Overexpression of Aurora-A in primary cells interferes with S-phase entry by diminishing Cyclin D1 dependent activities
Overexpression of Aurora-A in primary cells interferes with S-phase entry by diminishing Cyclin D1 dependent activities
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DOI：
10.1186/1476-4598-10-28
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发表时间：
2011-03-16
期刊：
影响因子：
37.3
通讯作者：
Sutterluety, Hedwig
中科院分区：
文献类型：
--
作者：
Jantscher, Florian;Pirker, Christine;Sutterluety, Hedwig
背景：Aurora-A是一种真正的癌基因，其表达与基因组不稳定和恶性转化有关。在几种类型的癌症中，Aurora-A的基因扩增和/或蛋白水平升高是一个共同的特征。结果：在本报告中，我们描述了在原代人类细胞中瞬时过表达Aurora-A后观察到的主要作用是抑制细胞增殖。除了已知的G2/M期细胞周期阻滞外，过表达Aurora-A的细胞未能克服G1/S期的限制点，这是由于Cyclin D1表达减少导致Rb磷酸化减弱所致。因此，Cyclin D1蛋白的过表达能够推翻Aurora-A介导的G1期阻断。Aurora-A介导的细胞周期停滞在G2中不受Cyclin D1的影响，因此细胞在G2中积累。当P53失活时，部分细胞逃脱了这种有丝分裂前的停滞而成为非整倍体。结论：我们的研究表明，Aurora-A表达水平的增加本身具有肿瘤抑制功能，但结合适当改变的细胞内环境，可能会发挥其致癌潜力。目前的数据表明，肿瘤抑制因子RB的失活是推翻由Aurora-A水平升高触发的细胞周期检查点的要求之一。
Background: Aurora-A is a bona-fide oncogene whose expression is associated with genomic instability and malignant transformation. In several types of cancer, gene amplification and/or increased protein levels of Aurora-A are a common feature.Results: In this report, we describe that inhibition of cell proliferation is the main effect observed after transient overexpression of Aurora-A in primary human cells. In addition to the known cell cycle block at the G2/M transition, Aurora-A overexpressing cells fail to overcome the restriction point at the G1/S transition due to diminished RB phosphorylation caused by reduced Cyclin D1 expression. Consequently, overexpression of Cyclin D1 protein is able to override the Aurora-A mediated G1 block. The Aurora-A mediated cell cycle arrest in G2 is not influenced by Cyclin D1 and as a consequence cells accumulate in G2. Upon deactivation of p53 part of the cells evade this premitotic arrest to become aneuploid.Conclusion: Our studies describe that an increase of Aurora-A expression levels on its own has a tumor suppressing function, but in combination with the appropriate altered intracellular setting it might exert its oncogenic potential. The presented data indicate that deactivation of the tumor suppressor RB is one of the requirements for overriding a cell cycle checkpoint triggered by increased Aurora-A levels.