[HTML][HTML] The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells
M Van de Wetering, E Sancho, C Verweij, W De Lau… - Cell, 2002 - cell.com
M Van de Wetering, E Sancho, C Verweij, W De Lau, I Oving, A Hurlstone, K Van Der Horn…
Cell, 2002•cell.comThe 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 p21 CIP1/WAF1 promoter. Following disruption …
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 p21 CIP1/WAF1 promoter. Following disruption …
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 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.
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