SP600125 suppresses Cdk1 and induces endoreplication directly from G2 phase, independent of JNK inhibition.
SP600125 suppresses Cdk1 and induces endoreplication directly from G2 phase, independent of JNK inhibition.
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DOI：
10.1038/onc.2009.464
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发表时间：
2010-03-18
期刊：
影响因子：
8
通讯作者：
Fotedar, R.
中科院分区：
文献类型：
--
作者：
Kim, J. A.;Lee, J.;Margolis, R. L.;Fotedar, R.
细胞周期控制确保DNA复制（S期）在有丝分裂后产生两个精确的基因组拷贝。控制机制的失败可能导致多轮DNA复制而没有细胞分裂。在内复制中，具有复制基因组的细胞绕过有丝分裂，然后再次复制它们的DNA，导致多倍体。G2期的内复制缺乏有丝分裂的所有特征。使用同步细胞，我们发现c-Jun n -末端激酶（JNK）抑制剂SP600125可以阻止细胞进入有丝分裂并导致G2期DNA的内复制。我们发现细胞在没有有丝分裂的情况下从G2期开始复制它们的DNA。SP600125的这种作用独立于其对JNK活性的抑制。相反，SP600125对有丝分裂进入的抑制作用主要发生在Aurora A激酶和polo样激酶1的上游，导致不能去除Cdk1的抑制磷酸化。重要的是，我们的结果直接表明Cdk1活性的抑制和Cdk2活性的持续在G2细胞中诱导无有丝分裂的内复制。此外，G2期的内复制与p53的控制无关。
Cell cycle controls ensure that DNA replication (S phase) follows mitosis resulting in two precise copies of the genome. A failure of the control mechanisms can result in multiple rounds of DNA replication without cell division. In endoreplication, cells with replicated genomes bypass mitosis, then replicate their DNA again, resulting in polyploidy. Endoreplication from G2 phase lacks all hallmarks of mitosis. Using synchronized cells, we show that the c-Jun N-terminal kinase (JNK) inhibitor, SP600125, prevents the entry of cells into mitosis and leads to endoreplication of DNA from G2 phase. We show that cells proceed from G2 phase to replicate their DNA in the absence of mitosis. This effect of SP600125 is independent of its suppression of JNK activity. Instead, the inhibitory effect of SP600125 on mitotic entry predominantly occurs upstream of Aurora A kinase and Polo-like kinase 1, resulting in a failure to remove the inhibitory phosphorylation of Cdk1. Importantly, our results directly show that the inhibition of Cdk1 activity and the persistence of Cdk2 activity in G2 cells induces endoreplication without mitosis. Furthermore, endoreplication from G2 phase is independent of p53 control.
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DOI：
10.1083/jcb.127.3.789
发表时间：
1994-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Andreassen PR;Margolis RL
通讯作者：
Margolis RL
DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
11.4
作者：
Bulavin, DV;Saito, S;Fornace, AJ
通讯作者：
Fornace, AJ
DOI：
10.1073/pnas.80.10.2926
发表时间：
1983-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
DAVIS, FM;TSAO, TY;RAO, PN
通讯作者：
RAO, PN
影响因子：
64.5
作者：
Hirota, T;Kunitoku, N;Saya, H
通讯作者：
Saya, H