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V600EBraf induces gastrointestinal crypt senescence and promotes tumour progression through enhanced CpG methylation of p16INK4a
Open accessAbstract
The majority of human colorectal cancers (CRCs) are initiated by mutations arising in the adenomatous polyposis coli (APC) tumour suppressor gene. However, a new class of non-APC mutated CRCs has been defined that have a serrated histopathology and carry the (V600E)BRAF oncogene. Here we have investigated the pathogenesis of serrated CRCs by expressing (V600E)Braf in the proliferative cells of the mouse gastrointestinal tract. We show that the oncogene drives an initial burst of Mek-dependent proliferation, leading to the formation of hyperplastic crypts. This is associated with β-catenin nuclear localization by a mechanism involving Mapk/Erk kinase (Mek)-dependent, Akt-independent phosphorylation of Gsk3β. However, hyperplastic crypts remain dormant for prolonged periods due to the induction of crypt senescence accompanied by upregulation of senescence-associated β-galactosidase and p16(Ink4a). We show that tumour progression is associated with down-regulation of p16(Ink4a) through enhanced CpG methylation of exon 1 and knockout of Cdkn2a confirms this gene is a barrier to tumour progression. Our studies identify (V600E)BRAF as an early genetic driver mutation in serrated CRCs and indicate that, unlike APC-mutated cancers, this subtype arises by the bypassing of a (V600E)Braf driven oncogene-induced senescence programme.
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“Colon SSAs are mainly driven by activating BRAF mutations that trigger OIS 31,34,35 .”
From A complex secretory program orchestrated by the inflammasome controls paracrine senescence (2013) · cites this paper as [31]
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Metadata
- Authors
- Carragher, L. A. S., Snell, K. R., Giblett, S. M., Aldridge, V. S. S., Patel, B., Cook, S. J., Winton, D. J., Marais, R., & Pritchard, C. A.
- Affiliations
- University of Leicester (GB)
- Babraham Institute (GB)
- Institute of Cancer Research (GB)
- Corresponding author
- Pritchard, Catrin A.
- Venue
- EMBO Molecular Medicine
- Published
- 2010-10-13
- Volume
- 2
- Issue
- 11
- Pages
- 458-471
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC3394506
- OpenAlex
- W2118133069
- Cited by
- 144
- References
- 52
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 10 · 2023: 7 · 2022: 3 · 2021: 6 · 2020: 9 · 2019: 10 · 2018: 11 · 2017: 7 · 2016: 11 · 2015: 10 · 2014: 12 · 2013: 17 · 2012: 10
- FWCI
- 8.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Funders
- Hope Against Cancer
- Cancer Research UK (C1362/A6969)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- p16INK4a, CpG methylation, CDKN2A, oncogene-induced senescence, MEK/ERK signaling, GSK3β phosphorylation, β-catenin nuclear localization, tumor progression
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Aging, Animals, Cell Nucleus, Hyperplasia, Colorectal Neoplasms, Up-Regulation, DNA Methylation, Cyclin-Dependent Kinase Inhibitor p16, Amino Acid Substitution, Mutation, Missense, Gene Expression Profiling, Glycogen Synthase Kinase 3, Gastrointestinal Tract, Proto-Oncogene Proteins B-raf, beta Catenin, Mice
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