Gene regulation of radiation response

辐射反应的基因调控

• 批准号: 06304049
• 负责人: SASAKI Masao
• 金额: $ 15.68万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-06304049/
• 关键词: Radiation response; Gene expression; Signal transduction; Cell cycle regulation; Oxidative stress; Mutation; Genetic instability; Radiosensitivity; 遺伝子的不安定性; 適応応答; 細胞内情報伝達; 放射線感受性遺伝子; ゲノム不安定性

The concept of the action of radiation as a stimuli is innovative. The aim the present study was to clarify the genetic control mechanisms of the radiation response and to establish a new biological basis of the effects of radiations. In response to small doses of radiations, mammalian cells become radioresistant (adaptive response) as well as stimulated to grow. The adaptive response were found to be mediated by PKC and p38 MAP kinase signalling pathways and continued for long time. While direct relationship was not known, p53 proteins were suggested to be downstream effector of the adaptive response (Sasaki). p53 proteins coprecipitate with heat-shock proteins such as HSP72 (Ohnishi), suggesting regulation of p53 by HSP.p53 proteins are also accumulated in response to microgravity indicating a key role of p53 in general stress response (Ohnishi). In p53 knock-out mouse cells, adaptive response was not induced (Sasaki) and UV-induced mutation showed different spectra as compared with those in wild-type cells (Ishizaki). These findings suggest that p53 regulates DNA replication and thence types and frequencies of mutations. In vitro assay system was established for the repair kinetics of formyluracil, most important oxidative damage to DNA (Yonei). In Drosophila, DNA damage-inducible mutagenesis was confirmed by the mutation of minisatellite loci in female genome fertilized by irradiated sperm, suggesting DNA damage-inducible genetic instability (Niwa). We were not able to clone a gene (ATM) responsible for ataxia telangiectasia, radiosensitive human disease. However, new mutations of ATM gene were found in Japanese patients (Ejima).

辐射作为刺激作用的概念是创新的。本研究的目的是阐明辐射反应的遗传控制机制，并为辐射效应建立新的生物学基础。在对小剂量辐射的反应中，哺乳动物细胞变得耐辐射（适应性反应），并受到刺激生长。发现这种适应性反应是由PKC和p38 MAP激酶信号通路介导的，并持续很长时间。虽然直接关系尚不清楚，但p53蛋白被认为是适应性反应的下游效应者（Sasaki）。p53蛋白与热休克蛋白如HSP72共沉淀（Ohnishi），提示HSP对p53有调控作用。在微重力条件下，p53蛋白也会积累，这表明p53在一般应激反应中起着关键作用（Ohnishi）。在p53敲除小鼠细胞中，没有诱导适应性反应（Sasaki），紫外线诱导的突变与野生型细胞相比表现出不同的光谱（Ishizaki）。这些发现表明，p53调节DNA复制，从而调节突变的类型和频率。建立了甲酰基尿嘧啶对DNA氧化损伤（Yonei）修复动力学的体外测定系统。在果蝇中，经辐照精子受精的雌性基因组中的小卫星位点突变证实了DNA损伤诱导的突变，提示DNA损伤诱导的遗传不稳定性（Niwa）。我们不能克隆一个基因（ATM）负责共济失调毛细血管扩张，辐射敏感的人类疾病。然而，在日本患者中发现了新的ATM基因突变（Ejima）。

项目成果

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