Overexpression of glycine-extended gastrin in transgenic mice results in increased colonic proliferation
Overexpression of glycine-extended gastrin in transgenic mice results in increased colonic proliferation
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DOI：
10.1172/jci4910
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发表时间：
1999-04-01
影响因子：
15.9
通讯作者：
Wang, TC
中科院分区：
文献类型：
--
作者：
Koh, TJ;Dockray, GJ;Wang, TC
胃泌素是一种肽类激素，参与正常和恶性胃肠道组织的生长。最近的研究表明，甘氨酸延伸的生物合成中间体介导了许多这些营养效应，但甘氨酸延伸的胃泌素（G-Gly）的体内相关性尚未得到测试。我们制造了过表达甘氨酸-72截短的原胃泌素的小鼠（MTI/G-GLY），在体内模型中评估G-GLY的营养作用。与野生型小鼠相比，MTI/G-GLY小鼠血清和结肠黏膜中G-GLY水平升高。MTI/G-GLY小鼠结肠粘膜厚度增加43%，每个隐窝杯状细胞百分比增加41%。与野生型对照相比，MTI/G-GLY小鼠的结肠增殖增加，增殖区扩大到结肠隐窝的上三分之一。与单纯接受生理盐水的胃泌素缺乏小鼠相比，连续向胃泌素缺乏小鼠输注G-Gly两周也导致G-Gly水平升高，结肠粘膜厚度增加10%，结肠增殖增加81%。据我们所知，这些研究首次证明G-Gly在体内促进结肠粘膜增殖。
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.