Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists
Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists
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DOI：
10.1073/pnas.96.8.4325
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发表时间：
1999-04-13
影响因子：
11.1
通讯作者：
Kaelin, WG
中科院分区：
文献类型：
--
作者：
Chen, YNP;Sharma, SK;Kaelin, WG
最近的研究发现了一个短肽基序，作为细胞周期蛋白/细胞周期蛋白依赖性激酶（cdk）2复合物的对接位点。含有该基序的肽阻断细胞周期蛋白A/cdk 2或细胞周期蛋白E/cdk 2对底物的磷酸化。在这里，我们报告说，细胞膜渗透形式的肽优先诱导转化细胞进行凋亡相对于非转化细胞。E2 F家族转录因子的失调是转化过程中的常见事件，足以使细胞对cyclin/cdk 2抑制肽敏感。这些结果表明，E2 F的失调和cdk 2的抑制是合成致死的，并为开发cdk 2拮抗剂作为抗肿瘤药物提供了理论基础。
Recent studies identified a short peptide motif that serves as a docking site for cyclin/cyclin-dependent kinase (cdk) 2 complexes. Peptides containing this motif block the phosphorylation of substrates by cyclin A/cdk2 or cyclin E/cdk2. Here we report that cell membrane-permeable forms of such peptides preferentially induced transformed cells to undergo apoptosis relative to nontransformed cells. Deregulation of E2F family transcription factors is a common event during transformation and was sufficient to sensitize cells to the cyclin/cdk2 inhibitory peptides, These results suggest that deregulation of E2F and inhibition of cdk2 are synthetically lethal and provide a rationale for the development of cdk2 antagonists as antineoplastic agents.