Haploinsufficiency of Krüppel-like factor 5 rescues the tumor-initiating effect of the Apc(Min) mutation in the intestine.
Haploinsufficiency of Krüppel-like factor 5 rescues the tumor-initiating effect of the Apc(Min) mutation in the intestine.
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DOI：
10.1158/0008-5472.can-08-4402
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发表时间：
2009-05-15
期刊：
影响因子：
11.2
通讯作者：
Yang VW
中科院分区：
文献类型：
--
作者：
McConnell BB;Bialkowska AB;Nandan MO;Ghaleb AM;Gordon FJ;Yang VW
肿瘤抑制基因腺瘤性结肠息肉病的失活，导致β-连环蛋白的活化，是大多数结直肠癌发展的起始事件。Krüppel样因子5（KLF 5）是一种促增殖转录因子，在肠腺上皮细胞增殖过程中高度表达。为了确定KLF 5是否有助于肠腺瘤形成，我们检查了ApcMin/+小鼠和ApcMin/+/Klf 5 +/−小鼠的肿瘤负荷。与ApcMin/+小鼠相比，ApcMin/+/Klf 5 +/-小鼠的肠道腺瘤数量减少了96%。ApcMin/+/Klf 5 +/−小鼠中致瘤性的降低与β-连环蛋白水平和核定位的降低以及两种β-连环蛋白靶点细胞周期蛋白D1和c-Myc的表达降低相关。体外研究显示KLF 5和β-catenin之间的物理相互作用增强了β-catenin的核定位和转录活性。因此，在ApcMin/+小鼠的肠腺瘤形成过程中，KLF 5对于β-连环蛋白的肿瘤起始活性是必需的，并且KLF 5的表达降低通过降低β-连环蛋白的核定位和活性来抵消ApcMin突变的肿瘤起始活性。
Inactivation of the tumor suppressor adenomatous polyposis coli, with the resultant activation of β-catenin, is the initiating event in the development of a majority of colorectal cancers. Krüppel-like factor 5 (KLF5), a proproliferative transcription factor, is highly expressed in the proliferating intestinal crypt epithelial cells. To determine whether KLF5 contributes to intestinal adenoma formation, we examined tumor burdens in ApcMin/+ mice and ApcMin/+/Klf5+/− mice. Compared with ApcMin/+ mice, ApcMin/+/Klf5+/− mice had a 96% reduction in the number of intestinal adenomas. Reduced tumorigenicity in the ApcMin/+/Klf5+/− mice correlated with reduced levels and nuclear localization of β-catenin as well as reduced expression of two β-catenin targets, cyclin D1 and c-Myc. In vitro studies revealed a physical interaction between KLF5 and β-catenin that enhanced the nuclear localization and transcriptional activity of β-catenin. Thus, KLF5 is necessary for the tumor-initiating activity of β-catenin during intestinal adenoma formation in ApcMin/+ mice, and reduced expression of KLF5 offsets the tumor-initiating activity of the ApcMin mutation by reducing the nuclear localization and activity of β-catenin.