The role of inhibitory phosphorylation of CDC2 following DNA replication block and radiation-induced damage in human cells
The role of inhibitory phosphorylation of CDC2 following DNA replication block and radiation-induced damage in human cells
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DOI：
10.1091/mbc.8.6.1013
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发表时间：
1997-06-01
影响因子：
3.3
通讯作者：
McGowan, CH
中科院分区：
文献类型：
--
作者：
Blasina, A;Paegle, ES;McGowan, CH
已经表明，p53缺陷型肿瘤细胞对抑制DNA复制或损伤DNA的试剂的存活反应可能在很大程度上依赖于调节有丝分裂开始的细胞周期检查点。在人类细胞中，有丝分裂诱导激酶CDC 2/细胞周期蛋白B被苏氨酸-14和酪氨酸-15的磷酸化抑制，但这些磷酸化在执行检查点中的作用尚不清楚。我们研究了人宫颈癌细胞系（HeLa细胞）中的情况，发现突变型非磷酸化形式的CDC 2的低水平表达废除了内源性CDC 2/细胞周期蛋白B的调节。该途径的破坏是有毒的，并且使细胞对通过DNA损伤或通过抑制DNA复制的杀伤高度敏感。这些发现确立了CDC 2抑制磷酸化在人类细胞暴露于一些最常见形式的抗癌治疗时使用的生存机制中的重要性。
It has been suggested that the survival response of p53 defective tumor cells to agents that inhibit DNA replication or damage DNA may be largely dependent on cell cycle checkpoints that regulate the onset of mitosis. In human cells, the mitosis-inducing kinase CDC2/cyclin B is inhibited by phosphorylation of threonine-14 and tyrosine-15, but the roles of these phosphorylations in enforcing checkpoints is not known. We have investigated the situation in a human cervical carcinoma cell line (HeLa cells) and found that low level expression of a mutant nonphosphorylatable form of CDC2 abrogates regulation of the endogenous CDC2/cyclin B. Disruption of this pathway is toxic and renders cells highly sensitive to killing by DNA damage or by inhibition of DNA replication. These findings establish the importance of inhibitory phosphorylation of CDC2 in the survival mechanism used by human cells when exposed to some of the most common forms of anticancer therapy.