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Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects
Open accessAbstract
Activating mutations in the ras oncogene are not considered sufficient to induce abnormal cellular proliferation in the absence of cooperating oncogenes. We demonstrate that the conditional expression of an endogenous K-ras(G12D) allele in murine embryonic fibroblasts causes enhanced proliferation and partial transformation in the absence of further genetic abnormalities. Interestingly, K-ras(G12D)-expressing fibroblasts demonstrate attenuation and altered regulation of canonical Ras effector signaling pathways. Widespread expression of endogenous K-ras(G12D) is not tolerated during embryonic development, and directed expression in the lung and GI tract induces preneoplastic epithelial hyperplasias. Our results suggest that endogenous oncogenic ras is sufficient to initiate transformation by stimulating proliferation, while further genetic lesions may be necessary for progression to frank malignancy.
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“Consistent with this view, mutational activation of RAS without overexpression stimulates cell proliferation and transformation, not cellular senescence (Tuveson et al., 2004).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Tuveson et al., 2004
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Metadata
- Authors
- Tuveson, D. A., Shaw, A. T., Willis, N. A., Silver, D. P., Jackson, E. L., Chang, S., Mercer, K. L., Grochow, R., Hock, H., Crowley, D., Hingorani, S. R., Zaks, T., King, C., Jacobetz, M. A., Wang, L., Bronson, R. T., Orkin, S. H., DePinho, R. A., & Jacks, T.
- Affiliations
- Abramson Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Dana-Farber Cancer Institute (US)
- Massachusetts Institute of Technology (US)
- The University of Texas MD Anderson Cancer Center (US)
- Tufts University (US)
- Boston Children's Hospital (US)
- Corresponding author
- Jacks, Tyler
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2004-04
- Volume
- 5
- Issue
- 4
- Pages
- 375-387
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2050389860
- Cited by
- 798
- References
- 49
- Citations by year
- 2026: 15 · 2025: 28 · 2024: 25 · 2023: 22 · 2022: 26 · 2021: 39 · 2020: 26 · 2019: 35 · 2018: 31 · 2017: 33 · 2016: 41 · 2015: 39 · 2014: 48 · 2013: 41 · 2012: 48
- FWCI
- 14.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK050306)
- 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 › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS G12D, ras oncogene activation, cell proliferation, fibroblast transformation, embryonic development, lung, gastrointestinal tract, conditional gene expression
- MeSH terms
- Congenital Abnormalities, Animals, Cell Cycle, Cell Division, Cell Transformation, Neoplastic, Crosses, Genetic, Embryo, Mammalian, Female, Fibroblasts, Male, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Neoplasms, Genes, ras, Stem Cells, Viral Proteins, Tumor Suppressor Protein p53, Cellular Senescence, Gene Expression Regulation, Developmental, Integrases, Cyclin-Dependent Kinase Inhibitor p16, Tumor Suppressor Protein p14ARF, Mice
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