Targeting Mitotic Exit Leads to Tumor Regression In Vivo: Modulation by Cdk1, Mastl, and the PP2A/B55α,δ Phosphatase
Targeting Mitotic Exit Leads to Tumor Regression In Vivo: Modulation by Cdk1, Mastl, and the PP2A/B55α,δ Phosphatase
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DOI：
10.1016/j.ccr.2010.10.028
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发表时间：
2010-12-14
期刊：
影响因子：
50.3
通讯作者：
Malumbres, Marcos
中科院分区：
文献类型：
--
作者：
Manchado, Eusebio;Guillamot, Maria;Malumbres, Marcos
靶向有丝分裂出口最近被认为是一种相关的抗癌治疗方法。通过使用基因工程小鼠，我们证明了APC/C辅因子CDC20对于体内胚胎或成体细胞(包括祖细胞/干细胞)的后期启动是必不可少的。CDC20的消融可以有效地消退侵袭性肿瘤，而目前的有丝分裂药物效果有限。然而，CDC20缺失细胞可以在CDK1和KMAST1(长城)失活后退出有丝分裂。这种有丝分裂的退出取决于含有B55α或B55 Delta调节亚基的PP2A磷酸酶复合体的活性。这些数据说明了哺乳动物中有丝分裂退出的关键角色的相关性，以及它们在肿瘤细胞中细胞死亡和有丝分裂退出之间的平衡中的意义。
Targeting mitotic exit has been recently proposed as a relevant therapeutic approach against cancer. By using genetically engineered mice, we show that the APC/C cofactor Cdc20 is essential for anaphase onset in vivo in embryonic or adult cells, including progenitor/stem cells. Ablation of Cdc20 results in efficient regression of aggressive tumors, whereas current mitotic drugs display limited effects. Yet, Cdc20 null cells can exit from mitosis upon inactivation of Cdk1 and the kinase Mastl (Greatwall). This mitotic exit depends on the activity of PP2A phosphatase complexes containing B55 alpha or B55 delta regulatory subunits. These data illustrate the relevance of critical players of mitotic exit in mammals and their implications in the balance between cell death and mitotic exit in tumor cells.