Cyclin D1 genetic heterozygosity regulates colonic epithelial cell differentiation and tumor number in ApcMin mice
Cyclin D1 genetic heterozygosity regulates colonic epithelial cell differentiation and tumor number in ApcMin mice
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DOI：
10.1128/mcb.24.17.7598-7611.2004
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发表时间：
2004-09-01
影响因子：
5.3
通讯作者：
Pestell, RG
中科院分区：
文献类型：
--
作者：
Hulit, J;Wang, CG;Pestell, RG
结构性β-连环蛋白/Tcf活性是结直肠癌的主要转化事件，通过诱导Wnt通路或APC基因突变而导致家族性腺瘤性息肉病。在其生殖系(APC(Min))中携带APC突变的小鼠会发生肠腺瘤。在这里，APC(Min)与细胞周期蛋白D1(-/-)小鼠的杂交减少了细胞周期蛋白D1基因杂合或无效的动物的肠道肿瘤数量。APC(Min)/Cyclin D1(+/-)小鼠十二指肠、肠道和结肠肿瘤数量减少与细胞增殖减少和分化增加相关。在体内，细胞周期蛋白D1缺乏降低了含有突变型APC的结肠上皮细胞的DNA合成，并诱导其分化。在以前的研究中，通过纯合子基因缺失而完全丧失的细胞周期蛋白D1传递了乳腺肿瘤的耐药性。通过细胞周期蛋白D1杂合性对遗传易感于肠道肿瘤发生的小鼠的保护表明，降低细胞周期蛋白D1丰度的方法可以提供化学保护。
Constitutive beta-catenin/Tcf activity, the primary transforming events in colorectal carcinoma, occurs through induction of the Wnt pathway or APC gene mutations that cause familial adenomatous polyposis. Mice carrying Apc mutations in their germ line (Apc(Min)) develop intestinal adenomas. Here, the crossing of Apc(Min) with cyclin D1(-/-) mice reduced the intestinal tumor number in animals genetically heterozygous or nullizygous for cyclin D1. Decreased tumor number in the duodenum, intestines, and colons of Apc(Min)/cyclin D1(+/-) mice correlated with reduced cellular proliferation and increased differentiation. Cyclin D1 deficiency reduced DNA synthesis and induced differentiation of colonic epithelial cells harboring mutant APC but not wild-type APC cells in vivo. In previous studies, the complete loss of cyclin D1 through homozygous genetic deletion conveyed breast tumor resistance. The protection of mice, genetically predisposed to intestinal tumorigenesis, through cyclin D1 heterozygosity suggests that modalities that reduce cyclin D1 abundance could provide chemoprotection.