Division of Molecular Biotherapy, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
Cancer Res. 2010 Mar 1;70(5):2041-52. doi: 10.1158/0008-5472.CAN-09-2008. Epub 2010 Feb 16.
Aurora-A, a conserved serine-threonine kinase, plays essential roles in mitosis. Aberrant upregulation of Aurora-A perturbs proper mitotic progression and results in a generation of multinucleated cells with centrosome amplification. The molecular mechanisms for these mitotic defects remain elusive. Here, we show that the overexpressed Aurora-A-induced mitotic defects depend on the telomeric protein TRF1. Live and fixed cell analyses revealed that Aurora-A overexpression in HeLa cells compromises chromosome biorientation, which leads to cytokinetic failure and tetraploidization with increased centrosome numbers. TRF1 depletion by small interfering RNAs or by tankyrase-1 overexpression suppresses Aurora-A-induced occurrence of unaligned chromosomes in metaphase, thus preventing the subsequent abnormalities. We found that Aurora-A binds and phosphorylates TRF1. When TRF1 knockdown cells are complemented with wild-type TRF1, Aurora-A-induced mitotic defects recur. By contrast, a TRF1 mutant that is not phosphorylatable by Aurora-A does not restore such Aurora-A-induced phenotype. We propose that TRF1 phosphorylation by excessive Aurora-A may provoke abnormal mitosis and chromosomal instability.
极光激酶 A（Aurora-A）是一种保守的丝氨酸/苏氨酸激酶，在有丝分裂中发挥着重要作用。极光激酶 A 的异常上调扰乱了有丝分裂的正常进行，导致具有中心体扩增的多核细胞的产生。这些有丝分裂缺陷的分子机制仍不清楚。在这里，我们表明，过表达的极光激酶 A 诱导的有丝分裂缺陷依赖于端粒蛋白 TRF1。活细胞和固定细胞分析显示，HeLa 细胞中过表达的极光激酶 A 会损害染色体的双定向，导致胞质分裂失败和四倍体形成，同时中心体数量增加。用小干扰 RNA 或端粒酶 1 过表达进行 TRF1 耗竭可抑制极光激酶 A 诱导的中期染色体不对齐，从而防止随后的异常。我们发现极光激酶 A 结合并磷酸化 TRF1。当用野生型 TRF1 补充 TRF1 敲低细胞时，极光激酶 A 诱导的有丝分裂缺陷再次出现。相比之下，不能被极光激酶 A 磷酸化的 TRF1 突变体不能恢复这种极光激酶 A 诱导的表型。我们提出，过多的极光激酶 A 磷酸化 TRF1 可能会引发异常有丝分裂和染色体不稳定。
