Mechanism of premature senescence induction through DNA damage responses

DNA损伤反应诱导早衰的机制

• 批准号: 23240124
• 负责人: NAKANISHI Makoto
• 金额: $ 31.62万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-23240124/
• 关键词: 癌; ゲノム; シグナル伝達; 発現抑制; 老化

Senescence is a state of permanent growth arrest and is a pivotal part of the anti-tumorigenic barrier in vivo. Although the tumor suppressor activities of p53 and pRb family proteins are essential for the induction of senescence, molecular mechanisms by which these proteins induce senescence are still not clear. Using time-lapse live-cell imaging, we demonstrate here that normal human diploid fibroblasts (HDFs) exposed to various senescence-inducing stimuli undergo a mitosis skip before entry into permanent cell cycle arrest. This mitosis skip is mediated by both p53-dependent premature activation of APC/CCdh1 and pRb family protein-dependent transcriptional suppression of mitotic regulators. Importantly, mitotic skipping is necessary and sufficient for senescence induction. Our findings provide decisive evidence for the molecular basis underlying the induction and maintenance of cellular senescence.

衰老是一种永久性生长停滞的状态，是体内抗肿瘤屏障的关键部分。虽然p53和pRb家族蛋白的肿瘤抑制活性对于诱导衰老是必不可少的，但是这些蛋白诱导衰老的分子机制仍然不清楚。使用延时活细胞成像，我们在这里证明，正常的人二倍体成纤维细胞（HDF）暴露于各种衰老诱导刺激进行有丝分裂跳跃进入永久性细胞周期停滞之前。这种有丝分裂跳跃由APC/CCDh 1的p53依赖性过早激活和有丝分裂调节因子的pRb家族蛋白依赖性转录抑制介导。重要的是，有丝分裂跳跃对于衰老诱导是必要和充分的。我们的研究结果为细胞衰老的诱导和维持的分子基础提供了决定性的证据。

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

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

Cell Cycle

• DOI: 10.1016/b978-0-12-809633-8.90189-4
• 发表时间: 2019
• 期刊: Reference Module in Life Sciences
• 作者: E. Ventura;A. Giordano

Genetic variation of the IL-28B promoter affecting gene expression.

• DOI: 10.1371/journal.pone.0026620
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sugiyama M;Tanaka Y;Wakita T;Nakanishi M;Mizokami M
• 通讯作者: Mizokami M

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