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A Two-Step Model for Colon Adenoma Initiation and Progression Caused by APC Loss
Open accessAbstract
Aberrant Wnt/beta-catenin signaling following loss of the tumor suppressor adenomatous polyposis coli (APC) is thought to initiate colon adenoma formation. Using zebrafish and human cells, we show that homozygous loss of APC causes failed intestinal cell differentiation but that this occurs in the absence of nuclear beta-catenin and increased intestinal cell proliferation. Therefore, loss of APC is insufficient for causing beta-catenin nuclear localization. APC mutation-induced intestinal differentiation defects instead depend on the transcriptional corepressor C-terminal binding protein-1 (CtBP1), whereas proliferation defects and nuclear accumulation of beta-catenin require the additional activation of KRAS. These findings suggest that, following APC loss, CtBP1 contributes to adenoma initiation as a first step, whereas KRAS activation and beta-catenin nuclear localization promote adenoma progression to carcinomas as a second step. Consistent with this model, human FAP adenomas showed robust upregulation of CtBP1 in the absence of detectable nuclear beta-catenin, whereas nuclear beta-catenin was detected in carcinomas.
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“improved diagnostic tools and better access to early lesions have found that this is not the case, at least during the earliest stages of malignant transformation [6–8]”
From Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells (2018) · cites this paper as [8]
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Metadata
- Authors
- Phelps, R. A., Chidester, S., Dehghanizadeh, S., Phelps, J., Sandoval, I. T., Rai, K., Broadbent, T., Sarkar, S., Burt, R. W., & Jones, D. A.
- Affiliations
- University of Utah (US)
- Corresponding author
- Jones, David A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2009-05
- Volume
- 137
- Issue
- 4
- Pages
- 623-634
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2706149
- OpenAlex
- W2018425992
- Cited by
- 286
- References
- 51
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 9 · 2022: 8 · 2021: 13 · 2020: 11 · 2019: 14 · 2018: 14 · 2017: 18 · 2016: 22 · 2015: 23 · 2014: 17 · 2013: 23 · 2012: 28
- FWCI
- 13.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Huntsman Cancer Foundation
- National Institutes of Health (5p01ca073992-15)
- National Cancer Institute (R01CA116468, P01‐CA073992, CA96934, CA042014, CA073992, P30CA042014)
- 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
- colonic adenoma, APC loss, Wnt/β-catenin signaling, β-catenin nuclear localization, CtBP1, KRAS activation, intestinal cell differentiation, intestinal cell proliferation, familial adenomatous polyposis, colorectal cancer, zebrafish
- MeSH terms
- Adenoma, Alcohol Oxidoreductases, Animals, Cell Differentiation, Colonic Neoplasms, DNA-Binding Proteins, Humans, Peptide Fragments, Adenomatous Polyposis Coli, Zebrafish, Signal Transduction, Gene Expression Regulation, Neoplastic, ras Proteins, Proto-Oncogene Proteins c-raf, rac1 GTP-Binding Protein, Adenomatous Polyposis Coli Protein, beta Catenin
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