DNA damage-induced activation of p53 by the checkpoint kinase Chk2
DNA damage-induced activation of p53 by the checkpoint kinase Chk2
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DOI：
10.1126/science.287.5459.1824
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发表时间：
2000-03-10
期刊：
影响因子：
56.9
通讯作者：
Mak, TW
中科院分区：
文献类型：
--
作者：
Hirao, A;Kong, YY;Mak, TW
Chk2是一种蛋白激酶，在DNA损伤时被激活，并可能调节细胞周期停滞。我们通过基因打靶获得了Chk2缺陷的小鼠细胞。Chk2(-/-)胚胎干细胞未能维持伽玛射线诱导的细胞周期Ci期停滞。Chk2(-/-)胸腺细胞能抵抗DNA损伤诱导的细胞凋亡。Chk2(-/-)细胞对P53的稳定和对p21等依赖于P53的转录本的诱导对伽玛射线的反应是缺陷的。重新导入Chk2基因恢复了p53依赖的转录，以响应伽马辐射。Chk2直接使丝氨酸20上的P53磷酸化，从而干扰MDM2的结合。这提供了一种机制，通过防止泛素化反应DNA损伤来提高P53的稳定性。
Chk2 is a protein kinase that is activated in response to DNA damage and may regulate cell cycle arrest. We generated Chk2-deficient mouse cells by gene targeting. Chk2(-/-) embryonic stem cells failed to maintain gamma-irradiation-induced arrest in the Ci phase of the cell cycle. Chk2(-/-) thymocytes were resistant to DNA damage-induced apoptosis. Chk2(-/-) cells were defective for p53 stabilization and for induction of p53-dependent transcripts such as p21 in response to gamma irradiation. Reintroduction of the Chk2 gene restored p53-dependent transcription in response to gamma irradiation. Chk2 directly phosphorylated p53 on serine 20, which is known to interfere with Mdm2 binding. This provides a mechanism for increased stability of p53 by prevention of ubiquitination in response to DNA damage.