Cited by 2,030Wnt/β-catenin signaling in development and cancerGenetic factors in colorectal cancerColorectal Cancer Treatments and Studies

The β-Catenin/TCF-4 Complex Imposes a Crypt Progenitor Phenotype on Colorectal Cancer Cells

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van de Wetering, Marc, Sancho, Elena, Verweij, Cornelis, de Lau, Wim, Oving, Irma, Hurlstone, Adam, van der Horn, Karin, Batlle, Eduard +10 more·2002·Cell

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.

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Authors
van de Wetering, M., Sancho, E., Verweij, C., de Lau, W., Oving, I., Hurlstone, A., van der Horn, K., Batlle, E., Coudreuse, D., Haramis, A.-P., Tjon-Pon-Fong, M., Moerer, P., van den Born, M., Soete, G., Pals, S., Eilers, M., Medema, R., & Clevers, H.
Affiliations
  • University Medical Center Utrecht (NL)
  • Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • Philipps University of Marburg (DE)
Corresponding author
Clevers, Hans
Venue
Cell
Publisher
Elsevier BV
Published
2002-10
Volume
111
Issue
2
Pages
241-250
ISSN
0092-8674 (ISSN-L)
OpenAlex
W2171996338
Cited by
2,030
References
51
Citations by year
2026: 23 · 2025: 31 · 2024: 35 · 2023: 44 · 2022: 43 · 2021: 53 · 2020: 76 · 2019: 54 · 2018: 71 · 2017: 66 · 2016: 69 · 2015: 88 · 2014: 118 · 2013: 100 · 2012: 110
FWCI
36.51
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion)
  • KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Utrecht University Repository (Utrecht University) (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Keywords
TCF4, colorectal cancer, Wnt signaling, c-Myc, p21, G1 cell cycle arrest, intestinal differentiation, transcriptional repression, intestinal epithelium
MeSH terms
Cell Cycle, Cell Differentiation, Cell Division, Cell Transformation, Neoplastic, Cytoskeletal Proteins, DNA-Binding Proteins, Humans, Intestinal Mucosa, Phenotype, Transcription Factors, Tumor Cells, Cultured, Colorectal Neoplasms, Trans-Activators, Cyclins, Proto-Oncogene Proteins c-myc, Cyclin-Dependent Kinase Inhibitor p21, beta Catenin, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein

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