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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Cell Cycle
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Cell Differentiation
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Cell Division
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Cell Transformation, Neoplastic
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Colorectal Neoplasms / genetics*
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / metabolism
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Cytoskeletal Proteins / genetics*
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DNA-Binding Proteins / genetics*
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Humans
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Intestinal Mucosa / metabolism
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Phenotype
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Proto-Oncogene Proteins c-myc / metabolism
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TCF Transcription Factors
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Trans-Activators / genetics*
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Transcription Factor 7-Like 2 Protein
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Transcription Factors / genetics*
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Tumor Cells, Cultured
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beta Catenin
Substances
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CDKN1A protein, human
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CTNNB1 protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Cytoskeletal Proteins
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DNA-Binding Proteins
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Proto-Oncogene Proteins c-myc
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TCF Transcription Factors
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TCF7L2 protein, human
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Trans-Activators
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Transcription Factor 7-Like 2 Protein
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Transcription Factors
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beta Catenin