Author/Authors :
Marc van de Wetering، نويسنده , , Elena Sancho، نويسنده , , Cornelis Verweij، نويسنده , , Wim de Lau، نويسنده , , Irma Oving، نويسنده , , Adam Hurlstone، نويسنده , , Karin van der Horn، نويسنده , , Eduard Batlle، نويسنده , , Damien Coudreuse، نويسنده , , Anna-Pavlina Haramis، نويسنده , , Menno Tjon-Pon-Fong، نويسنده , , Petra Moerer، نويسنده , , Maaike van den Born، نويسنده , , Gwen Soete، نويسنده , , Steven Pals، نويسنده , , Martin Eilers، نويسنده , , Rene Medema، نويسنده , , Hans Clevers، نويسنده ,
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 β-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 p21CIP1/WAF1 promoter. Following disruption of β-catenin/TCF-4 activity, the decreased expression of c-MYC releases p21CIP1/WAF1 transcription, which in turn mediates G1 arrest and differentiation. Thus, the β-catenin/TCF-4 complex constitutes the master switch that controls proliferation versus differentiation in healthy and malignant intestinal epithelial cells.
