Lats1 suppresses centrosome overduplication by modulating the stability of Cdc25B.
Lats1 suppresses centrosome overduplication by modulating the stability of Cdc25B.
复制标题
Lats1 通过调节 Cdc25B 的稳定性来抑制中心体的过度复制。
DOI：
10.1038/srep16173
复制
发表时间：
2015-11-04
影响因子：
4.6
通讯作者：
Nojima H
中科院分区：
文献类型：
--
作者：
Mukai S;Yabuta N;Yoshida K;Okamoto A;Miura D;Furuta Y;Abe T;Nojima H
中心体的数目畸变导致染色体错误分离，最终导致染色体不稳定，这是人类肿瘤恶性的标志。大肿瘤抑制因子1和2（Lats 1和Lats 2）是Hippo通路中的中心激酶，通过协调细胞增殖和凋亡之间的平衡来调节发育和肿瘤发生。重要的是，Lats 1和Lats 2也在细胞周期检查点和有丝分裂中发挥关键作用。Lats蛋白定位于中心体，但其中心体功能仍然难以捉摸。在这里，我们产生了Lats 1-null敲除（Lats 1 −/−）小鼠，并建立了Lats 1-null小鼠胚胎成纤维细胞（MEFs）。在Lats 1 −/− MEFs中，中心体明显过度复制，导致严重的有丝分裂缺陷，如染色体错误分离和胞质分裂失败。我们还发现Lats 1与Cdc 25 B磷酸酶相互作用，该磷酸酶定位于中心体和细胞核，并调节中心体周期和有丝分裂进程之间的联系。虽然Lats 1没有磷酸化Cdc 25 B，在MEFs中的Lats 1的损失引起的异常积累的Cdc 25 B蛋白和Cdk 2的超活化向核磷蛋白（NPM/B23），其中一个许可的因素参与中心粒复制。两者合计，这些数据表明，Lats 1调节Cdc 25 B蛋白水平和随后的Cdk 2活性，从而抑制中心体过度复制间期。
Numerical aberration of the centrosome results in chromosome missegregation, eventually leading to chromosomal instability, a hallmark of human tumor malignancy. Large tumor suppressors 1 and 2 (Lats1 and Lats2) are central kinases in the Hippo pathway and regulate development and tumorigenesis by coordinating the balance between cell proliferation and apoptosis. Importantly, Lats1 and Lats2 also play pivotal roles in cell cycle checkpoint and mitosis. The Lats proteins localize at centrosomes, but their centrosomal functions remain elusive. Here, we generated Lats1-null knockout (Lats1−/−) mice and established Lats1-null mouse embryonic fibroblasts (MEFs). In Lats1−/− MEFs, centrosomes were markedly overduplicated, leading to severe mitotic defects such as chromosome missegregation and cytokinesis failure. We also found that Lats1 physically interacts with Cdc25B phosphatase that localizes both at the centrosome and in the nucleus and regulates the linkage between the centrosome cycle and mitotic progression. Although Lats1 did not phosphorylate Cdc25B, loss of Lats1 in MEFs caused abnormal accumulation of Cdc25B protein and hyperactivation of Cdk2 toward nucleophosmin (NPM/B23), one of the licensing factors involved in centriole duplication. Taken together, these data suggest that Lats1 regulates Cdc25B protein level and subsequent Cdk2 activity, thereby suppressing centrosome overduplication during interphase.