Rapamycin disrupts cyclin/cyclin-dependent kinase/p21/proliferating cell nuclear antigen complexes and cyclin D1 reverses rapamycin action by stabilizing these complexes.
Rapamycin disrupts cyclin/cyclin-dependent kinase/p21/proliferating cell nuclear antigen complexes and cyclin D1 reverses rapamycin action by stabilizing these complexes.
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DOI：
10.1158/0008-5472.can-05-1672
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发表时间：
2006-01-15
期刊：
影响因子：
11.2
通讯作者：
Law, B
中科院分区：
文献类型：
--
作者：
Law, M;Forrester, E;Law, B
雷帕霉素及其衍生物是有前途的抗癌药物，但这些药物诱导细胞周期停滞和抑制肿瘤生长的确切机制尚不清楚。对人乳腺肿瘤细胞系的生化分析表明，雷帕霉素诱导的抗增殖作用与细胞 p21 水平以及细胞周期蛋白依赖性激酶 (Cdk) 2 和 4 复合物中 p21 水平的下调相关。细胞周期蛋白 D1 过表达可逆转雷帕霉素的作用，这种逆转与细胞 p21 水平升高、与 Cdk2 相关的 p21 水平升高以及细胞周期蛋白 D1/Cdk2/p21/增殖细胞核抗原 (PCNA) 复合物的稳定相关。使用新型细胞周期蛋白 D1-Cdk2 融合蛋白或融合蛋白的激酶死亡突变体进行的实验表明，雷帕霉素作用的逆转不仅需要与 p21 和 PCNA 形成复合物，还需要复合物相关的激酶活性。在体内观察到类似的结果。雷帕霉素衍生物 RAD001（依维莫司）可抑制小鼠乳腺肿瘤的生长，这与细胞周期蛋白 D1/Cdk2 复合物的破坏有关。讨论了这些结果对于雷帕霉素衍生物在乳腺癌治疗中的使用的潜在影响。
Rapamycin and its derivatives are promising anticancer agents, but the exact mechanisms by which these drugs induce cell cycle arrest and inhibit tumor growth are unknown. A biochemical analysis of human mammary tumor cell lines indicated that rapamycin-induced antiproliferative effects correlated with down-regulation of cellular p21 levels and the levels of p21 in cyclin-dependent kinase (Cdk) 2 and 4 complexes. Cyclin D1 overexpression reversed rapamycin action and this reversal correlated with increased levels of cellular p21, higher levels of p21 associated with Cdk2, and stabilization of cyclin D1/Cdk2/p21/proliferating cell nuclear antigen (PCNA) complexes. Experiments using a novel cyclin D1-Cdk2 fusion protein or a kinase-dead mutant of the fusion protein indicated that reversal of rapamycin action required not only the formation of complexes with p21 and PCNA but also complex-associated kinase activity. Similar results were observed in vivo. The rapamycin derivative RAD001 (everolimus) inhibited the growth of mouse mammary tumors, which correlated with the disruption of cyclin D1/Cdk2 complexes. The potential implications of these results with respect to the use of rapalmycin derivatives in breast cancer therapy are discussed.