CHEMICAL CARCINOGENESIS AND CELL PROLIFERATION

化学致癌和细胞增殖

• 批准号: 3165346
• 负责人: David G. Kaufman
• 金额: $ 13.91万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-02-01 至 1987-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3165346
• 关键词: DNA methylation; alkylating agents; antibody; autoradiography; carcinogens; cell population study; chemical carcinogenesis; density gradient ultracentrifugation; electron microscopy; gel electrophoresis; molecular site; mycotoxins; nitrosamines; nucleic acid sequence; radiotracer; synchronous cell division; tissue /cell culture

The objective of this research project is to investigate the molecular mechanisms underlying the relationship between cell proliferation and chemical carcinogenesis. It proposes to study how and where DNA replication is involved in the multi-stage transition of a cell to the malignant phenotype. One of the technical approaches of this project is the isolation of eukaryotic replication complexes which can be used to study DNA replication in vitro as well as to probe the mechanisms of action of chemical carcinogens. Efforts will be directed towards further purification and characterization of the constituents of the eukaryotic replication complex, analysis of the effect of carcinogens on the activity of replication complexes in vitro and isolation of DNA sequences that replicate early in the S phase. DNA at the replication complex is preferentially methylated by chemical carcinogens and this is due to a higher susceptibility of replication forks to chemical alkylation. The mechanisms responsible for this phenomemon will be investigated. Furthermore, the generality of such observations in relation to other carcinogens will be verified. Another technical approach in this project is the in vitro localization of DNA adducts with the help of specific antibodies and the electron microscope. This will allow the study of the relationship between replication forks and carcinogen damage and provide insight about the mechanisms of lesion bypass by the replication machinery. The studies in this project are directed towards a better understanding of the biochemistry of cell transformation and the biological mechanisms responsible for the initiation of cancer. The long-term objective of the above studies is to elucidate the higher frequency of transformation observed when cells are treated with carcinogens in S phase.

这个研究项目的目的是研究分子 细胞增殖与细胞增殖之间关系的机制 化学致癌。它建议研究DNA如何以及在哪里 复制参与了细胞到细胞的多阶段转变 恶性表型。该项目的技术途径之一是 真核细胞复制复合体的分离 研究DNA的体外复制并探讨其作用机制 化学致癌物。努力的方向将是进一步 真核细胞化学成分的纯化与鉴定 复制复合体，分析致癌物对活性的影响 体外复制复合体的研究和DNA序列的分离 在S阶段的早期复制。复制复合体上的DNA是 优先被化学致癌物甲基化，这是由于 复制叉子对化学烷基化的敏感性更高。这个 负责这一现象的机制将被调查。 此外，这种观察结果相对于其他观察结果的一般性 致癌物质将得到验证。此项目中的另一种技术方法 DNA加合物的体外定位是借助特异的 抗体和电子显微镜。这将使我们能够研究 复制叉与致癌物损伤和提供 通过复制洞察病变旁路的机制 机械设备。这个项目的研究是为了更好地 对细胞转化的生物化学和生物化学的认识 导致癌症发生的机制。长期的 上述研究的目的是阐明较高频率的 细胞经致癌物处理后，出现S期细胞转化现象。