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J. Biol. Chem., Vol. 279, Issue 11, 10476-10483, March 12, 2004

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High Incidence of Thymic Epithelial Tumors in E2F2 Transgenic Mice^*

Blanca Scheijen, Marieke Bronk, Tiffany van der Meer, Daphne De Jong¶, and René Bernards||

From the Divisions of Molecular Carcinogenesis and Center for Biomedical Genetics and ^¶Pathology, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands

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 Eµ and murine pim1 promoter (pp) direct high expression of E2F2 in thymic epithelial cells. Eµ-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, Eµ-pp-E2F1 mice do not display cortical thymomas. These data argue that E2F2 promotes unscheduled cell division and oncogenic transformation of thymic epithelial cells.

Received for publication, December 15, 2003

^* This work was supported by a Biomed-2 grant and grants from the Dutch Cancer Society (KWF). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. of Medical Oncology, Dana-Farber Cancer Institute and Dept. of Medicine, Brigham and Women's Hospital and Harvard Medical School, 44 Binney St., Boston, MA 02115.

^|| To whom correspondence should be addressed: Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, Netherlands. Tel.: 31-20-512-1952; Fax: 31-20-512-1954; E-mail: R.Bernards{at}nki.nl.

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