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周期蛋白 A-CDK1 通过抑制 CDK1 激活因子 CDC25A 的表达来保障细胞适时进入有丝分裂。

Cyclin A-CDK1 suppresses the expression of the CDK1 activator CDC25A to safeguard timely mitotic entry.

机构信息

Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China.

Department of Pathology, The University of Hong Kong, Hong Kong, China; State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.

出版信息

J Biol Chem. 2023 Mar;299(3):102957. doi: 10.1016/j.jbc.2023.102957. Epub 2023 Jan 28.

DOI:10.1016/j.jbc.2023.102957
PMID:36717077
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9986519/
Abstract

Cyclin A and CDC25A are both activators of cyclin-dependent kinases (CDKs): cyclin A acts as an activating subunit of CDKs and CDC25A a phosphatase of the inhibitory phosphorylation sites of the CDKs. In this study, we uncovered an inverse relationship between the two CDK activators. As cyclin A is an essential gene, we generated a conditional silencing cell line using a combination of CRISPR-Cas9 and degron-tagged cyclin A. Destruction of cyclin A promoted an acute accumulation of CDC25A. The increase of CDC25A after cyclin A depletion occurred throughout the cell cycle and was independent on cell cycle delay caused by cyclin A deficiency. Moreover, we determined that the inverse relationship with cyclin A was specific for CDC25A and not for other CDC25 family members or kinases that regulate the same sites in CDKs. Unexpectedly, the upregulation of CDC25A was mainly caused by an increase in transcriptional activity instead of a change in the stability of the protein. Reversing the accumulation of CDC25A severely delayed G-M in cyclin A-depleted cells. Taken together, these data provide evidence of a compensatory mechanism involving CDC25A that ensures timely mitotic entry at different levels of cyclin A.

摘要

细胞周期蛋白 A 和 CDC25A 都是细胞周期依赖性激酶 (CDKs) 的激活剂：细胞周期蛋白 A 作为 CDK 的激活亚基，CDC25A 作为 CDK 的抑制性磷酸化位点的磷酸酶。在这项研究中，我们揭示了这两种 CDK 激活剂之间的反比关系。由于细胞周期蛋白 A 是必需基因，我们使用 CRISPR-Cas9 和带有降解标签的细胞周期蛋白 A 的组合生成了一个条件沉默细胞系。细胞周期蛋白 A 的破坏促进了 CDC25A 的急性积累。细胞周期蛋白 A 耗竭后 CDC25A 的增加发生在整个细胞周期中，并且独立于细胞周期蛋白 A 缺乏引起的细胞周期延迟。此外，我们确定与细胞周期蛋白 A 的反比关系特异性针对 CDC25A，而不是针对其他 CDC25 家族成员或调节 CDK 中相同位点的激酶。出乎意料的是，CDC25A 的上调主要是由于转录活性的增加而不是蛋白质稳定性的变化引起的。逆转 CDC25A 的积累严重延迟了细胞周期蛋白 A 耗竭细胞的 G1-M 期。总之，这些数据提供了证据表明，CDC25A 参与了一种补偿机制，以确保在不同水平的细胞周期蛋白 A 下及时进入有丝分裂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1db6/9986519/a1534892aa14/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1db6/9986519/3bbffa11ec95/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1db6/9986519/7f7a07333af6/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1db6/9986519/9607d8a8c7cb/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1db6/9986519/25c7be5c58b7/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1db6/9986519/5cc587a6ac63/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1db6/9986519/3a4c77b3488e/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1db6/9986519/a1534892aa14/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1db6/9986519/3bbffa11ec95/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1db6/9986519/7f7a07333af6/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1db6/9986519/9607d8a8c7cb/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1db6/9986519/25c7be5c58b7/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1db6/9986519/5cc587a6ac63/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1db6/9986519/3a4c77b3488e/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1db6/9986519/a1534892aa14/gr7.jpg

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