支票1
DNA损伤
细胞周期蛋白依赖激酶2
检查点激酶2
细胞生物学
G2-M DNA损伤检查点
生物
福克斯O1
DNA修复
磷酸化
细胞周期检查点
细胞周期
小干扰RNA
癌症研究
细胞凋亡
蛋白激酶A
DNA
转染
生物化学
丝氨酸苏氨酸激酶
基因
蛋白激酶B
作者
Haojie Huang,Kevin M. Regan,Zhenkun Lou,Junjie Chen,Donald J. Tindall
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2006-10-13
卷期号:314 (5797): 294-297
被引量:304
标识
DOI:10.1126/science.1130512
摘要
The function of cyclin-dependent kinase 2 (CDK2) is often abolished after DNA damage. The inhibition of CDK2 plays a central role in DNA damage-induced cell cycle arrest and DNA repair. However, whether CDK2 also influences the survival of cells under genotoxic stress is unknown. Forkhead box O (FOXO) transcription factors are emerging as key regulators of cell survival. CDK2 specifically phosphorylated FOXO1 at serine-249 (Ser249) in vitro and in vivo. Phosphorylation of Ser249 resulted in cytoplasmic localization and inhibition of FOXO1. This phosphorylation was abrogated upon DNA damage through the cell cycle checkpoint pathway that is dependent on the protein kinases Chk1 and Chk2. Moreover, silencing of FOXO1 by small interfering RNA diminished DNA damage-induced death in both p53-deficient and p53-proficient cells. This effect was reversed by restored expression of FOXO1 in a manner depending on phosphorylation of Ser249. Functional interaction between CDK2 and FOXO1 provides a mechanism that regulates apoptotic cell death after DNA strand breakage.
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