Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Mouse Genome Editing Unit, CNIO, Madrid, Spain.
Cell Rep. 2024 Jul 23;43(7):114494. doi: 10.1016/j.celrep.2024.114494. Epub 2024 Jul 13.
Cell cycle progression is regulated by the orderly balance between kinase and phosphatase activities. PP2A phosphatase holoenzymes containing the B55 family of regulatory B subunits function as major CDK1-counteracting phosphatases during mitotic exit in mammals. However, the identification of the specific mitotic roles of these PP2A-B55 complexes has been hindered by the existence of multiple B55 isoforms. Here, through the generation of loss-of-function genetic mouse models for the two ubiquitous B55 isoforms (B55α and B55δ), we report that PP2A-B55α and PP2A-B55δ complexes display overlapping roles in controlling the dynamics of proper chromosome individualization and clustering during mitosis. In the absence of PP2A-B55 activity, mitotic cells display increased chromosome individualization in the presence of enhanced phosphorylation and perichromosomal loading of Ki-67. These data provide experimental evidence for a regulatory mechanism by which the balance between kinase and PP2A-B55 phosphatase activity controls the Ki-67-mediated spatial organization of the mass of chromosomes during mitosis.
细胞周期的进展是通过激酶和磷酸酶活性的有序平衡来调节的。在哺乳动物有丝分裂退出过程中，含有 B55 家族调节 B 亚基的 PP2A 磷酸酶全酶作为主要的 CDK1 拮抗磷酸酶发挥作用。然而，由于存在多种 B55 同工型，这些 PP2A-B55 复合物的特定有丝分裂作用的鉴定受到了阻碍。在这里，通过生成两种普遍存在的 B55 同工型（B55α 和 B55δ）的功能丧失遗传小鼠模型，我们报告 PP2A-B55α 和 PP2A-B55δ 复合物在控制有丝分裂过程中染色体适当个体化和聚类的动力学方面具有重叠作用。在缺乏 PP2A-B55 活性的情况下，有丝分裂细胞在 Ki-67 的磷酸化增强和周染色体加载的情况下显示出染色体个体化增加。这些数据为一种调节机制提供了实验证据，该机制通过激酶和 PP2A-B55 磷酸酶活性之间的平衡来控制 Ki-67 介导的有丝分裂过程中染色体大量的空间组织。
