title: The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells.
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.
authors.affiliation: Department of Immunology and Center for Biomedical Genetics, University Medical Center, 3584 CX, Utrecht, The Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: van de Wetering
authors.forename: Elena
authors.initials: E
authors.lastname: Sancho
authors.forename: Cornelis
authors.initials: C
authors.lastname: Verweij
authors.forename: Wim
authors.initials: W
authors.lastname: de Lau
authors.forename: Irma
authors.initials: I
authors.lastname: Oving
authors.forename: Adam
authors.initials: A
authors.lastname: Hurlstone
authors.forename: Karin
authors.initials: K
authors.lastname: van der Horn
authors.forename: Eduard
authors.initials: E
authors.lastname: Batlle
authors.forename: Damien
authors.initials: D
authors.lastname: Coudreuse
authors.forename: Anna Pavlina
authors.initials: AP
authors.lastname: Haramis
authors.forename: Menno
authors.initials: M
authors.lastname: Tjon-Pon-Fong
authors.forename: Petra
authors.initials: P
authors.lastname: Moerer
authors.forename: Maaike
authors.initials: M
authors.lastname: van den Born
authors.forename: Gwen
authors.initials: G
authors.lastname: Soete
authors.forename: Steven
authors.initials: S
authors.lastname: Pals
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
authors.forename: Rene
authors.initials: R
authors.lastname: Medema
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
mesh_terms: D002453:Cell Cycle; D002454:Cell Differentiation; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured; D051176:beta Catenin
chemical_list: C493956:CDKN1A protein, human; C495270:CTNNB1 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D016271:Proto-Oncogene Proteins c-myc; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin