Establishment of damage dose-dependent senescence inducible system and its application for understanding molecular basis underlying geriatiric diseases

损伤剂量依赖性衰老诱导系统的建立及其在老年疾病分子基础研究中的应用

• 批准号: 24659137
• 负责人: NAKANISHI Makoto
• 金额: $ 2.5万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2012
• 资助国家: 日本
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-24659137/
• 关键词: 老化; シグナル伝達; 発現抑制

Since induction of cellular senescence might be dependent on a number of DNA double strand breaks, we introduced various I-SceI restriction sites in normal human fibroblasts, which is not normally observed in normal human cells, and analysed whether these cells undergo senescence or not. However, during our experimental course, we found that only single DNA double strand break was sufficient for the induction of senescence when the break occurred during G2 phase. p53 activation during G2 resulted in a mitosis skip, leading to a generation of tetraploid G1 cells. This mitosis skip was collaboratively regulated by premature activation of APC-C/Cdh1 through Cdk1 and Cdk2 inhibition by induced p21 and pRb-family pocket protein dependent transcriptional repression of mitotic regulators.

由于细胞衰老的诱导可能依赖于许多DNA双链断裂，我们在正常的人类成纤维细胞中引入了不同的I-SceI限制性位点，这在正常的人类细胞中通常没有观察到，并分析了这些细胞是否会发生衰老。然而，在我们的实验过程中，我们发现只有单个DNA双链断裂才足以诱导衰老，当断裂发生在G2期。在G2期间p53的激活导致有丝分裂跳跃，导致四倍体G1细胞的产生。APC-C/Cdh1通过诱导p21和prb家族口袋蛋白依赖的有丝分裂调节因子的转录抑制抑制Cdk1和Cdk2，从而过早激活APC-C/Cdh1，从而协同调节这种有丝分裂跳跃。

项目成果

Role of DNA damage responses in induction of premature senescence.

DNA 损伤反应在诱导过早衰老中的作用。

• 发表时间: 2012
• 作者: Fiona OBrien;Elisa Venturi;Elena Galfre;Antoni Matyjaszkiewicz;Daiju Yamazaki;Miyuki Nishi;Hiroshi Takeshima;Rebecca Stisapesan;中西 真
• 通讯作者: 中西 真

Maintaining the integrity of genomic information by cell cycle checkpoints.

通过细胞周期检查点维持基因组信息的完整性。

• 发表时间: 2012
• 作者: 山崎大樹;趙成珠;陶晟辰;王朝弘;西美幸;竹島浩;中西 真
• 通讯作者: 中西 真

Increased protein stability of CDKN1C causes a gain-of-function phenotype in patients with IMAGe syndrome.

CDKN1C的蛋白质稳定性提高会导致图像综合征患者的功能型表型。

• DOI: 10.1371/journal.pone.0075137
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Hamajima N;Johmura Y;Suzuki S;Nakanishi M;Saitoh S
• 通讯作者: Saitoh S

Translational Epigenomics

转化表观基因组学

• 发表时间: 2013
• 作者: Yamazaki D;Tao S;Takeshima H.;中西真
• 通讯作者: 中西真

Necessary and Sufficient Role for a Mitosis Skip in Senescence Induction

• DOI: 10.1016/j.molcel.2014.05.003
• 发表时间: 2014-07-03
• 期刊: MOLECULAR CELL
• 影响因子: 16
• 作者: Johmura, Yoshikazu;Shimada, Midori;Nakanishi, Makoto
• 通讯作者: Nakanishi, Makoto