Aurora-A促进细胞周期从静止到初级纤毛的拆卸。

IF 4.3 2区 医学 Q1 ONCOLOGY
Cancer Science Pub Date : 2025-07-22 DOI:10.1111/cas.70153
Atsushi Kohso, Hironori Inaba, Masato T. Kanemaki, Esteban C. Gabazza, Hidemi Toyoda, Masahiro Hirayama, Hidemasa Goto
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引用次数: 0

摘要

Aurora-A (AurA)是有丝分裂激酶家族的成员,在多种肿瘤中高表达。抑制先兆通常会导致胎儿有丝分裂错误。我们之前报道过,AurA抑制通过促进初级纤毛的重组诱导非癌细胞的G0/G1细胞周期阻滞。然而,AurA调节有丝分裂以外的细胞周期进程的机制在很大程度上仍然未知。在这项研究中,我们使用基于CRISPR/ cas9的基因编辑技术,生成了非癌性RPE1和癌性HCT116细胞系,这些细胞系表达内源性的带有最小生长素诱导度(mAID)标记的AurA。该系统使内源性AurA蛋白特异性和快速耗竭。通过将这种方法与RPE1细胞的细胞同步相结合,我们研究了AurA在从静止细胞周期到增殖细胞周期转变中的功能。AurA的靶向降解不仅延迟了RPE1细胞的周期进程,而且在G0/G1过渡过程中破坏了初级纤毛的拆卸。由于这种细胞周期进程的延迟是通过敲除IFT20的强制降解来挽救的,因此AurA促进了降解,从而加速了RPE1细胞从细胞周期的静止阶段向增殖阶段的过渡。AurA耗竭4天增加了HCT116细胞的凋亡标记物,但在RPE1细胞中没有。值得注意的是,RPE1细胞的强制降解部分增强了AurA耗竭引起的细胞凋亡。这些结果表明,聚集初级纤毛的能力可能是防止AurA抑制后细胞死亡的保护机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Aurora-A Promotes Cell-Cycle Progression From Quiescence Through Primary Cilia Disassembly

Aurora-A Promotes Cell-Cycle Progression From Quiescence Through Primary Cilia Disassembly

Aurora-A (AurA) is a member of the mitotic kinase family and is highly expressed in various tumors. Inhibition of AurA generally leads to fetal mitotic errors. We previously reported that AurA inhibition induces G0/G1 cell cycle arrest in noncancerous cells by promoting the reassembly of primary cilia. However, the mechanisms by which AurA regulates cell cycle progression beyond mitosis remain largely unknown. In this study, we generated noncancerous RPE1 and cancerous HCT116 cell lines expressing endogenous AurA tagged with a minimal auxin-inducible degron (mAID) using CRISPR/Cas9-based gene editing. This system enabled specific and rapid depletion of endogenous AurA protein. By combining this approach with cell synchronization in RPE1 cells, we investigated AurA function specifically in the transition from quiescence to the proliferative cell cycle. Targeted degradation of AurA not only delayed cell cycle progression but also impaired the disassembly of primary cilia at the G0/G1 transition in RPE1 cells. Since this delay in cell cycle progression was rescued by forced deciliation via the knockout of IFT20, AurA facilitates deciliation, which in turn accelerates the transition from quiescence to the proliferative phase of the cell cycle in RPE1 cells. AurA depletion for 4 days increased apoptotic markers in HCT116 cells but not in RPE1 cells. Notably, forced deciliation in RPE1 cells partially enhanced apoptosis induced by AurA depletion. These results suggest that the ability to assemble primary cilia may serve as a protective mechanism against cell death following AurA inhibition.

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来源期刊
Cancer Science
Cancer Science 医学-肿瘤学
自引率
3.50%
发文量
406
审稿时长
2 months
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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