CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage
CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage
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DOI：
10.1126/science.1130512
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发表时间：
2006-10-13
期刊：
影响因子：
56.9
通讯作者：
Tindall, Donald J.
中科院分区：
文献类型：
--
作者：
Huang, Haojie;Regan, Kevin M.;Tindall, Donald J.
细胞周期蛋白依赖性激酶2(CDK2)的功能常在DNA损伤后丧失。CDK2的抑制在DNA损伤诱导的细胞周期停滞和DNA修复中起核心作用。然而，CDK2是否也影响遗传毒性应激下细胞的存活尚不清楚。Forkhead box O(FOXO)转录因子正在成为细胞生存的关键调节因子。在体外和体内，CDK2特异性地磷酸化丝氨酸-249位的FOXO1(Ser(249))。Ser249的磷酸化导致FOXO1的胞质定位和抑制。这种磷酸化在DNA损伤时被取消，通过依赖于蛋白激酶Chk1和Chk2的细胞周期检查点途径。此外，通过小干扰RNA沉默FOXO1可以减少P53缺失和P53熟练表达细胞中DNA损伤诱导的死亡。这种作用可以通过恢复FOXO1的表达来逆转，这种方式依赖于Ser249的磷酸化。CDK2和FOXO1之间的功能相互作用提供了一种调控DNA链断裂后细胞死亡的机制。
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 (Ser(249)) 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.