文章：

E2F在癌症中的新作用：退出细胞周期控制

Emerging roles of E2Fs in cancer: an exit from cell cycle control

原文发布日期：2009-11-01

DOI: 10.1038/nrc2696

类型: Review Article

开放获取: 否

要点：

1. A long-standing paradigm has been that E2F activity is tightly regulated by the RB tumour suppressor and that the disruption of this regulation leads to unscheduled progression through the cell cycle.
2. Based on structure–function studies in vitro, the mammalian E2F family of transcription factors has been artificially subdivided into activators (E2F1–E2F3) and repressors (E2F4–E2F8).
3. E2F1–E2F3 activators are highly redundant during development.
4. Tumour models using RB–E2F compound-mutant mice and E2F-transgenic mice show dual roles for E2Fs in tumour promotion and suppression. These results suggest tissue-specific functions and argue against a uniform role for E2Fs in cancer.
5. Mice lacking E2F1, E2F2 or E2F3 survive to mid gestation without global defects in the cell cycle, suggesting that the activators are not essential for normal mammalian cell proliferation. We propose that under normal conditions E2Fs do not substantially contribute to the proliferative potential of a cell.
6. Deregulated expression or activity of most members of the E2F family has been detected in many human cancers. We propose that the requirement for certain E2F family members in proliferation under oncogenic conditions represents a recent evolutionary adaptation.
7. RB inactivation and E2F amplification coexist in cancer. RB inactivation leads to inappropriate cell cycle progression through the deregulation of E2F function. We propose that the additional increase in E2F activity caused by amplification has cell proliferation-independent functions in cancer.

要点翻译：

1. 一个长期存在的范式是：E2F活性受到RB肿瘤抑制因子的严格调控，这种调控机制的破坏会导致细胞周期进程失控。
2. 基于体外结构功能研究，哺乳动物E2F转录因子家族被人为划分为激活因子（E2F1-E2F3）和抑制因子（E2F4-E2F8）。
3. E2F1-E2F3激活因子在发育过程中具有高度冗余性。
4. 使用RB-E2F复合突变小鼠和E2F转基因小鼠的肿瘤模型显示，E2F在肿瘤促进和抑制中具有双重作用。这些结果表明其功能具有组织特异性，反对E2F在癌症中具有统一作用的观点。
5. 缺失E2F1、E2F2或E2F3的小鼠可存活至妊娠中期，且未出现细胞周期的整体缺陷，表明这些激活因子对正常哺乳动物细胞增殖并非必需。我们认为在正常条件下，E2F对细胞增殖潜能的贡献有限。
6. 在多种人类癌症中检测到E2F家族大多数成员的表达或活性失调。我们提出，在致癌条件下某些E2F家族成员对增殖的需求代表了近期的进化适应。
7. RB失活与E2F扩增在癌症中并存。RB失活通过扰乱E2F功能导致异常细胞周期进程。我们认为由扩增引起的E2F活性额外增强，在癌症中具有不依赖于细胞增殖的功能。

英文摘要：

Mutations of the retinoblastoma tumour suppressor gene (RB1) or components regulating the RB pathway have been identified in almost every human malignancy. The E2F transcription factors function in cell cycle control and are intimately regulated by RB. Studies of model organisms have revealed conserved functions for E2Fs during development, suggesting that the cancer-related proliferative roles of E2F family members represent a recent evolutionary adaptation. However, given that some human tumours have concurrent RB1 inactivation and E2F amplification and overexpression, we propose that there are alternative tumour-promoting activities for the E2F family, which are independent of cell cycle regulation.

摘要翻译： 

视网膜母细胞瘤抑癌基因（RB1）或其通路调控组分的突变几乎见于所有人类恶性肿瘤。E2F转录因子在细胞周期调控中发挥作用，并受RB严密调控。模式生物研究揭示E2F在发育过程中具有保守功能，提示E2F家族成员与癌症相关的增殖作用可能是近期进化适应的结果。然而，鉴于部分人类肿瘤同时存在RB1失活与E2F扩增/过表达，我们推测E2F家族尚存在不依赖于细胞周期调控的促瘤活性。

原文链接：

Emerging roles of E2Fs in cancer: an exit from cell cycle control