Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context.
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.
Guerra
Carmen
C
Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain.
Mijimolle
Nieves
N
Dhawahir
Alma
A
Dubus
Pierre
P
Barradas
Marta
M
Serrano
Manuel
M
Campuzano
Victoria
V
Barbacid
Mariano
M
D000818:Animals; D002455:Cell Division; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D002869:Chromosome Aberrations; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D018390:Gene Targeting; D011905:Genes, ras / Q000235:genetics*; D005822:Genetic Vectors / Q000235:genetics; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000473:pathology; D015996:Survival Rate; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011518:Proto-Oncogene Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D015689:Oncogene Protein p21(ras)