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Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects.

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.

Pubmed ID: 15093544


  • 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


Cancer cell

Publication Data

April 19, 2004

Associated Grants

  • Agency: NIDDK NIH HHS, Id: P30 DK050306

Mesh Terms

  • Animals
  • Cell Aging
  • Cell Cycle
  • Cell Division
  • Cell Transformation, Neoplastic
  • Congenital Abnormalities
  • Crosses, Genetic
  • Cyclin-Dependent Kinase Inhibitor p16
  • Embryo, Mammalian
  • Female
  • Fibroblasts
  • Gene Expression Regulation, Developmental
  • Genes, ras
  • Integrases
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Neoplasms
  • Stem Cells
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53
  • Viral Proteins