Proteasome-mediated destruction of the cyclin A/cyclin-dependent kinase 2 complex suppresses tumor cell growth in vitro and in vivo
Proteasome-mediated destruction of the cyclin A/cyclin-dependent kinase 2 complex suppresses tumor cell growth in vitro and in vivo
复制标题
DOI：
10.1158/0008-5472.can-03-3906
复制
发表时间：
2004-06-01
期刊：
影响因子：
11.2
通讯作者：
Fine, HA
中科院分区：
文献类型：
--
作者：
Chen, W;Lee, JW;Fine, HA
细胞周期蛋白依赖性激酶（cdks）是癌症治疗策略中潜在的有前途的分子靶点。为了评估选择性cyclin/cdk抑制的抗肿瘤活性，我们构建了一个由F-box蛋白（TrCP）与p21样cdk抑制剂（TrCP- lfg）中含有cyclin/cdk2结合基序的肽融合组成的嵌合蛋白。我们现在证明内源性细胞周期蛋白A及其结合底物cdk2可以与β - trcp结合，泛素化并有效降解。cdk2和细胞周期蛋白A共同降解，而不是cdk2单独降解，在体外和体内以蛋白酶体依赖的方式导致大量肿瘤细胞凋亡，对正常组织无毒性。这些数据表明，细胞周期蛋白A和/或细胞周期蛋白A/cdk2复合物是一个有希望的抗癌靶点，具有很高的治疗指数。
Cyclin-dependent kinases (cdks) represent potentially promising molecular targets for cancer therapeutic strategies. To evaluate the antitumor activity of selective cyclin/cdk inhibition, we constructed a chimeric protein composed of a F-box protein (TrCP) fused to a peptide comprising the cyclin/cdk2 binding motif in p21-like cdk inhibitors (TrCP-LFG). We now demonstrate that endogenous cyclin A and its binding substrate, cdk2, can be tethered to beta-TrCP, ubiquitinated, and effectively degraded. Degradation of cdk2 and cyclin A together, but not cdk2 alone, results in massive tumor cell apoptosis in vitro and in vivo in a proteasome-dependent manner with no toxicity to normal tissue. These data demonstrate that cyclin A and/or the cyclin A/cdk2 complex is a promising anticancer target with a high therapeutic index.