Disrupting Skp2-cyclin A interaction with a blocking peptide induces selective cancer cell killing
Disrupting Skp2-cyclin A interaction with a blocking peptide induces selective cancer cell killing
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DOI：
10.1158/1535-7163.mct-06-0538
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发表时间：
2007-02-01
影响因子：
5.7
通讯作者：
Zhu, Liang
中科院分区：
文献类型：
--
作者：
Ji, Peng;Sun, Daqian;Zhu, Liang
Skp 2符合癌蛋白的定义，其在癌细胞中的频繁过表达和在各种实验室测定中的致癌活性，因此是潜在的癌症治疗靶点。Skp 2最著名的功能是靶向细胞周期蛋白依赖性激酶抑制剂P27（Kip 1）的SCFSkp 2-Roc 1 E3泛素连接酶的F盒蛋白。Skp 2的敲除通常导致p27的积累，但其对癌细胞的影响不太确定。Skp 2的另一个功能是其与细胞周期蛋白A的稳定相互作用，其在体外激酶测定中直接保护细胞周期蛋白A免受p27的抑制。在这里，我们报告说，18个残基的阻断肽Skp 2-细胞周期蛋白A的相互作用可以间接抑制细胞周期蛋白A/Cdk 2激酶活性依赖于p27的存在下，在体外激酶测定。这种阻断肽的跨膜递送可以在一组四种癌细胞系中诱导细胞死亡，其中Skp 2敲低仅具有轻度抑制作用。这种Skp 2-细胞周期蛋白A相互作用阻断肽可以与先前鉴定的E2 F1衍生的LDL肽协同作用，其阻断其接近细胞周期蛋白A，杀死癌细胞。Skp 2-细胞周期蛋白A阻断肽的IC 50与癌细胞中Skp 2（其预期靶点）的丰度相关。这些结果表明，Skp 2-细胞周期蛋白A相互作用在癌细胞存活中起着重要作用，并且是癌症药物发现的有吸引力的靶点。
Skp2 fulfills the definition of an oncoprotein with its frequent overexpression in cancer cells and oncogenic activity in various laboratory assays and therefore is a potential cancer therapy target. The best-known function of Skp2 is that of an F-box protein of the SCFSkp2-Roc1 E3 ubiquitin ligase targeting the cyclin-dependent kinase inhibitor P27(Kip1). Knockdown of Skp2 generally leads to accumulation of p27 but its effects on cancer cells are less certain. Another function of Skp2 is its stable interaction with cyclin A, which directly protects cyclin A from inhibition by p27 in in vitro kinase assays. Here, we report that an 18-residue blocking peptide of Skp2-cyclin A interaction can indirectly inhibit cyclin A/Cdk2 kinase activity dependent on the presence of p27 in in vitro kinase assays. Transmembrane delivery of this blocking peptide can induce cell death in a panel of four cancer cell lines in which Skp2 knockdown only have mild inhibitory effects. This Skp2-cyclin A interaction blocking peptide can synergize with a previously identified E2F1-derived LDL peptide, which blocks its access to cyclin A, in killing cancer cells. IC50 of the Skp2-cyclin A blocking peptide correlated with abundance of Skp2, its intended target, in cancer cells. These results suggest that Skp2-cyclin A interaction plays an important role in cancer cell survival and is an attractive target for cancer drug discovery.