title: Resistance of R-Ras knockout mice to skin tumour induction.
abstract: The R-ras gene encodes a small GTPase that is a member of the Ras family. Despite close sequence similarities, R-Ras is functionally distinct from the prototypic Ras proteins; no transformative activity and no activating mutations of R-Ras in human malignancies have been reported for it. R-Ras activity appears inhibitory towards tumour proliferation and invasion, and to promote cellular quiescence. Contrary to this, using mice with a deletion of the R-ras gene, we found that R-Ras facilitates DMBA/TPA-induced skin tumour induction. The tumours appeared in wild-type (WT) mice on average 6 weeks earlier than in R-Ras knockout (R-Ras KO) mice. WT mice developed almost 6 times more tumours than R-Ras KO mice. Despite strong R-Ras protein expression in the dermal blood vessels, no R-Ras could be detected in the epidermis from where the tumours arose. The DMBA/TPA skin tumourigenesis-model is highly dependent upon inflammation, and we found a greatly attenuated skin inflammatory response to DMBA/TPA-treatment in the R-Ras KO mice in the context of leukocyte infiltration and proinflammatory cytokine expression. Thus, these data suggest that despite its characterised role in promoting cellular quiescence, R-Ras is pro-tumourigenic in the DMBA/TPA tumour model and important for the inflammatory response to DMBA/TPA treatment.
authors.affiliation: School of Medicine, Department of Anatomy and Cell Biology, University of Tampere, Tampere, Finland.
authors.forename: Ulrike
authors.initials: U
authors.lastname: May
authors.affiliation: School of Medicine, Department of Anatomy and Cell Biology, University of Tampere, Tampere, Finland.
authors.forename: Stuart
authors.initials: S
authors.lastname: Prince
authors.affiliation: School of Medicine, Department of Anatomy and Cell Biology, University of Tampere, Tampere, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Vähätupa
authors.affiliation: School of Medicine, Department of Anatomy and Cell Biology, University of Tampere, Tampere, Finland.
authors.forename: Anni M
authors.initials: AM
authors.lastname: Laitinen
authors.affiliation: School of Medicine, Department of Anatomy and Cell Biology, University of Tampere, Tampere, Finland.
authors.forename: Katriina
authors.initials: K
authors.lastname: Nieminen
authors.affiliation: 1] School of Medicine, Department of Anatomy and Cell Biology, University of Tampere, Tampere, Finland [2] Department of Ophthalmology, Tampere University Hospital, Tampere, Finland.
authors.forename: Hannele
authors.initials: H
authors.lastname: Uusitalo-Järvinen
authors.affiliation: 1] School of Medicine, Department of Anatomy and Cell Biology, University of Tampere, Tampere, Finland [2] Department of Ophthalmology, Tampere University Hospital, Tampere, Finland [3] Department of Orthopedics &Traumatology, Tampere University Hospital, Tampere, Finland.
authors.forename: Tero A H
authors.initials: TA
authors.lastname: Järvinen
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D020405:Dermis / Q000098:blood supply / Q000473:pathology; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate; D018631:ras Proteins / Q000235:genetics*
chemical_list: D015127:9,10-Dimethyl-1,2-benzanthracene; C513254:Rras protein, mouse; D018631:ras Proteins; D013755:Tetradecanoylphorbol Acetate