Mechanisms of apoptotic cell death caused by radiation-induced perturbation in checkpoint regulations.

检查点调节中辐射引起的扰动引起细胞凋亡的机制。

• 批准号: 13480168
• 负责人: SUZUKI Fumio
• 金额: $ 4.54万
• 依托单位: HIROSHIMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13480168/
• 关键词: Radiation; Ultraviolet light; Apoptosis; Mitotic checkpoint; Chromosome instability; Mitochondria; Aurora; p53; γ線; シグナル伝達; 細胞応答; Jurkat; Aurora kinase; cytochrome C; caspase; HeLa; MCF-7; cytochrome c

To elucidate the mechanisms of chromosome instability and apoptosis caused by radiation-induced perturbations in mitotic checkpoint regulations, we have isolated serin/threonine protein kinases that regulate mitotic cell division and analyzed their properties associated with apoptotic cell death. The results obtained for the past 3 years can be summarized as follows:1. Phosphorylation of histone H3 at Ser-10 is required for maintenance of proper chromosome dynamics during mitosis. We found that exogenous overexpression of Aurora-B kinase AIM-1 in cultured mammalian cells caused increased mitotic Ser-10 phosphorylation with concomitant of lagging chromosomes during mitosis, and that chromosome number instability and increased tumor invasiveness were noted AIM-1 overexpression cell in vivo. These data suggest that increased H3 histone phosphorylation as a result of AIM-1 overexpression is a major precipitating factor of chromosome instability and, thus may play a role in carcinogenesis.2 … More . To analyze the mechanism of delayed form of apoptosis that is a common feature of various mammalian cells when irradiated with ionizing radiation, we examined the induction of apoptosis by γ or UV radiation and compared the activation of mitochondrial signaling pathways. The results indicate that delayed or rapid form of apoptosis strongly depend on types of radiation and might be due to the existence of cytosolic factors regulating release of cytochrome c from mitochondria, which functions at the upstream of apoptosis signaling pathways.3. Since overexpression of Aurora kinase-A and loss of wild-type of p53 function induce similar chromosome instability, which commonly appears in the process of malignant transformation, we have analyzed the relationship between the phosphorylation of Aurora-A and p53 activity. Our data suggest that overexpression of Aurora-A lead to increased degradation of p53, causing downregulation of checkpoint-response pathways and tolerance to apoptotic cells death. Less

为了阐明有丝分裂检查点调控中辐射诱导的扰动引起的染色体不稳定和凋亡的机制，我们分离了调节有丝分裂细胞分裂的丝氨酸/苏氨酸蛋白激酶，并分析了它们与凋亡性细胞死亡相关的特性。在过去三年中取得的成果可以概括如下：1。在有丝分裂期间，组蛋白H3在Ser-10处的磷酸化是维持适当的染色体动力学所必需的。我们发现外源性Aurora-B激酶AIM-1在培养的哺乳动物细胞中的过表达导致有丝分裂中Ser-10磷酸化增加，伴随有丝分裂中的落后染色体，并且在体内观察到AIM-1过表达细胞的染色体数目不稳定和肿瘤侵袭性增加。这些数据表明，AIM-1过表达导致的H3组蛋白磷酸化增加是染色体不稳定性的主要沉淀因素，因此可能在致癌中发挥作用。2 ...更多信息 .为了分析电离辐射照射时各种哺乳动物细胞的共同特征--延迟型细胞凋亡的机制，我们检查了γ或紫外线辐射对细胞凋亡的诱导，并比较了线粒体信号通路的激活。结果表明，细胞凋亡的延迟或快速形式强烈依赖于辐射的类型，可能是由于细胞质中存在调节线粒体释放细胞色素c的因子，而细胞色素c在细胞凋亡信号通路的上游发挥作用.由于Aurora激酶-A的过度表达和野生型p53功能的丧失诱导类似的染色体不稳定性，这通常出现在恶性转化的过程中，我们分析了Aurora-A的磷酸化和p53活性之间的关系。我们的数据表明，Aurora-A的过度表达导致p53的降解增加，导致检查点反应途径的下调和对凋亡细胞死亡的耐受。少

项目成果

Minoshima, Y: "Phosphorylation by aurora B converts MgcRacGAP to a RhoGAP during cytokinesis."Developmental Cell. 4. 549-560 (2003)

Minoshima, Y：“aurora B 的磷酸化在胞质分裂过程中将 MgcRacGAP 转化为 RhoGAP。”发育细胞。

Suzuki, F.: "Cellular radiosensitivity and cell-type-specific activation of apoptosis signaling pathways."Proceedings of the 1st Nagasaki Symposium of International Consortium for Medical Care of Hibakusya and Radiation Life Science. 233-237 (2003)

Suzuki, F.：“细胞放射敏感性和细胞类型特异性凋亡信号通路激活。”Hibakusya 医疗保健和放射生命科学国际联盟第一届长崎研讨会论文集。

K.Sasai: "Suppression of postmitochondrial signaling and delayed response to UV-induced nuclear apoptosis in HeLa cells."Japanese Journal of Cancer Research. 93・3(印刷中). (2002)

K. Sasai：“HeLa 细胞中线粒体后信号传导的抑制和对紫外线诱导的核细胞凋亡的延迟反应”。《日本癌症研究杂志》93·3（出版中）。

Suzuki, F. et al.: "Cell type specific morphological changes and caspase activation in radiation-induced apoptosis."The Journal of The Hiroshima Medical Association. 55(3). 263-266 (2002)

Suzuki, F. 等人：“辐射诱导的细胞凋亡中细胞类型特异性形态变化和半胱天冬酶激活。”广岛医学会杂志。

Ota, T., et al.: "Cationic liposomes with plasmid DNA influence cancer metastatic capability."Anticancer Research. 22. 4049-4052 (2002)

Ota, T. 等人：“带有质粒 DNA 的阳离子脂质体影响癌症转移能力。”抗癌研究。