The ubiquitin ligase CRL2zYG11 targets cyclin B1 for degradation in a conserved pathway that facilitates mitotic slippage
The ubiquitin ligase CRL2zYG11 targets cyclin B1 for degradation in a conserved pathway that facilitates mitotic slippage
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DOI：
10.1083/jcb.201601083
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发表时间：
2016-10-24
影响因子：
7.8
通讯作者：
Kipreos, Edward T.
中科院分区：
文献类型：
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作者：
Balachandran, Riju S.;Heighington, Cassandra S.;Kipreos, Edward T.
后期促进复合物/细胞周期体（APC/C）泛素连接酶是已知的目标细胞周期蛋白B1的降解，这是至关重要的有丝分裂在动物细胞中的进展。在这项研究中，我们表明，泛素连接酶CRL 2（zYG-11）冗余的目标细胞周期蛋白B1在秀丽隐杆线虫和人类细胞的降解。In C.在秀丽隐杆线虫中，CRL 2（zYG-11）和APC/C两者都是通过减数分裂的适当进展所必需的。在人类细胞中，当APC/C有活性时，CRL 2（zYG 11 A/B）的失活对有丝分裂进程的影响最小。然而，当APC/C失活或细胞周期蛋白B1过表达时，CRL 2（zYG 11 A/B）介导的细胞周期蛋白B1降解是通过中期正常进展所必需的。被纺锤体组装检查点（其使APC/C失活）阻止的有丝分裂细胞通常在称为“有丝分裂滑移”的过程中退出有丝分裂，这产生四倍体细胞并限制抗有丝分裂化疗药物的有效性。我们表明，ZYG 11 A/B亚基敲除或小分子MLN 4924使广泛的cullin RING遍在蛋白连接酶失活，可以抑制人类细胞的有丝分裂滑动，这表明抗有丝分裂联合治疗的潜力。
The anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase is known to target the degradation of cyclin B1, which is crucial for mitotic progression in animal cells. In this study, we show that the ubiquitin ligase CRL2(zYG-11) redundantly targets the degradation of cyclin B1 in Caenorhabditis elegans and human cells. In C. elegans, both CRL2(zYG-11) and APC/C are required for proper progression through meiotic divisions. In human cells, inactivation of CRL2(zYG11A/B) has minimal effects on mitotic progression when APC/C is active. However, when APC/C is inactivated or cyclin B1 is overexpressed, CRL2(zYG11A/B)-mediated degradation of cyclin B1 is required for normal progression through metaphase. Mitotic cells arrested by the spindle assembly checkpoint, which inactivates APC/C, often exit mitosis in a process termed "mitotic slippage," which generates tetraploid cells and limits the effectiveness of antimitotic chemotherapy drugs. We show that ZYG11A/B subunit knockdown, or broad cullin RING ubiquitin ligase inactivation with the small molecule MLN4924, inhibits mitotic slippage in human cells, suggesting the potential for antimitotic combination therapy.