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.
Pubmed ID: 12408868 RIS Download
Mesh terms: Cell Cycle | Cell Differentiation | Cell Division | Cell Transformation, Neoplastic | Colorectal Neoplasms | Cyclin-Dependent Kinase Inhibitor p21 | Cyclins | Cytoskeletal Proteins | DNA-Binding Proteins | Humans | Intestinal Mucosa | Phenotype | Proto-Oncogene Proteins c-myc | TCF Transcription Factors | Trans-Activators | Transcription Factor 7-Like 2 Protein | Transcription Factors | Tumor Cells, Cultured | beta Catenin
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