Forced expression of the tumor suppressor adenomatosis polyposis coli protein induces disordered cell migration in the intestinal epithelium.
Forced expression of the tumor suppressor adenomatosis polyposis coli protein induces disordered cell migration in the intestinal epithelium.
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DOI：
10.1073/pnas.93.18.9588
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发表时间：
1996-09
影响因子：
11.1
通讯作者：
Melissa H. Wong;Michelle L. Hermiston;A. Syder;J. I. Gordon
中科院分区：
文献类型：
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作者：
Melissa H. Wong;Michelle L. Hermiston;A. Syder;J. I. Gordon
人类大肠腺瘤性息肉病（APC）基因突变与家族性和散发性肠肿瘤的发生有关。为了检查APC的体内功能，用编码野生型人蛋白的DNA转染129/Sv胚胎干（ES）细胞，所述野生型人蛋白在其迁移相关分化期间在小肠的所有四种主要上皮谱系中具有活性的启动子的控制下。然后将ES-APC细胞引入C57 BL/6-R 0 SA 26胚泡中。对成年B6-R 0 SA 26129/Sv-APC嵌合小鼠的分析显示，APC的强制表达导致明显紊乱的细胞迁移。当与E-钙粘蛋白的强制表达的影响相比，数据表明，APC-连环蛋白和E-钙粘蛋白-连环蛋白复合物对肠上皮细胞运动/粘附具有相反的影响;增强E-钙粘蛋白-β-连环蛋白复合物产生高度有序的“粘附性”迁移，而增强APC-β-连环蛋白复合物产生无序的非粘附性迁移表型。我们认为APC突变可能通过增加钙粘蛋白-连环蛋白复合物的相对活性来促进肿瘤发生，从而增强肠隐窝内启动细胞的粘附和功能锚定。我们的研究还表明，从B6-ROSA 26囊胚和遗传操作的ES细胞产生的嵌合小鼠应该是有用的审计基因功能在胃肠道和其他组织。
Mutations of the human adenomatosis polyposis coli (APC) gene are associated with the development of familial as well as sporadic intestinal neoplasia. To examine the in vivo function of APC, 129/Sv embryonic stem (ES) cells were transfected with DNA encoding the wild-type human protein under the control of a promoter that is active in all four of the small intestine's principal epithelial lineages during their migration-associated differentiation. ES-APC cells were then introduced into C57BL/6-ROSA26 blastocysts. Analyses of adult B6-ROSA26129/Sv-APC chimeric mice revealed that forced expression of APC results in markedly disordered cell migration. When compared with the effects of forced expression of E-cadherin, the data suggest that APC-catenin and E-cadherin-catenin complexes have opposing effects on intestinal epithelial cell movement/adhesiveness; augmentation of E-cadherin-beta-catenin complexes produces a highly ordered, "adhesive" migration, whereas augmentation of APC-beta-catenin complexes produces a disordered, nonadhesive migratory phenotype. We propose that APC mutations may promote tumorigenesis by increasing the relative activity of cadherin-catenin complexes, resulting in enhanced adhesiveness and functional anchorage of initiated cells within the intestinal crypt. Our studies also indicate that chimeric mice generated from B6-ROSA26 blastocysts and genetically manipulated ES cells should be useful for auditing gene function in the gastrointestinal tract and in other tissues.