RAN cycle and cellular senescence

RAN 周期和细胞衰老

• 批准号: 23657130
• 负责人: YONEDA Yoshihiro
• 金额: $ 2.58万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-23657130/
• 关键词: 核輸送; 細胞老化; Ran; importin; RanBP1

The small GTPase Ran, Ras-related nuclear protein, plays important roles in multiple fundamental cellular functions such as nucleocytoplasmic transport, mitotic spindle assembly, and nuclear envelope formation, by binding to either GTP or GDP as a molecular switch. During the long-term culture of normal mammalian cells, I found that the endogenous Ran level gradually reduced in a passage-dependent manner. To examine the physiological significance of Ran reduction, I first performed small interfering RNA(siRNA)-mediated abrogation of Ran in human diploid fibroblasts. Ran-depleted cells showed several senescent phenotypes. Furthermore, I found that nuclear accumulation of importinα, which was also observed in cells treated with siRNA against CAS, a specific export factor for importinα, occurred in the Ran-depleted cells before the cells showed senescent phenotypes. Further, the CAS-depleted cells also exhibited cellular senescence. Indeed, importinα gradually accumulated in a passage-dependent manner. Thus, reduction in Ran levels causes nuclear accumulation of importinα, leading to cellular senescence in normal cells. The amount of intracellular Ran may be critically related to cell senescence. The cellular aging process may proceed through gradual regression of Ran-dependent nucleocytoplasmic transport competency.

Ras相关的核蛋白小GTP酶Ran通过与GTP或GDP结合作为分子开关，在多种基本细胞功能如核质转运、有丝分裂纺锤体组装和核膜形成中起重要作用。在正常哺乳动物细胞的长期培养过程中，我发现内源性Ran水平以一种依赖性的方式逐渐降低。为了研究Ran减少的生理意义，我首先在人二倍体成纤维细胞中进行了小干扰RNA（siRNA）介导的Ran消除。RAN耗竭细胞表现出几种衰老表型。此外，我发现，在RAN耗尽的细胞中，在细胞表现出衰老表型之前，发生了importinα的核积累，这也在用针对CAS的siRNA处理的细胞中观察到，CAS是importinα的特异性输出因子。此外，CAS耗尽的细胞也表现出细胞衰老。事实上，输入蛋白α以α依赖性方式逐渐积累。因此，Ran水平的降低导致importinα在核中积累，导致正常细胞中的细胞衰老。细胞内Ran的量可能与细胞衰老密切相关。细胞衰老过程可能通过Ran依赖的核质转运能力的逐渐消退而进行。

项目成果

The role of Rael in Nup98-fusion mediated leukemogenesis

Rael 在 Nup98 融合介导的白血病发生中的作用

• DOI: 10.4161/cc.10.12.15759
• 发表时间: 2011
• 期刊: Cell Cycle.
• 作者: Oka;M.;Yoneda;Y.
• 通讯作者: Y.

The involvement of small GTPase Ran in cellular aging

小GTPase Ran参与细胞衰老

• 发表时间: 2011
• 作者: 永井理博;米田悦啓
• 通讯作者: 米田悦啓

Nuclear importinτand its physiological importance

核输入τ及其生理重要性

• 发表时间: 2012
• 期刊: Commun. Integ. Biol
• 作者: Miyamoto;Y.;Loveland;K. L. and Yoneda;Y.
• 通讯作者: Y.

Importin alpha mediates biased translocation through nuclear pores in conjunction with Nup153

Importin alpha 与 Nup153 一起介导通过核孔的偏向易位

• 发表时间: 2011
• 作者: Ogawa;Y.;Miyamoto;Y.;Oka;M. and Yoneda;Y
• 通讯作者: Y

Intrinsic and extrinsic negative regulators of nuclear protein transport processes.

• DOI: 10.1111/j.1365-2443.2012.01609.x
• 发表时间: 2012-07
• 期刊: Genes to cells : devoted to molecular & cellular mechanisms
• 作者: Sekimoto T;Yoneda Y
• 通讯作者: Yoneda Y