Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration
Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration
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DOI：
10.1073/pnas.1115201109
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发表时间：
2012-03-06
影响因子：
11.1
通讯作者：
Kaldis, Philipp
中科院分区：
文献类型：
--
作者：
Diril, M. Kasim;Ratnacaram, Chandrahas Koumar;Kaldis, Philipp
细胞周期蛋白依赖性激酶1 （Cdk1）是一种典型的激酶，是驱动细胞经历G2期和有丝分裂的中枢调节因子。敲除Cdk2、Cdk3、Cdk4或Cdk6可以在小鼠中存活，但在哺乳动物中尚未充分探索Cdk1的体内功能。在这里，我们建立了一个条件敲除小鼠模型来研究Cdk1在体内的功能。Cdk1的消融导致胚泡期左右的胚胎发育停止。有趣的是，肝脏特异性缺失Cdk1耐受性良好，部分肝切除术后肝脏再生不受损，表明再生可以由细胞生长而非细胞分裂驱动。Cdk1的缺失不影响S期进展，但由于Cdk2/cyclin A2活性的增加而导致DNA再复制。与其他Cdks不同，肝脏中Cdk1的缺失可以完全抵抗Ras激活和p53沉默诱导的肿瘤发生。
Cyclin-dependent kinase 1 (Cdk1) is an archetypical kinase and a central regulator that drives cells through G2 phase and mitosis. Knockouts of Cdk2, Cdk3, Cdk4, or Cdk6 have resulted in viable mice, but the in vivo functions of Cdk1 have not been fully explored in mammals. Here we have generated a conditional-knockout mouse model to study the functions of Cdk1 in vivo. Ablation of Cdk1 leads to arrest of embryonic development around the blastocyst stage. Interestingly, liver-specific deletion of Cdk1 is well tolerated, and liver regeneration after partial hepatectomy is not impaired, indicating that regeneration can be driven by cell growth without cell division. The loss of Cdk1 does not affect S phase progression but results in DNA re-replication because of an increase in Cdk2/cyclin A2 activity. Unlike other Cdks, loss of Cdk1 in the liver confers complete resistance against tumorigenesis induced by activated Ras and silencing of p53.