Processing and proliferative effects of human progastrin in transgenic mice
Processing and proliferative effects of human progastrin in transgenic mice
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DOI：
10.1172/jci118993
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发表时间：
1996-10-15
影响因子：
15.9
通讯作者：
Dockray, GJ
中科院分区：
文献类型：
--
作者：
Wang, TC;Koh, TJ;Dockray, GJ
不完全加工的胃泌素被假定在胃肠道的生长中起作用，但是很少有研究检查前胃泌素对体内粘膜增殖的影响。因此，在含有人胃泌素（hGAS）小基因的转基因小鼠中研究了人胃泌素基因表达和前胃泌素加工，并与携带过表达酰胺化胃泌素的胰岛素胃泌素（INS-GAS）转基因的小鼠中的加工进行比较。使用区域特异性抗血清和放射免疫测定、生物合成标记、免疫沉淀和HPLC研究前胃泌素加工，使用常规组织学和BrdU掺入分别测定INS-GAS和hGAS小鼠中加工和未加工胃泌素过表达的抑制作用。INS-GAS小鼠的胰岛能够产生羧酰胺化G-17，导致血清酰胺化胃泌素升高两倍，泌酸粘膜显著增厚，胃体BrdU标记指数（LI）增加。与此相反，成年hGAS小鼠的肝脏表达丰富的人胃泌素mRNA和人前胃泌素，但不能将该肽加工成成熟的酰胺化形式，导致血清前胃泌素水平显著升高和正常的酰胺化胃泌素水平，然而，hGAS小鼠的结肠BrdU标记指数显著增加与年龄匹配的野生型对照小鼠（LI 4.01+/-0.98%，P < 0.05）相比，INS-GAS小鼠（LI 6.16+/-1.17%）中的表达水平显著降低（LI 7.46+/-1.90%，P < 0.05）。这些研究表明，不完全加工的胃泌素前体可能有助于体内结肠粘膜增殖。
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+/-1.90%), as well as in INS-GAS mice (LI 6.16+/-1.17%), compared to age-matched, wild type control mice (LI 4.01+/-0.98%, P < 0.05). These studies suggest that incompletely processed gastrin precursors may contribute to colonic mucosal proliferation in vivo.