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 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.
Koh
T J
TJ
Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Dockray
G J
GJ
Varro
A
A
Cahill
R J
RJ
Dangler
C A
CA
Fox
J G
JG
Wang
T C
TC
D000818:Animals; D002455:Cell Division; D003106:Colon / Q000473:pathology*; D005755:Gastrins / Q000235:genetics / Q000502:physiology*; D005770:Gastrointestinal Neoplasms / Q000517:prevention & control; D015870:Gene Expression; D005998:Glycine; D020397:Goblet Cells / Q000473:pathology; D006801:Humans; D006965:Hyperplasia / Q000473:pathology; D006984:Hypertrophy / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011498:Protein Precursors / Q000235:genetics / Q000502:physiology*; D013270:Stomach / Q000473:pathology; D014407:Tumor Cells, Cultured
D005755:Gastrins; D011498:Protein Precursors; C013706:big gastrin; D005998:Glycine