Regulatory mechanisms for mutagenesis and carcinogenesis

突变和致癌的调控机制

• 批准号: 11694100
• 负责人: SEKIGUCHI Mutsuo
• 金额: $ 2.56万
• 依托单位: Fukuoka Dental College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11694100/
• 关键词: active oxygen; cancer; mutation; gene targeting; gene cloning; oxidized RNA; E.coli; mouse; 活性酵素; 細胞株

Oxygen radicals, which can be produced through normal cellular metabolism, play important roles in mutagenesis and carcinogenesis. Among various classes of oxidative DNA damage, 8-oxoguanine (8-oxo-7,8-dihydroguanine) is most important because of its abundance and mutagenicity. The MTH1 gene encodes an enzyme that hydrolyzes 8-oxo-dGTP to monophosphate in the nucleotide pool, thereby preventing occurrence of transversion mutations. By means of gene targeting, we have established MTH1 gene-knockout cell lines and mice. When examined 18 monthe after birth, a greater number of tumors were formed in the lungs, livers and stomachs of MTH1-deficient mice. The MTH1-defient mice will provide a useful model for investigating the role of oxygen radicals in spontaneous carcinogenesis. We also found that the persistence of 8-oxoguanine in messenger RNA causes translational errors. To prevent this outcome, at least two gene products act in Escherichia coli cells. It is of interest to know if similar mechanisms function in mammalian cells.

氧自由基可以通过正常的细胞代谢产生，在突变和癌变中发挥重要作用。在各类 DNA 氧化损伤中，8-氧代鸟嘌呤 (8-oxo-7,8-二氢鸟嘌呤) 由于其丰富性和致突变性而最为重要。 MTH1 基因编码一种酶，可将核苷酸库中的 8-oxo-dGTP 水解为单磷酸盐，从而防止颠换突变的发生。通过基因打靶，我们建立了MTH1基因敲除细胞系和小鼠。出生后 18 个月进行检查时发现，MTH1 缺陷小鼠的肺、肝和胃中形成了更多的肿瘤。 MTH1 缺陷小鼠将为研究氧自由基在自发癌发生中的作用提供有用的模型。我们还发现 8-氧代鸟嘌呤在信使 RNA 中的持续存在会导致翻译错误。为了防止这种结果，至少有两种基因产物在大肠杆菌细胞中起作用。了解类似的机制是否在哺乳动物细胞中发挥作用是很有趣的。

项目成果

H.Kawate: "A defect in a single allele of the Mlh1 gene causes dissociation of killing and tumorigenic action of an alkylating carcunogen in methyltransferase-deficient mice."Carcinogenesis. 21. 301-305 (2000)

H.Kawate：“Mlh1 基因的单个等位基因的缺陷导致甲基转移酶缺陷小鼠中烷基化致癌物的杀伤和致瘤作用的分离。”致癌作用。

H.Hayakawa, M.Sekiguchi et al.: "Metabolic fate of oxidized guanine ribonucleotides in mammalian cells"Biochemistry. 38. 3610-3614 (1999)

H.Hayakawa、M.Sekiguchi 等人：“哺乳动物细胞中氧化鸟嘌呤核糖核苷酸的代谢命运”生物化学。

H.Shimokawa: "Functional significance of conserved residues in the phosphohydrolase module of Escherichia coli MutT protein."Nucl.Acids.Res.. 28. 3240-3249 (2000)

H.Shimokawa：“大肠杆菌 MutT 蛋白磷酸水解酶模块中保守残基的功能意义。”Nucl.Acids.Res.. 28. 3240-3249 (2000)

H.Oda: "Multi-forms of human MTH1 polypeptides produced by alternative translation initiation and single nucleotide polymorphism"Nucl.Acids Res.. 27. 4335-4343 (1999)

H.Oda：“通过选择性翻译起始和单核苷酸多态性产生的人类 MTH1 多肽的多种形式”Nucl.Acids Res.. 27. 4335-4343 (1999)

H.Kawate: "A defect in a single allele of the Mlh1 gene causes dissociation of killing and tumorigenic action of an alkylating carcinogen in methyltransferase-deficient mice"Carcinogenesis. 21-2. 301-205 (2000)

H.Kawate：“Mlh1 基因的单个等位基因的缺陷导致甲基转移酶缺陷小鼠中烷化致癌物的杀伤和致瘤作用的分离”致癌作用。