Chen Y N, Sharma S K, Ramsey T M, Jiang L, Martin M S, Baker K, Adams P D, Bair K W, Kaelin W G
Novartis Institute for Biomedical Research, Novartis Pharmaceuticals Corporation, 556 Morris Avenue, Summit, NJ 07901, USA.
Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4325-9. doi: 10.1073/pnas.96.8.4325.
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.
最近的研究发现了一种短肽基序，它作为细胞周期蛋白/细胞周期蛋白依赖性激酶（cdk）2复合物的对接位点。含有该基序的肽可阻断细胞周期蛋白A/cdk2或细胞周期蛋白E/cdk2对底物的磷酸化作用。在此我们报告，相对于未转化细胞，这种肽的细胞膜可渗透形式优先诱导转化细胞发生凋亡。E2F家族转录因子的失调是转化过程中的常见事件，并且足以使细胞对细胞周期蛋白/cdk2抑制肽敏感。这些结果表明，E2F失调和cdk2抑制具有合成致死性，并为开发作为抗肿瘤药物的cdk2拮抗剂提供了理论依据。
