The β-Catenin/TCF-4 Complex Imposes a Crypt Progenitor Phenotype on Colorectal Cancer Cells
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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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KRAS G12V had an increased rate of comutation with TCF7L2, specifically the R488C mutation.
“KRAS G12V had an increased rate of comutation with TCF7L2, which encodes TCF4, a regulator of Wnt signaling often dysregulated in COAD49–51, specifically the R488C mutation.”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [51]
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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
- ORCID
- 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
- bronze
- doi.org
- Licence
- 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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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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