β-连环蛋白/TCF-4复合物赋予结肠癌细胞隐窝祖细胞表型。

The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells.

作者信息

van de Wetering Marc, Sancho Elena, Verweij Cornelis, de Lau Wim, Oving Irma, Hurlstone Adam, van der Horn Karin, Batlle Eduard, Coudreuse Damien, Haramis Anna Pavlina, Tjon-Pon-Fong Menno, Moerer Petra, van den Born Maaike, Soete Gwen, Pals Steven, Eilers Martin, Medema Rene, Clevers Hans

机构信息

Department of Immunology and Center for Biomedical Genetics, University Medical Center, 3584 CX, Utrecht, The Netherlands.

出版信息

Cell. 2002 Oct 18;111(2):241-50. doi: 10.1016/s0092-8674(02)01014-0.

DOI:10.1016/s0092-8674(02)01014-0

PMID:12408868

Abstract

The transactivation of TCF target genes induced by Wnt 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.

摘要

Wnt信号通路突变诱导的TCF靶基因反式激活是结直肠癌（CRC）中的主要转化事件。我们发现，CRC细胞中β-连环蛋白/TCF-4活性的破坏会诱导快速的G1期阻滞，并阻断在结肠隐窝增殖区生理活性的遗传程序。巧合的是，肠道分化程序被诱导。TCF-4靶基因c-MYC通过直接抑制p21（CIP1/WAF1）启动子在这种转换中起核心作用。β-连环蛋白/TCF-4活性破坏后，c-MYC表达降低释放p21（CIP1/WAF1）转录，进而介导G1期阻滞和分化。因此，β-连环蛋白/TCF-4复合物构成了控制健康和恶性肠上皮细胞增殖与分化的主开关。