title: Inducible activation of Ras and Raf in adult epidermis.
abstract: Ras effects vary with developmental setting, with oncogenic RAS activation implicated in epithelial carcinogenesis. In epidermal cells, previous studies described conflicting Ras impacts on growth and differentiation, with the only in vivo studies relying on constitutive alterations of Ras function throughout development. To study Ras effects in developmentally mature adult epidermis, we expressed a 4-hydroxytamoxifen (4OHT)-regulated Ras fusion in transgenic mice using the keratin 14 promoter. Resulting adult K14-ER:Ras mice displayed 4OHT-inducible activation of Ras as well as elements of Raf/mitogen-activated protein kinase (MAPK) but not RalGDS/Ral or phosphatidylinositol 3'-kinase (PI3K)/Akt downstream Ras effector pathways. Ras reversibly induced massive cutaneous hyperplasia and suppressed differentiation. Ras-driven hyperproliferation was accompanied by increases in beta1 and beta4 integrin epidermal progenitor markers. Epidermal expression of inducible Raf produced similar changes. These findings indicate that activation of Ras in adult epidermis promotes proliferation and inhibits differentiation and that Raf is sufficient to mediate these effects.
authors.affiliation: Veterans Affairs Valo Alto Healthcare System and the Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Masahito
authors.initials: M
authors.lastname: Tarutani
authors.forename: Ti
authors.initials: T
authors.lastname: Cai
authors.forename: Maya
authors.initials: M
authors.lastname: Dajee
authors.forename: Paul A
authors.initials: PA
authors.lastname: Khavari
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D019908:Proto-Oncogene Proteins c-raf / Q000096:biosynthesis / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D012867:Skin / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D018631:ras Proteins / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D011993:Recombinant Fusion Proteins; D013629:Tamoxifen; C016601:afimoxifene; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins