生物
内复制
细胞周期蛋白
有丝分裂
细胞生物学
癌症研究
G2-M DNA损伤检查点
细胞周期蛋白B
基因复制
细胞周期
细胞周期检查点
遗传学
癌症
基因
作者
Jingkun Zeng,Stephanie A. Hills,Eiko Ozono,John F X Diffley
出处
期刊:Cell
[Elsevier]
日期:2023-01-19
卷期号:186 (3): 528-542.e14
标识
DOI:10.1016/j.cell.2022.12.036
摘要
Whole-genome duplication (WGD) is a frequent event in cancer evolution and an important driver of aneuploidy. The role of the p53 tumor suppressor in WGD has been enigmatic: p53 can block the proliferation of tetraploid cells, acting as a barrier to WGD, but can also promote mitotic bypass, a key step in WGD via endoreduplication. In wild-type (WT) p53 tumors, WGD is frequently associated with activation of the E2F pathway, especially amplification of CCNE1, encoding cyclin E1. Here, we show that elevated cyclin E1 expression causes replicative stress, which activates ATR- and Chk1-dependent G2 phase arrest. p53, via its downstream target p21, together with Wee1, then inhibits mitotic cyclin-dependent kinase activity sufficiently to activate APC/CCdh1 and promote mitotic bypass. Cyclin E expression suppresses p53-dependent senescence after mitotic bypass, allowing cells to complete endoreduplication. Our results indicate that p53 can contribute to cancer evolution through the promotion of WGD.
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