Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context

Cancer Cell. 2003 Aug;4(2):111-20. doi: 10.1016/s1535-6108(03)00191-0.

Abstract

We have targeted a K-ras allele in mouse embryonic stem (ES) cells to express a K-Ras(V12) oncoprotein along with a marker protein (beta-geo) from a single bicistronic transcript. Expression of this oncogenic allele requires removal of a knocked in STOP transcriptional cassette by Cre recombinase. Primary mouse embryonic fibroblasts expressing this K-ras(V12) allele do not undergo proliferative senescence and proliferate as immortal cells. In mice, expression of K-ras(V12) throughout the body fails to induce unscheduled proliferation or other growth abnormalities for up to eight months. Only a percentage of K-ras(V12)-expressing lung bronchiolo-alveolar cells undergo malignant transformation leading to the formation of multiple adenomas and adenocarcinomas. These results indicate that neoplastic growth induced by an endogenous K-ras oncogene depends upon cellular context.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Division
  • Cell Line, Transformed
  • Cell Transformation, Neoplastic*
  • Cellular Senescence
  • Chromosome Aberrations
  • Cyclin-Dependent Kinase Inhibitor p16
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Gene Targeting
  • Genes, ras / genetics*
  • Genetic Vectors / genetics
  • MAP Kinase Signaling System
  • Mice
  • Mice, Transgenic
  • Neoplasms / genetics*
  • Neoplasms / pathology*
  • Oncogene Protein p21(ras) / genetics
  • Oncogene Protein p21(ras) / metabolism
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stem Cells / pathology
  • Survival Rate
  • Tumor Suppressor Protein p14ARF / genetics
  • Tumor Suppressor Protein p14ARF / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Oncogene Protein p21(ras)