Ectopic expression of cyclin E in estrogen responsive cells abrogates antiestrogen mediated growth arrest
Ectopic expression of cyclin E in estrogen responsive cells abrogates antiestrogen mediated growth arrest
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DOI：
10.1038/sj.onc.1205576
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发表时间：
2002-07-11
期刊：
影响因子：
8
通讯作者：
Mudryj, M
中科院分区：
文献类型：
--
作者：
Dhillon, NK;Mudryj, M
雌激素刺激雌激素受体阳性MCF7乳腺癌细胞增殖；而抗雌激素则表明G0/G1生长停滞。在MCF7细胞中，抑制是通过CDK抑制剂p21和p27以及细胞周期蛋白E/CDK2激酶活性的降低介导的。我们发现，在MCF7细胞中，cyclin E的过度表达部分消除了他莫昔芬介导的生长停滞。cyclin E的过表达伴随着RB和CDK抑制剂p21水平的降低，而CDK抑制剂p27水平的升高。Cyclin E过表达也会改变E2F转录因子复合物的组成。E2F4/p107/cyclin E/CDK2复合物是增殖控制细胞中的一个次要成分，在生长受阻的细胞中不存在，但在增殖和他莫昔芬处理过表达cyclin E的细胞中都更丰富。相反，在这些细胞中未检测到与静止相关的E2F/p130复合物的水平。在增殖和他莫昔芬处理过表达周期蛋白E的细胞中，E2F依赖启动子的表达升高。本研究表明，cyclin E的适度过表达通过修饰RB/E2F途径消除了他莫昔芬介导的生长停滞。此外，这些结果提供了一种解释，为什么一些表达雌激素受体的细胞可能对抗雌激素没有反应。
Estrogens stimulate proliferation of estrogen receptor positive MCF7 breast cancer cells; while antiestrogens signal a G0/G1 growth arrest. In MCF7 cells, arrest is mediated through the CDK inhibitors p21 and p27 and through a decrease in cyclin E/CDK2 kinase activity. We found that in MCF7 cells, overexpression of cyclin E partially abrogates a tamoxifen mediated growth arrest. Overexpression of cyclin E is accompanied by a decrease in the levels of RB and CDK inhibitor p21 but an increase in CDK inhibitor p27. Cyclin E overexpression also alters the composition of E2F transcription factor complexes. The E2F4/p107/cyclin E/CDK2 complex, a minor component in proliferating control cells that is absent in growth-arrested cells, is more abundant in both proliferating and tamoxifen treated cyclin E overexpressing cells. Conversely, levels of the quiescence associated E2F/p130 complex is not detected in these cells. Expression from the E2F dependant promoter is elevated in proliferating and tamoxifen treated cyclin E overexpressing cells. This study suggests that a modest overexpression of cyclin E abrogates the tamoxifen mediated growth arrest through modification of the RB/E2F pathway. Moreover, these, results provide one explanation of why some cells that express the estrogen receptor may be unresponsive to antiestrogens.