Cyclin E both regulates and is regulated by calpain 2, a protease associated with metastatic breast cancer phenotype
Cyclin E both regulates and is regulated by calpain 2, a protease associated with metastatic breast cancer phenotype
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DOI：
10.1158/0008-5472.can-05-1666
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发表时间：
2005-12-01
期刊：
影响因子：
11.2
通讯作者：
Mudryj, M
中科院分区：
文献类型：
--
作者：
Libertini, SJ;Robinson, BS;Mudryj, M
乳腺肿瘤中细胞周期蛋白 E 的过度表达与他莫昔芬治疗的不良反应、更大的基因组不稳定性、更具攻击性的行为和不良的临床预后相关。这些肿瘤还表达细胞周期蛋白 E 的低分子量亚型，其与较高的激酶活性和增加的转移潜力相关。在当前的研究中，我们发现 MCF7 细胞中细胞周期蛋白 E 的过度表达会反式激活钙蛋白酶 2 的表达，导致细胞周期蛋白 E 以及几种已知的钙蛋白酶底物（包括粘着斑激酶 (FAK)、钙蛋白酶抑制剂、pp60src 和 p53）的蛋白水解。体内抑制 MCF7-细胞周期蛋白 E 细胞中的钙蛋白酶活性会阻碍细胞周期蛋白 E 蛋白水解，而体内诱导钙蛋白酶活性则会促进细胞周期蛋白 E 蛋白水解。对人类乳腺肿瘤的分析表明，高水平的细胞周期蛋白 E 与低分子量亚型、高水平的钙蛋白酶 2 蛋白和 FAK 蛋白水解的表达一致。最后，使用小鼠转移模型的研究表明，与低转移潜力的肿瘤相比，高转移性肿瘤表达蛋白水解的细胞周期蛋白 E 和 FAK。我们的结果表明，细胞周期蛋白 E 依赖性的钙蛋白酶失调可能在改变多种细胞过程中发挥关键作用，而这些细胞过程在乳腺癌的病因学和进展中发挥着重要作用。 （癌症研究 2005 年；65(23)：10700-8）。
Overexpression of cyclin E in breast tumors is associated with a poor response to tamoxifen therapy, greater genomic instability, more aggressive behavior, and a poor clinical prognosis. These tumors also express low molecular weight isoforms of cyclin E that are associated with higher kinase activity and increased metastatic potential. In the current study, we show that cyclin E overexpression in MCF7 cells transactivates the expression of calpain 2, leading to proteolysis of cyclin E as well as several known calpain substrates including focal adhesion kinase (FAK), calpastatin, pp60src, and p53. In vivo inhibition of calpain activity in MCF7-cyclin E cells impedes cyclin E proteolysis, whereas in vivo induction of calpain activity promotes cyclin E proteolysis. An analysis of human breast tumors shows that high levels of cyclin E are coincident with the expression of the low molecular weight isoforms, high levels of calpain 2 protein, and proteolysis of FAK. Lastly, studies using a mouse model of metastasis reveal that highly metastatic tumors express proteolyzed cyclin E and FAK when compared to tumors with a low metastatic potential. Our results suggest that cyclin E-dependent deregulation of calpain may be pivotal in modifying multiple cellular processes that are instrumental in the etiology and progression of breast cancer. (Cancer Res 2005; 65(23): 10700-8).