Blasina A, Paegle E S, McGowan C H
Department of Molecular Biology, Scripps Research Institute, La Jolla, California 92037, USA.
Mol Biol Cell. 1997 Jun;8(6):1013-23. doi: 10.1091/mbc.8.6.1013.
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.
有人提出，p53缺陷型肿瘤细胞对抑制DNA复制或损伤DNA的药物的存活反应可能在很大程度上依赖于调节有丝分裂起始的细胞周期检查点。在人类细胞中，诱导有丝分裂的激酶CDC2/细胞周期蛋白B通过苏氨酸-14和酪氨酸-15的磷酸化而被抑制，但这些磷酸化在强化检查点中的作用尚不清楚。我们研究了一种人宫颈癌细胞系（HeLa细胞）中的情况，发现一种突变的不可磷酸化形式的CDC2的低水平表达消除了对内源性CDC2/细胞周期蛋白B的调节。该途径的破坏是有毒的，使细胞对DNA损伤或DNA复制抑制的杀伤高度敏感。这些发现确立了CDC2的抑制性磷酸化在人类细胞暴露于一些最常见的抗癌治疗形式时所采用的存活机制中的重要性。
