E2F7 Is a Potent Inhibitor of Liver Tumor Growth in Adult Mice.
E2F7 Is a Potent Inhibitor of Liver Tumor Growth in Adult Mice.
复制标题
DOI：
10.1002/hep.31259
复制
发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
de Bruin A
中科院分区：
文献类型：
--
作者：
Moreno E;Toussaint MJM;van Essen SC;Bongiovanni L;van Liere EA;Koster MH;Yuan R;van Deursen JM;Westendorp B;de Bruin A
几乎在所有人类恶性肿瘤中都发现了E2F依赖的转录网络的上调，这是肿瘤发生的重要驱动因素。E2F家族的两个成员E2F7和E2F8是E2F依赖的转录的有效抑制因子。它们是非典型的，因为它们不与二聚化伙伴蛋白结合，也不受视网膜母细胞瘤蛋白的控制。E2F7和E2F8的生理相关性仍不完全清楚，这主要是因为缺乏在体内操纵它们活动的工具。在这里，我们建立了多西环素控制的E2f7和E2f8转录激活的转基因小鼠，并在出生后发育、成年和癌症背景下诱导它们的表达。E2f7和E2f8转基因在幼鼠体内的系统诱导会损害细胞的增殖，导致复制应激、DNA损伤和细胞凋亡，并抑制动物的生长。然而，在成年小鼠中，E2F7和E2F8的诱导可以很好地耐受，但在二乙基亚硝胺诱导的肝肿瘤中，E2F7和E2F8的诱导对DNA复制、DNA完整性和细胞增殖有深远的干扰作用。总而言之，我们的发现表明，非典型的E2F可以超越其他E2F家族成员控制的细胞周期进入和进展，并表明当成年期间生长和发育停止时，可以利用这一特性来抑制肿瘤肝细胞的增殖。
Up‐regulation of the E2F‐dependent transcriptional network has been identified in nearly every human malignancy and is an important driver of tumorigenesis. Two members of the E2F family, E2F7 and E2F8, are potent repressors of E2F‐dependent transcription. They are atypical in that they do not bind to dimerization partner proteins and are not controlled by retinoblastoma protein. The physiological relevance of E2F7 and E2F8 remains incompletely understood, largely because tools to manipulate their activity in vivo have been lacking. Here, we generated transgenic mice with doxycycline‐controlled transcriptional activation of E2f7 and E2f8 and induced their expression during postnatal development, in adulthood, and in the context of cancer. Systemic induction of E2f7 and, to lesser extent, E2f8 transgenes in juvenile mice impaired cell proliferation, caused replication stress, DNA damage, and apoptosis, and inhibited animal growth. In adult mice, however, E2F7 and E2F8 induction was well tolerated, yet profoundly interfered with DNA replication, DNA integrity, and cell proliferation in diethylnitrosamine‐induced liver tumors. Collectively, our findings demonstrate that atypical E2Fs can override cell‐cycle entry and progression governed by other E2F family members and suggest that this property can be exploited to inhibit proliferation of neoplastic hepatocytes when growth and development have subsided during adulthood.
登录
查看更多内容
影响因子：
0.4
作者：
Nuo, M. T.;Yuan, J. L.;Liu, D. J.
通讯作者：
Liu, D. J.
影响因子：
14.9
作者：
Gödecke N;Zha L;Spencer S;Behme S;Riemer P;Rehli M;Hauser H;Wirth D
通讯作者：
Wirth D
影响因子：
8
作者：
Logan, N;Graham, A;La Thangue, NB
通讯作者：
La Thangue, NB
E2F8 通过调节细胞增殖促进人类肝细胞癌
影响因子：
11.2
作者：
Deng, Qing;Wang, Qun;Han, Ze-Guang
通讯作者：
Han, Ze-Guang
影响因子：
3.9
作者：
Lv Y;Xiao J;Liu J;Xing F
通讯作者：
Xing F