Modulation of the E2F1-driven cancer cell fate by the DNA damage response machinery and potential novel E2F1 targets in osteosarcomas

TY - JOUR

T1 - Modulation of the E2F1-driven cancer cell fate by the DNA damage response machinery and potential novel E2F1 targets in osteosarcomas

AU - Liontos, Michalis

AU - Niforou, Katerina

AU - Velimezi, Georgia

AU - Vougas, Konstantinos

AU - Evangelou, Konstantinos

AU - Apostolopoulou, Kalliopi

AU - Vrtel, Radek

AU - Damalas, Alexandros

AU - Kontovazenitis, Panayiotis

AU - Kotsinas, Athanassios

AU - Zoumpourlis, Vassilis

AU - Tsangaris, George Th

AU - Kittas, Christos

AU - Ginsberg, Doron

AU - Halazonetis, Thanos D

AU - Bartek, Jiri

AU - Gorgoulis, Vassilis G

N1 - Keywords: Adolescent; Adult; Aged; Aged, 80 and over; Apoptosis; Blotting, Western; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Child; DNA Damage; DNA Repair; DNA-Binding Proteins; E2F1 Transcription Factor; Electrophoresis, Gel, Two-Dimensional; Female; Flow Cytometry; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Male; Middle Aged; Nuclear Proteins; Osteosarcoma; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Young Adult

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.2353/ajpath.2009.081160

DO - 10.2353/ajpath.2009.081160

M3 - Journal article

C2 - 19541929

SN - 0002-9440

VL - 175

SP - 376

EP - 391

JO - American Journal of Pathology

JF - American Journal of Pathology

IS - 1

ER -