Cyclin E, a redundant cyclin in breast cancer
Cyclin E, a redundant cyclin in breast cancer
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DOI：
10.1073/pnas.93.26.15215
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发表时间：
1996-12-24
影响因子：
11.1
通讯作者：
Keyomarsi, K
中科院分区：
文献类型：
--
作者：
GrayBablin, J;Zalvide, J;Keyomarsi, K
细胞周期蛋白E是细胞周期进程的重要调节因子，与细胞周期蛋白依赖性激酶（cdk）2一起对哺乳动物细胞周期中的G（1）/S转换至关重要。以前，我们发现，在肿瘤细胞和组织中细胞周期蛋白E蛋白的严重过表达导致细胞周期蛋白E的低分子量亚型的出现，其与CDK 2一起可以形成在整个细胞周期中有活性的激酶复合物。在这项研究中，我们报道了在过表达p16的乳腺癌细胞和组织中，这种组成型活性细胞周期蛋白E/cdk 2复合物的底物之一是视网膜母细胞瘤易感基因产物（pRb）。在这些肿瘤细胞和组织中，我们表明p16和pRb的表达并不相互排斥，p16在这些细胞中的过表达导致cdk 4和cdk 6的隔离，使细胞周期蛋白D1/cdk复合物失活，然而，pRb似乎在整个细胞周期中在初始滞后后被磷酸化，揭示了类似于由这些同步化细胞制备的细胞周期蛋白E免疫沉淀物对谷胱甘肽S-转移酶视网膜母细胞瘤的磷酸化的时间过程。因此，细胞周期蛋白E激酶复合物可以冗余地发挥作用，并取代功能性地抑制pRb的细胞周期蛋白D依赖性激酶复合物的损失。此外，组成性过表达的细胞周期蛋白E也是在整个肿瘤中p107/E2 F复合物中发现的主要细胞周期蛋白，而不是正常细胞周期。这些观察结果表明，在肿瘤细胞中过表达细胞周期蛋白E，也过表达p16，可以绕过细胞周期蛋白D/cdk 4-cdk 6/p16/pRb反馈环，提供了另一种机制，肿瘤可以获得生长优势。
Cyclin E is an important regulator of cell cycle progression that together with cyclin-dependent kinase (cdk) 2 is crucial for the G(1)/S transition during the mammalian cell cycle, Previously, we showed that severe overexpression of cyclin E protein in tumor cells and tissues results in the appearance of lower molecular weight isoforms of cyclin E, which together with cdk2 can form a kinase complex active throughout the cell cycle. In this study, we report that one of the substrates of this constitutively active cyclin E/cdk2 complex is retinoblastoma susceptibility gene product (pRb) in populations of breast cancer cells and tissues that also overexpress p16, In these tumor cells and tissues, we show that the expression of p16 and pRb is not mutually exclusive, Overexpression of p16 in these cells results in sequestering of cdk4 and cdk6, rendering cyclin D1/cdk complexes inactive, However, pRb appears to be phosphorylated throughout the cell cycle following an initial lag, revealing a time course similar to phosphorylation of glutathione S-transferase retinoblastoma by cyclin E immunoprecipitates prepared from these synchronized cells. Hence, cyclin E kinase complexes can function redundantly and replace the loss of cyclin D-dependent kinase complexes that functionally inactivate pRb. In addition, the constitutively overexpressed cyclin E is also the predominant cyclin found in p107/E2F complexes throughout the tumor, but not the normal, cell cycle. These observations suggest that overexpression of cyclin E in tumor cells, which also overexpress p16, can bypass the cyclin D/cdk4-cdk6/p16/pRb feedback loop, providing yet another mechanism by which tumors can gain a growth advantage.