Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects.
Document Type
Article
Publication Date
2004
Keywords
Animals, Cell-Aging, Cell-Cycle, Cell-Division, Cell-Transformation-Neoplastic, Crosses-Genetic, Embryo, Female, Fibroblasts, Gene-Expression-Regulation-Developmental, Genes-ras, Integrases, Male, Mice, Mice-Inbred-C57BL, Mice-Transgenic, Mutation, Neoplasms, Protein-p53, Stem-Cells, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S, Viral-Proteins, p14ARF-Protein
First Page
375
Last Page
387
JAX Source
Cancer Cell 2004 Apr; 5(4):375-87.
Abstract
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.
Recommended Citation
Tuveson DA,
Shaw AT,
Willis NA,
Silver DP,
Jackson EL,
Chang S,
Mercer KL,
Grochow R,
Hock H,
Crowley D,
Hingorani SR,
Zaks T,
King C,
Jacobetz MA,
Wang L,
Bronson RT,
Orkin SH,
DePinho RA,
Jacks T.
Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 2004 Apr; 5(4):375-87.