TY - JOUR
T1 - The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells
AU - Van de Wetering, Marc
AU - Sancho, Elena
AU - Verweij, Cornelis
AU - De Lau, Wim
AU - Oving, Irma
AU - Hurlstone, Adam
AU - Van der Horn, Karin
AU - Batlle, Eduard
AU - Coudreuse, Damien
AU - Haramis, Anna Pavlina
AU - Tjon-Pon-Fong, Menno
AU - Moerer, Petra
AU - Van den Born, Maaike
AU - Soete, Gwen
AU - Pals, Steven
AU - Eilers, Martin
AU - Medema, Rene
AU - Clevers, Hans
N1 - Funding Information:
We thank Patrick Brown for making DNA microarrays and support services available for the DNA microarray studies. E.S. and E.B. are recipients of Marie Curie Fellowships. This work was supported in part by a grant from the NCI to P.O. Brown.
PY - 2002/10/18
Y1 - 2002/10/18
N2 - 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 p21CIP1/WAF1 promoter. Following disruption of β-catenin/TCF-4 activity, the decreased expression of c-MYC releases p21CIP1/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.
AB - 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 p21CIP1/WAF1 promoter. Following disruption of β-catenin/TCF-4 activity, the decreased expression of c-MYC releases p21CIP1/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.
UR - http://www.scopus.com/inward/record.url?scp=18644373146&partnerID=8YFLogxK
U2 - 10.1016/S0092-8674(02)01014-0
DO - 10.1016/S0092-8674(02)01014-0
M3 - Article
C2 - 12408868
AN - SCOPUS:18644373146
SN - 0092-8674
VL - 111
SP - 241
EP - 250
JO - Cell
JF - Cell
IS - 2
ER -