Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1.
Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1.
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DOI：
10.1083/jcb.200111001
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发表时间：
2002-06-24
影响因子：
7.8
通讯作者：
Pines, Jonathon
中科院分区：
文献类型：
--
作者：
Hagting, Anja;Den Elzen, Nicole;Vodermaier, Hartmut C;Waizenegger, Irene C;Peters, Jan-Michael;Pines, Jonathon
有丝分裂的过程是由关键调节因子的顺序破坏控制的，包括有丝分裂周期蛋白和安全蛋白，安全蛋白是一种后期抑制剂，其破坏是姐妹染色单体分离所必需的。在这里，我们使用活细胞成像来确定人类安全蛋白在有丝分裂中降解的确切时间。我们证明了安全销毁的时间是由纺锤形检查点设定的；一旦满足检查点，安全销毁将在中期开始。此外，重新设置检查点会迅速使安全破坏失效。因此，securin和cyclin B1的破坏具有非常相似的性质。此外，我们发现在姐妹染色单体分离之前，细胞周期蛋白B1和安全蛋白都必须被降解。缺乏破坏盒（D-box）的一种突变形式的安全蛋白在有丝分裂中仍然被降解，但现在这是在后期。这种破坏需要在securin的NH2末端有一个KEN box，并且可能指示有丝分裂中泛素化从APCCdc20切换到APCCdh1的时间。最后，在中期不能降解的securin的D-box突变体抑制姐妹染色单体分离，产生切割表型，其中一个细胞可以继承两个基因组拷贝。因此，安全蛋白破坏的缺陷改变了染色体分离，可能与癌症中非整倍体的发展有关。
Progress through mitosis is controlled by the sequential destruction of key regulators including the mitotic cyclins and securin, an inhibitor of anaphase whose destruction is required for sister chromatid separation. Here we have used live cell imaging to determine the exact time when human securin is degraded in mitosis. We show that the timing of securin destruction is set by the spindle checkpoint; securin destruction begins at metaphase once the checkpoint is satisfied. Furthermore, reimposing the checkpoint rapidly inactivates securin destruction. Thus, securin and cyclin B1 destruction have very similar properties. Moreover, we find that both cyclin B1 and securin have to be degraded before sister chromatids can separate. A mutant form of securin that lacks its destruction box (D-box) is still degraded in mitosis, but now this is in anaphase. This destruction requires a KEN box in the NH2 terminus of securin and may indicate the time in mitosis when ubiquitination switches from APCCdc20 to APCCdh1. Lastly, a D-box mutant of securin that cannot be degraded in metaphase inhibits sister chromatid separation, generating a cut phenotype where one cell can inherit both copies of the genome. Thus, defects in securin destruction alter chromosome segregation and may be relevant to the development of aneuploidy in cancer.