title: High incidence of thymic epithelial tumors in E2F2 transgenic mice.
abstract: In virtually all human tumors, genetic and epigenetic alterations have been found which affect the INK4/-CYCLIN D/RB pathway, which regulates cell cycle entry and exit in normal cells. E2F transcription factors are important downstream components of this pathway, which act by controlling the expression of genes involved in DNA replication and cell cycle progression. To determine whether E2F2 deregulation promotes proliferation and tumorigenesis in vivo, we generated E2F2 transgenic mice, in which the Emu and murine pim1 promoter (pp) direct high expression of E2F2 in thymic epithelial cells. Emu-pp-E2F2 mice start to develop cytokeratin- and ER-TR4-positive cortical thymomas from the age of 20 weeks, and within 1 year, nearly all mice succumb to gross thymic epithelial tumors. General thymic morphology is largely maintained, but T cell development is perturbed in thymomas, with proportionately less CD4(+)CD8(+) double-positive thymocytes. In the first 3 months, E2F2 transgenic thymi exhibit only mild epithelial hyperplasia, and thereafter thymomas arise stochastically, probably following additional mutations. Interestingly, Emu-pp-E2F1 mice do not display cortical thymomas. These data argue that E2F2 promotes unscheduled cell division and oncogenic transformation of thymic epithelial cells.
authors.affiliation: Division of Molecular Carcinogenesis and Center for Biomedical Genetics, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands.
authors.forename: Blanca
authors.initials: B
authors.lastname: Scheijen
authors.forename: Marieke
authors.initials: M
authors.lastname: Bronk
authors.forename: Tiffany
authors.initials: T
authors.lastname: van der Meer
authors.forename: Daphne
authors.initials: D
authors.lastname: De Jong
authors.forename: René
authors.initials: R
authors.lastname: Bernards
mesh_terms: D000367:Age Factors; D000818:Animals; D015152:Blotting, Northern; D015139:Blotting, Southern; D015153:Blotting, Western; D002453:Cell Cycle; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D050703:E2F2 Transcription Factor; D004847:Epithelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D006965:Hyperplasia / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics*; D011401:Promoter Regions, Genetic; D013945:Thymoma / Q000235:genetics / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D019076:Transgenes
chemical_list: D050703:E2F2 Transcription Factor; C484940:E2f2 protein, mouse; D015534:Trans-Activators