title: Oncogenic potential of cyclin E in T-cell lymphomagenesis in transgenic mice: evidence for cooperation between cyclin E and Ras but not Myc.
abstract: To study the oncogenic activity of cyclin E in an in vivo system we generated transgenic mice expressing high levels of cyclin E in T-lymphocytes by using a construct containing the CD2 locus control region. These animals were neither predisposed to develop any tumors spontaneously nor showed an increased incidence when crossbred with Emu L-myc transgenic mice but developed hyperplasia in peripheral lymphoid organs at later age with an incidence of 27%. When treated with the DNA methylating carcinogen N-methylnitrosourea (MNU) that provokes the development of T-cell lymphomas, CD2-cyclin E transgenic animals came down with T-cell neoplasia showing a significant higher incidence (54%) than normal non transgenic controls (31%). In one of eight tumors that arose in normal MNU treated mice we could find an expected activating point mutation in the Ki-ras gene (12.5%). In contrast, the same mutation occurred in five of 16 tumors from CD2-cyclin E transgenic mice (31.2%). Whereas cyclin E overexpression alone did not lead to an increased CDK2 activity we observed in all tumors that emerged from either MNU treated normal mice or treated CD2-cyclin E transgenics a downregulation of p27KIP1 and a higher histone H1 kinase activity in CDK2 immunoprecipitates compared to normal tissue. These findings demonstrate that high level expression of cyclin E can predispose T-cells for hyperplasia and malignant transformation. However, the results also suggest that this activity of cyclin E is manifest only when other cooperating oncogenes in particular ras genes are present and activated. This would be consistent with our previous finding that cyclin E and Ha-Ras cooperate in focus formation assays in rat embryo fibroblasts.
authors.affiliation: Institut für Zellbiologie (Tumorforschung), IFZ, Universitätsklinikum Essen, Virchowstrasse 173, D-45122 Essen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Karsunky
authors.forename: C
authors.initials: C
authors.lastname: Geisen
authors.forename: T
authors.initials: T
authors.lastname: Schmidt
authors.forename: K
authors.initials: K
authors.lastname: Haas
authors.forename: B
authors.initials: B
authors.lastname: Zevnik
authors.forename: E
authors.initials: E
authors.lastname: Gau
authors.forename: T
authors.initials: T
authors.lastname: Möröy
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D019927:Cyclin E / Q000235:genetics*; D004622:Embryo, Mammalian; D005347:Fibroblasts; D016259:Genes, myc; D011905:Genes, ras; D006965:Hyperplasia; D015759:Ionomycin / Q000494:pharmacology; D019901:Locus Control Region; D008221:Lymphoid Tissue / Q000187:drug effects / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000139:chemically induced / Q000235:genetics*; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017354:Point Mutation; D006656:Protamine Kinase / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D013950:Thymus Gland / Q000166:cytology / Q000473:pathology
chemical_list: D019927:Cyclin E; D015759:Ionomycin; D008770:Methylnitrosourea; D006656:Protamine Kinase; D013755:Tetradecanoylphorbol Acetate