@article{3b1105e91e0043b682c665c6caa60fdc,
title = "Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects",
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-rasG12D-expressing fibroblasts demonstrate attenuation and altered regulation of canonical Ras effector signaling pathways. Widespread expression of endogenous K-rasG12D 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.",
author = "Tuveson, {David A.} and Shaw, {Alice T.} and Willis, {Nicholas A.} and Silver, {Daniel P.} and Jackson, {Erica L.} and Sandy Chang and Mercer, {Kim L.} and Rebecca Grochow and Hanno Hock and Denise Crowley and Hingorani, {Sunil R.} and Tal Zaks and Catrina King and Jacobetz, {Michael A.} and Lifu Wang and Bronson, {Roderick T.} and Orkin, {Stuart H.} and DePinho, {Ronald A.} and Tyler Jacks",
note = "Funding Information: We apologize to our colleagues for not citing many primary references due to space constraints. We thank Dr. Klaus Rajewsky for the CMV-cre transgenic mice, Dr. S. O'Gorman for the Prmcre transgenic mice, Dr. Kay Wagner for the MMTV-cre transgenic mice, Dr. Jeff Gordon for the Fapb-cre transgenic mice, Dr. Elaine Fuchs for the K14-Cre and K14-CreERT mice, Dr. Michelle LeBeau for preliminary SKY analysis, Dr. Alan Diehl for advice with Cdk2/Cdk4 kinase assays, Dr. Hiroaki Kiyokawa for advice with the SAβ-gal assay, Dr. Scott Lowe for H-ras V12 cDNA, E1a, and c-Myc retroviral vectors, Dr. J. Morgenstern for the WZL.hygro vector, Dr. G. Nolan for the phoenix retroviral packaging system, Dr. Swain and Dr. Q.C. Yu for histological expertise and advice, and Dr. Robert Weinberg, Dr. Charles Sherr, Dr. Gideon Bollag, Dr. Kevin Shannon, and current and former members of our labs for helpful suggestions and critical review of this manuscript. D.A.T. acknowledges support from HHMI (Physician Postdoctoral Research Fellow), the Abramson Cancer Center of the University of Pennsylvania Pilot Projects Program and Grant IRG 78-002-26 from the American Cancer Society, and the AACR-PANCAN career development award. T.J. is an Investigator of HHMI. Support from the Center Grant P30 DK050306 is acknowledged.",
year = "2004",
month = apr,
doi = "10.1016/S1535-6108(04)00085-6",
language = "English (US)",
volume = "5",
pages = "375--387",
journal = "Cancer cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "4",
}