Modulation of the E2F1-Driven Cancer Cell Fate by the DNA Damage Response Machinery and Potential Novel E2F1 Targets in Osteosarcomas
Modulation of the E2F1-Driven Cancer Cell Fate by the DNA Damage Response Machinery and Potential Novel E2F1 Targets in Osteosarcomas
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DOI：
10.2353/ajpath.2009.081160
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发表时间：
2009-07-01
影响因子：
6
通讯作者：
Gorgoulis, Vassilis G.
中科院分区：
文献类型：
--
作者：
Liontos, Michalis;Niforou, Katerina;Gorgoulis, Vassilis G.
骨肉瘤是最常见的原发性骨癌。 RB 基因突变代表了这种恶性肿瘤中最常见的分子缺陷。这种改变的一个主要结果是关键细胞周期调节因子 E2F1 的活性从 pRb 的抑制作用中释放出来。对动物模型和人类癌症的研究表明，E2F1 过度表达失调具有“致癌”或“抑癌”特性，具体取决于细胞环境。为了解决骨肉瘤中的这个问题，我们在人类原发性骨肉瘤的临床环境和野生型且缺乏 p53 的 E2F1 诱导骨肉瘤细胞系模型中检查了 E2F1 相对于细胞增殖和凋亡的状态。总的来说，我们的数据表明，高 E2F1 水平会发挥生长抑制作用，这种作用依赖于 DNA 损伤反应网络的完整性。令人惊讶的是，p73（一种已确定的 E2F1 靶标）的诱导也是 DNA 损伤反应依赖性的。此外，与生物信息学相关的全球蛋白质组分析揭示了新的 E2F1 调节基因和潜在的 E2F1 驱动信号网络，可以为通过创新疗法挑战这种侵袭性肿瘤提供有用的靶点。 （Am J Pathol 2009，175：376-391；DOI：10.2353/ajpath.2009.081160）
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. (Am J Pathol 2009, 175:376-391; DOI: 10.2353/ajpath.2009.081160)