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Conditional E2F1 activation in transgenic mice causes testicular atrophy and dysplasia mimicking human CIS

Oncogene volume 24, pages 780–789 (2005)Cite this article

Abstract

E2F1 is a crucial downstream effector of the retinoblastoma protein (pRB) pathway. To address the consequences of short-term increase in E2F1 activity in adult tissues, we generated transgenic mice expressing the human E2F1 protein fused to the oestrogen receptor (ER) ligand-binding domain. The expression of the ER-E2F1 fusion protein, which is inactive in the absence of 4-hydroxy tamoxifen (OHT), was targeted to the testes. We show that short-term activation of E2F1 results in activation of E2F target genes and apoptosis of germ cells. Consistent with our previously published results, the apoptotic response was independent of p53. Persistent E2F1 activation for 3 weeks led to massive apoptosis and severe testicular atrophy with seminiferous tubules containing only Sertoli cells and clusters of undifferentiated spermatogonia. The latter showed high expression of ER-E2F1 and excessive mitotic activity, including atypical mitoses. In addition, gonocyte-like dysplastic germ cells, resembling carcinoma in situ (CIS) cells in humans, appeared. Our results show that a relatively short period of deregulated E2F1 activity in testicles can induce premalignant changes. Moreover, we demonstrate the feasibility of tissue-specific expression of conditional ER-E2F1 in transgenic mice.

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Acknowledgements

We thank Claire Attwooll and Eros Lazzerini Denchi for critical reading of the manuscript, and members of the Helin laboratory for discussions. KA was supported by Dagmar Marchalls Fond, Harboefonden, Fonden til fremme af medicinsk behandling af cancer, Direktør Jacob Madsen and Hustru Olga Madsens Fond, Fabrikant Einar Willumsens Mindelegat and Beckett-Fonden during the course of this work. This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) and Fondazione Italiana per la Ricerca sul Cancro (FIRC), the Danish Cancer Society and the Danish Ministry of Research.

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Authors and Affiliations

  1. Biotech Research & Innovation Centre, 2100, Copenhagen, Denmark

    Karl Agger & Kristian Helin

  2. Department of Molecular Cell Biology, Institute of Molecular Biology, University of Copenhagen, 1353, Copenhagen, Denmark

    Karl Agger, Christian Holmberg & Olle Karlström

  3. European Institute of Oncology, Department of Experimental Oncology, 20141, Milan, Italy

    Karl Agger & Kristian Helin

  4. Department of Pathology, Rigshospitalet, Copenhagen University Hospital, 2100, Copenhagen, Denmark

    Eric Santoni-Rugiu

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Correspondence to Kristian Helin.

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Agger, K., Santoni-Rugiu, E., Holmberg, C. et al. Conditional E2F1 activation in transgenic mice causes testicular atrophy and dysplasia mimicking human CIS. Oncogene 24, 780–789 (2005). https://doi.org/10.1038/sj.onc.1208248

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