The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells
The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells
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DOI：
10.1016/s0092-8674(02)01014-0
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发表时间：
2002-10-18
期刊：
影响因子：
64.5
通讯作者：
Clevers, H
中科院分区：
文献类型：
--
作者：
van de Wetering, M;Sancho, E;Clevers, H
Writ通路突变诱导的TCF靶基因的反式激活构成结直肠癌（CRC）的主要转化事件。我们发现，在CRC细胞中β-连环蛋白/TCF-4活性的破坏诱导了快速的G1期阻滞，并阻断了在结肠隐窝的增殖区室中具有生理活性的遗传程序。巧合的是，肠分化程序被诱导。TCF-4靶基因c-MYC通过直接抑制p21（CIP 1/WAF 1）启动子在该开关中发挥核心作用。在β-连环蛋白/TCF-4活性被破坏后，c-MYC的表达减少释放p21（CIP 1/WAF 1）转录，这反过来介导G1停滞和分化。因此，β-连环蛋白/TCF-4复合物构成控制健康和恶性肠上皮细胞增殖与分化的主开关。
The transactivation of TCF target genes induced by Writ pathway mutations constitutes the primary transforming event in colorectal cancer (CRC). We show that disruption of beta-catenin/TCF-4 activity in CRC cells induces a rapid G1 arrest and blocks a genetic program that is physiologically active in the proliferative compartment of colon crypts. Coincidently, an intestinal differentiation program is induced. The TCF-4 target gene c-MYC plays a central role in this switch by direct repression of the p21(CIP1/WAF1) promoter. Following disruption of beta-catenin/TCF-4 activity, the decreased expression of c-MYC releases p21(CIP1/WAF1), transcription, which in turn mediates G1 arrest and differentiation. Thus, the beta-catenin/TCF-4 complex constitutes the master switch that controls proliferation versus differentiation in healthy and malignant intestinal epithelial cells.