Antizyme restrains centrosome amplification by regulating the accumulation of Mps1 at centrosomes.
Antizyme restrains centrosome amplification by regulating the accumulation of Mps1 at centrosomes.
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DOI：
10.1091/mbc.e10-04-0281
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发表时间：
2010-11-15
影响因子：
3.3
通讯作者：
Fisk HA
中科院分区：
文献类型：
--
作者：
Kasbek C;Yang CH;Fisk HA
中心体无法降解 Mps1 会导致中心体过量产生，但导致 Mps1 降解的因素尚不清楚。这项研究表明，抗酶是一种不依赖于泛素的降解介质，它与 Mps1 结合并通过蛋白酶体调节中心体 Mps1，揭示了 Mps1 在原中心粒组装中的作用。在许多肿瘤中发现了额外的中心体，它们的出现是一种早期事件，可以产生异常的有丝分裂纺锤体和非整倍性。由于未能适当降解 Mps1 蛋白激酶与肿瘤来源细胞中中心体过量产生相关，因此促进 Mps1 降解的因素的缺陷可能会导致肿瘤中产生额外的中心体。然而，虽然我们最近表征了 Mps1 降解信号，但调节 Mps1 中心体 Mps1 的因素尚不清楚。抗酶 (OAZ) 是一种不依赖于泛素的降解介质，也是一种可疑的肿瘤抑制因子，最近被证明可以定位于中心体并调节中心体的过度生产，但已知的 OAZ 底物与其对中心体的影响无关。我们发现OAZ通过Mps1对中心体发挥作用。 OAZ促进Mps1从中心体中去除，而减少OAZ活性导致的中心体过量产生需要Mps1。 OAZ 通过 Mps1 降解信号与 Mps1 结合，并调节 Mps1 在中心体过量产生中的功能。此外，OAZ 调节典型的中心体复制周期，并揭示了 Mps1 在原中心体组装中的功能。总之，我们的数据表明，OAZ 通过 Cdk2 调节的 Mps1 降解信号控制中心体 Mps1 的水平，从而抑制中心粒的组装。
The failure to degrade Mps1 at centrosomes causes centrosome overproduction, but the factors that target Mps1 for degradation are unknown. This study shows that antizyme, a mediator of ubiquitin-independent degradation, binds to Mps1 and modulates centrosomal Mps1 via the proteasome, revealing a role for Mps1 in procentriole assembly. Extra centrosomes are found in many tumors, and their appearance is an early event that can generate aberrant mitotic spindles and aneuploidy. Because the failure to appropriately degrade the Mps1 protein kinase correlates with centrosome overproduction in tumor-derived cells, defects in the factors that promote Mps1 degradation may contribute to extra centrosomes in tumors. However, while we have recently characterized an Mps1 degradation signal, the factors that regulate Mps1 centrosomal Mps1 are unknown. Antizyme (OAZ), a mediator of ubiquitin-independent degradation and a suspected tumor suppressor, was recently shown to localize to centrosomes and modulate centrosome overproduction, but the known OAZ substrates were not responsible for its effect on centrosomes. We have found that OAZ exerts its effect on centrosomes via Mps1. OAZ promotes the removal of Mps1 from centrosomes, and centrosome overproduction caused by reducing OAZ activity requires Mps1. OAZ binds to Mps1 via the Mps1 degradation signal and modulates the function of Mps1 in centrosome overproduction. Moreover, OAZ regulates the canonical centrosome duplication cycle, and reveals a function for Mps1 in procentriole assembly. Together, our data suggest that OAZ restrains the assembly of centrioles by controlling the levels of centrosomal Mps1 through the Cdk2-regulated Mps1 degradation signal.