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 a...

Full description

Saved in:
Bibliographic Details
Published in:Cancer cell 2004-04, Vol.5 (4), p.375-387
Main Authors: Tuveson, David A, Shaw, Alice T, Willis, Nicholas A, Silver, Daniel P, Jackson, Erica L, Chang, Sandy, Mercer, Kim L, Grochow, Rebecca, Hock, Hanno, Crowley, Denise, Hingorani, Sunil R, Zaks, Tal, King, Catrina, Jacobetz, Michael A, Wang, Lifu, Bronson, Roderick T, Orkin, Stuart H, DePinho, Ronald A, Jacks, Tyler
Format: Article
Language:English
Subjects:
Animals
Cell Cycle
Cell Division
Cell Transformation, Neoplastic
Cellular Senescence
Congenital Abnormalities - genetics
Congenital Abnormalities - pathology
Crosses, Genetic
Cyclin-Dependent Kinase Inhibitor p16
Embryo, Mammalian - cytology
Female
Fibroblasts - metabolism
Fibroblasts - pathology
Gene Expression Regulation, Developmental - physiology
Genes, ras - physiology
Integrases - metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Neoplasms - genetics
Neoplasms - pathology
Stem Cells - pathology
Tumor Suppressor Protein p14ARF - genetics
Tumor Suppressor Protein p14ARF - metabolism
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Viral Proteins - metabolism
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1535-6108
DOI:10.1016/S1535-6108(04)00085-6