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.
Tuveson
David A
DA
Abramson Family Cancer Research Institute, Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA.
Shaw
Alice T
AT
Willis
Nicholas A
NA
Silver
Daniel P
DP
Jackson
Erica L
EL
Chang
Sandy
S
Mercer
Kim L
KL
Grochow
Rebecca
R
Hock
Hanno
H
Crowley
Denise
D
Hingorani
Sunil R
SR
Zaks
Tal
T
King
Catrina
C
Jacobetz
Michael A
MA
Wang
Lifu
L
Bronson
Roderick T
RT
Orkin
Stuart H
SH
DePinho
Ronald A
RA
Jacks
Tyler
T
D000818:Animals; D002453:Cell Cycle; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D000013:Congenital Abnormalities / Q000235:genetics* / Q000473:pathology; D003433:Crosses, Genetic; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D011905:Genes, ras / Q000502:physiology*; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D013234:Stem Cells / Q000473:pathology; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases