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细胞周期蛋白A2-细胞周期蛋白依赖性激酶2对分裂间期后期促进复合物/细胞分裂周期蛋白20的抑制作用确保了有丝分裂的有效启动。

Interphase APC/C-Cdc20 inhibition by cyclin A2-Cdk2 ensures efficient mitotic entry.

作者信息

Hein Jamin B, Nilsson Jakob

机构信息

The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.

出版信息

Nat Commun. 2016 Mar 10;7:10975. doi: 10.1038/ncomms10975.

DOI:10.1038/ncomms10975
PMID:26960431
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4792957/
Abstract

Proper cell-cycle progression requires tight temporal control of the Anaphase Promoting Complex/Cyclosome (APC/C), a large ubiquitin ligase that is activated by one of two co-activators, Cdh1 or Cdc20. APC/C and Cdc20 are already present during interphase but APC/C-Cdc20 regulation during this window of the cell cycle, if any, is unknown. Here we show that cyclin A2-Cdk2 binds and phosphorylates Cdc20 in interphase and this inhibits APC/C-Cdc20 activity. Preventing Cdc20 phosphorylation results in pre-mature activation of the APC/C-Cdc20 and several substrates, including cyclin B1 and A2, are destabilized which lengthens G2 and slows mitotic entry. Expressing non-degradable cyclin A2 but not cyclin B1 restores mitotic entry in these cells. We have thus uncovered a novel positive feedback loop centred on cyclin A2-Cdk2 inhibition of interphase APC/C-Cdc20 to allow further cyclin A2 accumulation and mitotic entry.

摘要

正常的细胞周期进程需要对后期促进复合体/细胞周期体（APC/C）进行严格的时间控制，APC/C是一种大型泛素连接酶，可被两种共激活因子之一Cdh1或Cdc20激活。APC/C和Cdc20在间期就已存在，但在细胞周期的这个阶段，APC/C-Cdc20的调控情况（如果存在的话）尚不清楚。在这里，我们表明细胞周期蛋白A2-Cdk2在间期结合并磷酸化Cdc20，这会抑制APC/C-Cdc20的活性。阻止Cdc20磷酸化会导致APC/C-Cdc20过早激活，包括细胞周期蛋白B1和A2在内的几种底物会不稳定，从而延长G2期并减缓有丝分裂进入。在这些细胞中表达不可降解的细胞周期蛋白A2而不是细胞周期蛋白B1可恢复有丝分裂进入。因此，我们发现了一个以细胞周期蛋白A2-Cdk2对间期APC/C-Cdc20的抑制为中心的新型正反馈回路，以允许细胞周期蛋白A2进一步积累并进入有丝分裂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd2a/4792957/7c85bcb50ea6/ncomms10975-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd2a/4792957/4ba339af8835/ncomms10975-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd2a/4792957/4e3c0c138430/ncomms10975-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd2a/4792957/afbc73c8217c/ncomms10975-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd2a/4792957/51b1fdd62965/ncomms10975-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd2a/4792957/16afdf574b1d/ncomms10975-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd2a/4792957/9eae960fe5be/ncomms10975-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd2a/4792957/7c85bcb50ea6/ncomms10975-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd2a/4792957/4ba339af8835/ncomms10975-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd2a/4792957/4e3c0c138430/ncomms10975-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd2a/4792957/afbc73c8217c/ncomms10975-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd2a/4792957/51b1fdd62965/ncomms10975-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd2a/4792957/16afdf574b1d/ncomms10975-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd2a/4792957/9eae960fe5be/ncomms10975-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd2a/4792957/7c85bcb50ea6/ncomms10975-f7.jpg

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