Department of Molecular Oncology and Gonzmart Research Laboratory, Sarcoma Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Oncogene. 2012 Aug 30;31(35):3989-98. doi: 10.1038/onc.2011.550. Epub 2011 Dec 12.
Mitotic catastrophe occurs when cells enter mitosis with damaged DNA or excess centrosomes. Cells overexpressing the centrosome protein CP110 or depleted of cyclin F, which targets CP110 for destruction, have more than two centrosomes and undergo mitotic catastrophe. Our studies show centrosome reduplication and mitotic catastrophe in osteosarcoma cells inducibly expressing a p27Kip1 mutant (termed p27K) that binds cyclins but not cyclin-dependent kinases (CDKs). p27K inhibited cell proliferation but not CDK activity or cell cycle progression. It did not induce apoptosis; however, cells expressing p27K had more than two centrosomes and, indicative of mitotic catastrophe, irregularly shaped nuclei or multiple micronuclei. p27K interacted with cyclin F in vivo (as did endogenous p27Kip1) and displaced cyclin F from CP110. Depletion of CP110 rescued p27K-expressing cells from centrosome reduplication and mitotic catastrophe. Collectively, our data show that p27Kip1 can perturb mitosis and suggest that it does so by sequestering cyclin F, which prevents its interaction with and the subsequent degradation of CP110, ultimately resulting in centrosome reduplication, mitotic catastrophe and abrogation of cell proliferation.
当细胞的 DNA 受损或中心体过多时，就会发生有丝分裂灾难。过表达中心体蛋白 CP110 或耗尽细胞周期蛋白 F（其可靶向 CP110 进行降解）的细胞具有两个以上的中心体，并发生有丝分裂灾难。我们的研究表明，在可诱导表达 p27Kip1 突变体（称为 p27K）的骨肉瘤细胞中发生了中心体复制和有丝分裂灾难，p27K 可以结合细胞周期蛋白但不能结合细胞周期蛋白依赖性激酶（CDKs）。p27K 抑制细胞增殖，但不抑制 CDK 活性或细胞周期进程。它不会诱导细胞凋亡；然而，表达 p27K 的细胞具有两个以上的中心体，并且细胞核形状不规则或有多核仁，这表明发生了有丝分裂灾难。p27K 在体内与细胞周期蛋白 F 相互作用（内源性 p27Kip1 也是如此），并将细胞周期蛋白 F 从 CP110 上置换下来。CP110 的耗竭可使表达 p27K 的细胞免于中心体复制和有丝分裂灾难。总的来说，我们的数据表明 p27Kip1 可以扰乱有丝分裂，并表明它通过隔离细胞周期蛋白 F 来实现这一点，这防止了其与 CP110 的相互作用及其随后的降解，最终导致中心体复制、有丝分裂灾难和细胞增殖的中断。
