title: Temporal dissection of K-ras(G12D) mutant in vitro and in vivo using a regulatable K-ras(G12D) mouse allele.
abstract: Animal models which allow the temporal regulation of gene activities are valuable for dissecting gene function in tumorigenesis. Here we have constructed a conditional inducible estrogen receptor-K-ras(G12D) (ER-K-ras(G12D)) knock-in mice allele that allows us to temporally switch on or off the activity of K-ras oncogenic mutant through tamoxifen administration. In vitro studies using mice embryonic fibroblast (MEF) showed that a dose of tamoxifen at 0.05 µM works optimally for activation of ER-K-ras(G12D) independent of the gender status. Furthermore, tamoxifen-inducible activation of K-ras(G12D) promotes cell proliferation, anchor-independent growth, transformation as well as invasion, potentially via activation of downstream MAPK pathway and cell cycle progression. Continuous activation of K-ras(G12D) in vivo by tamoxifen treatment is sufficient to drive the neoplastic transformation of normal lung epithelial cells in mice. Tamoxifen withdrawal after the tumor formation results in apoptosis and tumor regression in mouse lungs. Taken together, these data have convincingly demonstrated that K-ras mutant is essential for neoplastic transformation and this animal model may provide an ideal platform for further detailed characterization of the role of K-ras oncogenic mutant during different stages of lung tumorigenesis.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zuoyun
authors.initials: Z
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardessy
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Liu
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
mesh_terms: D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D011905:Genes, ras; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D011960:Receptors, Estrogen / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D017931:DNA Primers; D011960:Receptors, Estrogen; D013629:Tamoxifen