The β-Catenin/TCF-4 Complex Imposes a Crypt Progenitor Phenotype on Colorectal Cancer Cells

• Published in: Cell 2002-10, Vol.111 (2), p.241-250
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: beta Catenin; Cell Cycle; Cell Differentiation; Cell Division; Cell Transformation, Neoplastic; Colorectal Neoplasms - genetics; Cyclin-Dependent Kinase Inhibitor p21; Cyclins - metabolism; Cytoskeletal Proteins - genetics; DNA-Binding Proteins - genetics; Humans; Intestinal Mucosa - metabolism; Phenotype; Proto-Oncogene Proteins c-myc - metabolism; TCF Transcription Factors; Trans-Activators - genetics; Transcription Factor 7-Like 2 Protein; Transcription Factors - genetics; Tumor Cells, Cultured
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(02)01014-0

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 p21 CIP1/WAF1 promoter. Following disruption of β-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 β-catenin/TCF-4 complex constitutes the master switch that controls proliferation versus differentiation in healthy and malignant intestinal epithelial cells.