Overexpression of glycine-extended gastrin in transgenic mice results in increased colonic proliferation

Gastrin is a peptide hormone involved in the growth of both normal and malignant gastrointestinal tissue. Recent studies suggest that the glycine-extended biosynthetic intermediates mediate many of these trophic effects, but the in vivo relevance of glycine-extended gastrin (G-Gly) has not been test...

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Bibliographic Details
Published in:The Journal of clinical investigation 1999-04, Vol.103 (8), p.1119-1126
Main Authors: Koh, T J, Dockray, G J, Varro, A, Cahill, R J, Dangler, C A, Fox, J G, Wang, T C
Format: Article
Language:English
Subjects:
Animals
Cell Division
Colon - pathology
Gastrins - genetics
Gastrins - physiology
Gastrointestinal Neoplasms - prevention & control
Gene Expression
Glycine
Goblet Cells - pathology
Humans
Hyperplasia - pathology
Hypertrophy - pathology
Male
Mice
Mice, Transgenic
Protein Precursors - genetics
Protein Precursors - physiology
Stomach - pathology
Tumor Cells, Cultured
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Summary:Gastrin is a peptide hormone involved in the growth of both normal and malignant gastrointestinal tissue. Recent studies suggest that the glycine-extended biosynthetic intermediates mediate many of these trophic effects, but the in vivo relevance of glycine-extended gastrin (G-Gly) has not been tested. We have generated mice (MTI/G-GLY) that overexpress progastrin truncated at glycine-72 to evaluate the trophic effects of G-Gly in an in vivo model. MTI/G-GLY mice have elevated serum and colonic mucosal levels of G-Gly compared with wild-type mice. MTI/G-GLY mice had a 43% increase in colonic mucosal thickness and a 41% increase in the percentage of goblet cells per crypt. MTI/G-GLY mice exhibited increased colonic proliferation compared with wild-type controls, with an expansion of the proliferative zone into the upper third of the colonic crypts. Continuous infusion of G-Gly into gastrin-deficient mice for two weeks also resulted in elevated G-Gly levels, a 10% increase in colonic mucosal thickness, and an 81% increase in colonic proliferation when compared with gastrin-deficient mice that received saline alone. To our knowledge, these studies demonstrate for the first time that G-Gly's contribute to colonic mucosal proliferation in vivo.
ISSN:0021-9738
DOI:10.1172/jci4910