The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells

Marc Van de Wetering, Elena Sancho, Cornelis Verweij, Wim De Lau, Irma Oving, Adam Hurlstone, Karin Van der Horn, Eduard Batlle, Damien Coudreuse, Anna Pavlina Haramis, Menno Tjon-Pon-Fong, Petra Moerer, Maaike Van den Born, Gwen Soete, Steven Pals, Martin Eilers, Rene Medema, Hans Clevers

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

1779 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)241-250
Aantal pagina's10
TijdschriftCell
Volume111
Nummer van het tijdschrift2
DOI's
StatusGepubliceerd - 18 okt. 2002
Extern gepubliceerdJa

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