title: Modulation of the E2F1-driven cancer cell fate by the DNA damage response machinery and potential novel E2F1 targets in osteosarcomas.
abstract: 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.
authors: Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece.
authors: Michalis
authors: M
authors: Liontos
authors: Katerina
authors: K
authors: Niforou
authors: Georgia
authors: G
authors: Velimezi
authors: Konstantinos
authors: K
authors: Vougas
authors: Konstantinos
authors: K
authors: Evangelou
authors: Kalliopi
authors: K
authors: Apostolopoulou
authors: Radek
authors: R
authors: Vrtel
authors: Alexandros
authors: A
authors: Damalas
authors: Panayiotis
authors: P
authors: Kontovazenitis
authors: Athanassios
authors: A
authors: Kotsinas
authors: Vassilis
authors: V
authors: Zoumpourlis
authors: George Th
authors: GT
authors: Tsangaris
authors: Christos
authors: C
authors: Kittas
authors: Doron
authors: D
authors: Ginsberg
authors: Thanos D
authors: TD
authors: Halazonetis
authors: Jiri
authors: J
authors: Bartek
authors: Vassilis G
authors: VG
authors: Gorgoulis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002648:Child; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins