Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon
Open accessAbstract
Kras is commonly mutated in colon cancers, but mutations in Nras are rare. We have used genetically engineered mice to determine whether and how these related oncogenes regulate homeostasis and tumorigenesis in the colon. Expression of K-Ras(G12D) in the colonic epithelium stimulated hyperproliferation in a Mek-dependent manner. N-Ras(G12D) did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis. In the context of an Apc-mutant colonic tumor, activation of K-Ras led to defects in terminal differentiation and expansion of putative stem cells within the tumor epithelium. This K-Ras tumor phenotype was associated with attenuated signaling through the MAPK pathway, and human colon cancer cells expressing mutant K-Ras were hypersensitive to inhibition of Raf, but not Mek. These studies demonstrate clear phenotypic differences between mutant Kras and Nras, and suggest that the oncogenic phenotype of mutant K-Ras might be mediated by noncanonical signaling through Ras effector pathways.
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Additional biochemical, structural, and signaling distinctions have been identified between different mutant KRAS alleles, including between those at the same amino acid position.
“Additional biochemical, structural, and signaling distinctions have been identified between different mutant alleles, including between those at the same amino acid position4,8,13–20.”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [15]
Mutant KRAS is more effective at promoting colonic epithelial cell proliferation in mice.
“It has been shown that mutant KRAS is more effective at promoting colonic epithelial cell proliferation in mice (14)”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [14]
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- Authors
- Haigis, K. M., Kendall, K. R., Wang, Y., Cheung, A., Haigis, M. C., Glickman, J. N., Niwa-Kawakita, M., Sweet-Cordero, A., Sebolt-Leopold, J., Shannon, K. M., Settleman, J., Giovannini, M., & Jacks, T.
- Affiliations
- Massachusetts General Hospital (US)
- Massachusetts Institute of Technology (US)
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Stanford Medicine (US)
- University of California, San Francisco (US)
- Inserm (FR)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Jacks, Tyler
- ORCID
- Venue
- Nature Genetics
- Published
- 2008-03-30
- Volume
- 40
- Issue
- 5
- Pages
- 600-608
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2410301
- OpenAlex
- W2044210875
- Cited by
- 610
- References
- 36
- Citations by year
- 2026: 16 · 2025: 29 · 2024: 18 · 2023: 21 · 2022: 31 · 2021: 45 · 2020: 30 · 2019: 31 · 2018: 30 · 2017: 32 · 2016: 34 · 2015: 39 · 2014: 40 · 2013: 44 · 2012: 40
- FWCI
- 17.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- American Cancer Society
- Massachusetts Institute of Technology
- Association pour la Recherche sur le Cancer
- National Institutes of Health (5k01ca118425-05)
- National Cancer Institute (R01-CA 72614, P50CA127003, U01-CA84306, U54CA112967, U01 CA 84221, R01CA072614, K01-CA118425, U01CA084221, U01CA084306, R37CA072614, P30CA014051, P30-CA-14051)
- National Institute of General Medical Sciences (R01GM088827)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- KRAS, NRAS, colon cancer, colonic epithelium, cell proliferation, apoptosis resistance, terminal differentiation, cancer stem cells, APC mutation, MAPK signaling, RAF inhibition, MEK, Ras effector pathways, tumor progression, genetically modified mice
- MeSH terms
- Animals, Cell Differentiation, Colonic Neoplasms, Epithelium, Homeostasis, Humans, Mice, Transgenic, Mutation, Genes, ras, Signal Transduction, Apoptosis, Mitogen-Activated Protein Kinase Kinases, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Cell Proliferation, Mice
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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