title: Endogenous oncogenic K-ras(G12D) 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-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.
authors.affiliation: Abramson Family Cancer Research Institute, Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Willis
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Silver
authors.forename: Erica L
authors.initials: EL
authors.lastname: Jackson
authors.forename: Sandy
authors.initials: S
authors.lastname: Chang
authors.forename: Kim L
authors.initials: KL
authors.lastname: Mercer
authors.forename: Rebecca
authors.initials: R
authors.lastname: Grochow
authors.forename: Hanno
authors.initials: H
authors.lastname: Hock
authors.forename: Denise
authors.initials: D
authors.lastname: Crowley
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Hingorani
authors.forename: Tal
authors.initials: T
authors.lastname: Zaks
authors.forename: Catrina
authors.initials: C
authors.lastname: King
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jacobetz
authors.forename: Lifu
authors.initials: L
authors.lastname: Wang
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
mesh_terms: 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
chemical_list: 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