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, Vassilis G. Gorgoulis

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


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.

Original languageEnglish
Pages (from-to)376-391
Number of pages16
JournalAmerican Journal of Pathology
Issue number1
StatePublished - Jul 2009
Externally publishedYes

Bibliographical note

Funding Information:
Supported by the European Commission (FP7-project GENICA), NKUA - SARG grants No 70/3/8916 and 70/3/1703, the Czech Ministry of Education (MSM6198959216), the Danish Cancer Society, and the Danish National Research Foundation and the NIH, USA (grant CA118827).


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