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 mali gnant gastrointestinal tissue. Recent studies suggest that the glycine-exte nded biosynthetic intermediates mediate many of these trophic effects, but the in vivo relevance of glycine-extended gastrin (G-Gly) has not been test ed. We have generated mice (MTI/G-GLY) that overexpress progastrin truncate d at glycine-72 to evaluate the trophic effects of G-Gly in an in vivo mode l. MTI/G-GLY mice have elevated serum and colonic mucosal levels of G-Gly c ompared with wild-type mice. MTI/G-GLY mice had a 43% increase in colonic m ucosal thickness and a 41% increase in the percentage of goblet cells per c rypt. MTI/G-GLY mice exhibited increased colonic proliferation compared wit h wild-type controls, with an expansion of the proliferative zone into the upper third of the colonic crypts. Continuous infusion of G-Gly into gastri n-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 pro liferation when compared with gastrin-deficient mice that received saline a lone. To our knowledge, these studies demonstrate for the first time that G -Gly's contribute to colonic mucosal proliferation in vivo.