Studies on Molecular Mechanisms of Radiation Response

辐射响应的分子机制研究

• 批准号: 05404078
• 负责人: SASAKI Masao
• 金额: $ 19.01万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (A)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-05404078/
• 关键词: Radiation response; Low dose radiation; Adaptive response; Signal transduction; Early response gene; Gene expression; MAP kinase; Inverse dose-rate effect; 細胞内情報伝達; Cキナーゼ; JNKキナーゼ; 即発応答遺伝子; OHラジカル; 増殖刺激; マウス培養細胞; 染色体導入

Mammalian cells are highly sensitive to small doses of radiations and exppress variable physiological functions. The present study was started in 1993 to clarify the molecular mechanisms of such radiation response and to provide a new biological basis of radiation effects. During the past 2 years of the study, it has been found that (1) the cultured mouse cells previously irradiated with small doses of X-rays become refractory to chromosome aberration formation, mutation induction and cell killing but more susceptible to malignant transformation by subsequent challenging doses, (2) the optimum doses for such response is below 0.1 Gy, (3) oxidative radicals may be responsible for such effect, and (4) the cells express early response genes such as jun and fos. In this year, studies were extended to clarify the cellular signal transduction pathways, and revealed that the delta-isoform of phospholipase C is responsible for the radiation respopnse where X-ray signals were transmitted to protein kinase C and p38 kinase. The signal transduction pathways are thus unique to X-ray exposures and distinct from that for UV exposure, where JNK kinase is responsible. With this signalling pathway cells show adaptive response and growth stimulatory response towards the enhancement of malignant transformation. Taken those response characteristics obtaianed in this study together, the consequences of low dose-rate protracted exposures to radiations were simulated by computer. The results suggest that with the decrease of dose-rate transformation will be enhanced resulting in the inverse dose-rate effect while the mutation will be suppressed to occur. This is consistent with the observations in the literatures and provides a new theory for the inverse dose-rate effect of in vitro malignant transformation.

哺乳动物细胞对小剂量辐射高度敏感，并表现出多种生理功能。本研究始于1993年，旨在阐明这种辐射反应的分子机制，并为辐射效应提供新的生物学基础。在过去2年的研究中，发现（1）先前用小剂量X射线照射的培养小鼠细胞对染色体畸变形成、突变诱导和细胞杀伤变得不敏感，但对随后的挑战剂量更容易发生恶性转化，（2）这种反应的最佳剂量低于0.1戈伊，（3）氧化自由基可能是这种作用的原因;（4）细胞表达早期反应基因如Jun和Fos。近年来，对细胞信号转导途径的研究进一步深入，发现磷脂酶C的δ-异构体是辐射反应的主要途径，X射线信号通过磷脂酶C和p38激酶传递到细胞内。因此，信号转导途径对X射线暴露是独特的，并且不同于其中JNK激酶负责的UV暴露。通过这种信号传导途径，细胞显示出对恶性转化增强的适应性反应和生长刺激反应。综合这些响应特征，用计算机模拟了低剂量率长期照射的后果。结果表明，随着剂量率的降低，转化作用增强，出现剂量率反效应，而突变的发生受到抑制。这与文献中的观察结果一致，并为体外恶性转化的剂量率效应提供了新的理论。

项目成果

Sasaki, M.S.: "Radioadaptive response : an implication for the biological consequences of low dose-rate exposure to radiations." Mutation Res.(in press). (1996)

Sasaki, M.S.：“放射适应性反应：对低剂量率辐射暴露的生物学后果的影响。”

佐々木正夫: "低線量放射線に対する細胞の適応応答" 医学のあゆみ. 166. 208 (1993)

Masao Sasaki：“细胞对低剂量辐射的适应性反应”医学史 166. 208 (1993)。

Kato,M.V.et al.: "Parental origin of germ-line and somatic mutations in the retinoblastoma gene." Human Genetics. 94. 31-38 (1994)

Kato，M.V.等人：“视网膜母细胞瘤基因种系和体细胞突变的父母起源。”

Matsubara,S.et al.: "The effects of X-ray energy and an iodine-based contrast agent on chromosome aberration." Radiation Research. 137. 231-237 (1994)

Matsubara,S.et al.：“X 射线能量和碘造影剂对染色体畸变的影响。”

Shimizu,T.et al.: "Detection of mutations of the RB1 gene in retinoblastoma patients by using exon-by-exon PCR-SSCP analysis." American Journal of Human Genetics. 54. 793-800 (1994)

Shimizu,T.et al.：“通过使用逐个外显子 PCR-SSCP 分析检测视网膜母细胞瘤患者 RB1 基因的突变。”