The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells.
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.
van de Wetering
Marc
M
Department of Immunology and Center for Biomedical Genetics, University Medical Center, 3584 CX, Utrecht, The Netherlands.
Sancho
Elena
E
Verweij
Cornelis
C
de Lau
Wim
W
Oving
Irma
I
Hurlstone
Adam
A
van der Horn
Karin
K
Batlle
Eduard
E
Coudreuse
Damien
D
Haramis
Anna Pavlina
AP
Tjon-Pon-Fong
Menno
M
Moerer
Petra
P
van den Born
Maaike
M
Soete
Gwen
G
Pals
Steven
S
Eilers
Martin
M
Medema
Rene
R
Clevers
Hans
H
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
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