The Evi5 oncogene regulates cyclin accumulation by stabilizing the anaphase-promoting complex inhibitor Emi1
The Evi5 oncogene regulates cyclin accumulation by stabilizing the anaphase-promoting complex inhibitor Emi1
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DOI：
10.1016/j.cell.2005.10.038
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发表时间：
2006-01-27
期刊：
影响因子：
64.5
通讯作者：
Jackson, PK
中科院分区：
文献类型：
--
作者：
Eldridge, AG;Loktev, AV;Jackson, PK
后期促进复合物/细胞周期体（APC/C）抑制剂RIP 1通过稳定关键的APC/C泛素化底物（包括细胞周期蛋白A）来控制S期和有丝分裂的进程。通过检查Emi 1结合蛋白，我们确定Evi 5癌基因是Emi 1积累的调节因子。Evi 5通过结合到与DSGxxS降解决定子相邻的位点并阻断Polo样激酶的降解决定子磷酸化和随后的β TrCP结合来拮抗SCF β TrCP依赖性DSGxx 1泛素化和破坏。因此，Evi 5作为稳定因子在S/G2期维持EST 1水平。Evi 5蛋白在Plk 1破坏后的早期G1中积累，并在早期有丝分裂中以Plk 1和泛素依赖的方式降解。Evi 5的消融通过Plk/SCF β TrCP途径诱导E11的早熟降解，导致APC/C过早激活;细胞周期蛋白破坏;细胞周期停滞;中心体过度复制;以及最终的有丝分裂灾难。我们认为Evi 5和Polike激酶活性的平衡决定了EST 1和细胞周期蛋白的及时积累，确保了有丝分裂的保真度。
The anaphase-promoting complex/cyclosome (APC/C) inhibitor Emi1 controls progression to S phase and mitosis by stabilizing key APC/C ubiquitination substrates, including cyclin A. Examining Emi1 binding proteins, we identified the Evi5 oncogene as a regulator of Emi1 accumulation. Evi5 antagonizes SCF beta TrCP-dependent Emi1 ubiquitination and destruction by binding to a site adjacent to Emi1's DSGxxS degron and blocking both degron phosphorylation by Polo-like kinases and subsequent beta TrCP binding. Thus, Evi5 functions as a stabilizing factor maintaining Emi1 levels in S/G2 phase. Evi5 protein accumulates in early G1 following Plk1 destruction and is degraded in a Plk1 - and ubiquitin-dependent manner in early mitosis. Ablation of Evi5 induces precocious degradation of Emi1 by the Plk/SCF beta TrCP pathway, causing premature APC/C activation; cyclin destruction; cell-cycle arrest; centrosome overduplication; and, finally, mitotic catastrophe. We propose that the balance of Evi5 and Pololike kinase activities determines the timely accumulation of Emi1 and cyclin, ensuring mitotic fidelity.