Published online before print June 18, 2009

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(American Journal of Pathology. 2009;175:376-391.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.081160

Modulation of the E2F1-Driven Cancer Cell Fate by the DNA Damage Response Machinery and Potential Novel E2F1 Targets in Osteosarcomas

Michalis Liontos^*, Katerina Niforou^*, Georgia Velimezi^*, Konstantinos Vougas, Konstantinos Evangelou^*, Kalliopi Apostolopoulou^*, Radek Vrtel, Alexandros Damalas^¶, Panayiotis Kontovazenitis^||, Athanassios Kotsinas^*, Vassilis Zoumpourlis^**, George Th. Tsangaris, Christos Kittas^*, Doron Ginsberg, Thanos D. Halazonetis, Jiri Bartek and Vassilis G. Gorgoulis^*

From the Molecular Carcinogenesis Group,^* Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece; the Division of Biotechnology, Centre of Basic Research II, Foundation for Biomedical Research of the Academy of Athens, Athens, Greece; the Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Copenhagen, Denmark; the Laboratory of Genome Integrity, Palacky University, Olomouc, Czech Republic; the Department of Biology,^¶ University of Ioannina, Ioannina, Greece; the 1^st Orthopedic Department,|| University of Athens, Attikon Hospital, Athens, Greece; the Unit of Biomedical Applications,^** Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Athens, Greece; The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan, Israel; and the Department of Molecular Biology, University of Geneva, Geneva, Switzerland

Osteosarcoma is the most common primary bone cancer. Mutations of the RB gene represent the most frequent molecular defect in this malignancy. A major consequence of this alteration is that the activity of the key cell cycle regulator E2F1 is unleashed from the inhibitory effects of pRb. Studies in animal models and in human cancers have shown that deregulated E2F1 overexpression possesses either "oncogenic" or "oncosuppressor" properties, depending on the cellular context. To address this issue in osteosarcomas, we examined the status of E2F1 relative to cell proliferation and apoptosis in a clinical setting of human primary osteosarcomas and in E2F1-inducible osteosarcoma cell line models that are wild-type and deficient for p53. Collectively, our data demonstrated that high E2F1 levels exerted a growth-suppressing effect that relied on the integrity of the DNA damage response network. Surprisingly, induction of p73, an established E2F1 target, was also DNA damage response-dependent. Furthermore, a global proteome analysis associated with bioinformatics revealed novel E2F1-regulated genes and potential E2F1-driven signaling networks that could provide useful targets in challenging this aggressive neoplasm by innovative therapies.

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