrin receptors bind C-terminally amidated gastrin-17 and related peptides, thereby inducing intracelluiar signal transduction. Two types of receptors for gastrin and cholecystokinin have been cloned and identified [ 1 -41. Cholecystokinin-A receptors (cholecystokinin-preferring receptors) are expressed in pancreas and in restricted parts of the brain, while cholecystokinin-B/gastrin receptors (recognizing gastrin and cholecystokinin with the same affinity) occur in gastric glands and are widespread in the brain [ 1-51. Cholecystokinin-A receptors in the pancreas control pancreatic enzyme secretion and growth, while cholecystokinin-B/gastrin receptors in the gastric gland control gastric acid secretion (via the so-called enterochromaffin-like cells) and growth of the acid-producing mucosa [6-91. Neither of these two receptors accepts glycine-extended gastrin (gastrin-Gly). An autocrine proliferative loop involving gastrin and gastrin-Gly in colonic and gastric carcinoma cells has been postulated. Gastrin and/or gastrin-Gly have growth-promoting effects on such tumors and on cell lines derived from them [lo-161. Studies on the binding and covalent cross-linking of labeled gastrin to partially purified preparations of canine and porcine gastric parietal cell membranes have revealed the presence of a gastrin-binding protein of similar molecular mass (78 kDa) as the recognized cholecystokinin-B/gastrin receptor [ 17, 181. It has been shown that gastrin-binding-protein mRNA is expressed in human colorectal carcinomas and colon carcinoma cell lines. Since the gastrin-binding protein has a similar affinity for gastrin-Gly as for gastrin-17, it was postulated that the gastrin-binding protein is Note. The nucleotide sequence of the rat gastrin-binding-protein cDNA reported here has been deposited with the EMBL database with accession number X98225.the target for the growth-promoting effect of gastrin-Gly in col...

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“…Because the presence of a third CCK receptor, the 72-kd CCK C receptor (Baldwin, 1994), has been reported in human tumors, we assayed the presence of CCK A , CCK B , and CCK C mRNAs in the U373 human glioma model. RNA extraction, DNAse treatment, and Reverse Transcription were performed as described above for the C6 and 9L rat tumor cells.…”

Section: Pcr Products Analyzed By Electrophoresis On 1% Agarose Gelsmentioning

confidence: 99%

“…The presence of mRNAs of cholecystokinin (CCK A ) and gastrin (CCK B ) receptors was assayed on the U373, C6, and 9L models by means of RT-PCR techniques. The presence of CCK C in human tumors, a third CCK/gastrin receptor, has already been described (Baldwin, 1994). We therefore also assayed the presence of mRNAs for CCK C receptors in the U373 human glioma model.…”

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confidence: 99%

Gastrin Significantly Modifies the Migratory Abilities of Experimental Glioma Cells

Lefranc

Camby

Belot

et al. 2002

Laboratory Investigation

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SUMMARY:Malignant astrocytic tumors are characterized by the pronounced and diffuse migration of tumor astrocytes into the brain parenchyma. The present study shows that gastrin is a brain neuropeptide that is able to significantly modulate astrocytic tumor migration at both invasion and motility levels. In the matter of invasion, gastrin severely reduces the in vitro invasive abilities of C6 rat glioma, 9L rat gliosarcoma, and U373 human glioma cells in a collagen matrix. In vitro, gastrin also markedly modifies the motility features in both C6 and U373 cells, at least partly through a decrease in the expression of the RhoA small GTPase, and so brings about some dramatic modifications to the organization in the actin cytoskeleton. The in vitro preincubation of C6 tumor cells with gastrin significantly increases the life spans of rats stereotactically implanted with these cells as compared with the survival periods of rats implanted with gastrin-untreated C6 cells. As suggested by our in vitro experiments, these effects, observed in vivo cannot relate to only the gastrin-induced decrease in tumor astrocyte migratory abilities. Indeed, gastrin also induces immunomodulatory effects, because we observed a marked gastrin-induced recruitment of lymphocytes into C6 gliomas and 9L gliosarcomas. These data all suggest that gastrin can act as an endogenous modulator of glioma progression. (Lab Invest 2002, 82:1241-1252.

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Antiproliferative gastrin/cholecystokinin receptor antagonists target the 78-kDa gastrin-binding protein.

Cited by 53 publications

References 30 publications

Processing and proliferative effects of human progastrin in transgenic mice.

Processing and proliferative effects of human progastrin in transgenic mice.

Widespread Tissue Expression of Gastrin‐Binding‐Protein Mrna

Gastrin Significantly Modifies the Migratory Abilities of Experimental Glioma Cells

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