Who guards the guardian? Mechanisms that restrain APC/C during the cell cycle.
Who guards the guardian? Mechanisms that restrain APC/C during the cell cycle.
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DOI：
10.1016/j.bbamcr.2018.09.011
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发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
Emanuele MJ
中科院分区：
文献类型：
--
作者：
Kernan J;Bonacci T;Emanuele MJ
细胞周期主要由细胞周期蛋白依赖性激酶（CDK）控制，其振荡活性由与细胞周期蛋白共激活因子的结合决定。细胞周期蛋白在细胞周期中表现出动态的丰度变化。细胞周期蛋白以及许多其他蛋白质的连续、定时积累和降解，对细胞周期施加了秩序，并有助于基因组的维持。许多细胞周期调节蛋白（包括细胞周期蛋白A和B）的破坏由称为后期促进复合物/环体（APC/C）的大的多亚基E3泛素连接酶控制。APC/C活性在细胞周期中受到严格调节。它的激活状态在有丝分裂中期急剧增加，并保持活性，直到G1期结束。APC/C在G1/S边界强制性失活后，其活性保持较低，直到随后的有丝分裂。由于其在防止细胞周期蛋白的不适当或不合时宜的积累中的作用，APC/C是细胞周期振荡器的核心组成部分。除了调控细胞周期蛋白外，APC/C还控制许多其他底物的降解。因此，必须严格保护APC/C本身的活性。APC/C在有丝分裂过程中的作用和调控研究最多。然而，APC/C在维持G1期中也起着同样重要和保守的作用。在这里，我们回顾了在整个细胞周期中抵消APC/C活性的不同机制，以及它们对细胞生长，增殖和疾病的协调作用的重要性。
The cell cycle is principally controlled by Cyclin Dependent Kinases (CDKs), whose oscillating activities are determined by binding to Cyclin coactivators. Cyclins exhibit dynamic changes in abundance as cells pass through the cell cycle. The sequential, timed accumulation and degradation of Cyclins, as well as many other proteins, imposes order on the cell cycle and contributes to genome maintenance. The destruction of many cell cycle regulated proteins, including Cyclins A and B, is controlled by a large, multi-subunit E3 ubiquitin ligase termed the Anaphase Promoting Complex/Cyclosome (APC/C). APC/C activity is tightly regulated during the cell cycle. Its activation state increases dramatically in mid-mitosis and it remains active until the end of G1-phase. Following its mandatory inactivation at the G1/S boundary, APC/C activity remains low until the subsequent mitosis. Due to its role in guarding against the inappropriate or untimely accumulation of Cyclins, the APC/C is a core component of the cell cycle oscillator. In addition to the regulation of Cyclins, APC/C controls the degradation of many other substrates. Therefore, it is vital that the activity of APC/C itself be tightly guarded. The APC/C is most well studied for its role and regulation during mitosis. However, the APC/C also plays a similarly important and conserved role in the maintenance of G1 phase. Here we review the diverse mechanisms counteracting APC/C activity throughout the cell cycle and the importance of their coordinated actions on cell growth, proliferation, and disease.
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