MOLECULAR MECHANISMS OF MULTI-STAGE CARCINOGENESIS

多阶段致癌的分子机制

• 批准号: 3071917
• 负责人: CURTIS L. ASHENDEL
• 金额: $ 6.86万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-18 至 1994-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3071917
• 关键词: biological signal transduction; calcium flux; carcinogenesis; cellular oncology; chemical carcinogenesis; embryo /fetus tissue /cell culture; genetic transcription; immunoelectron microscopy; laboratory mouse; molecular oncology; mutant; neoplasm /cancer genetics; oncogenes; phorbols; protein kinase C; skin neoplasms; tumor promoters

The experimental approach to understanding the molecular basis of multistage carcinogenesis focuses on unraveling the puzzle of how cellular regulation occurs in the presence of multiple influences. As such the results will uniquely complement studies of components of signal transduction paths done largely in isolation of the many other facets of cellular regulation. The primary points of this investigation are the signal transducing enzyme protein kinase C (PKC), also known to be the receptor for tumor promoting phorbol esters, and proteins encoded by oncogenes that have demonstrated roles in intracellular signal transduction, such as src, ras, raf, mye, and jun. A molecular approach will be used to modify the signal transducing apparatus of mouse embryo C3H 10T1/2 cells and to analyze the effects of these cellular phenotype. Since the major subject of this investigation is signal transduction mediated by PKC a large segment of the effort is to be put into understanding the biochemistry of PKC function and regulation as well as to learn more about the molecular and cellular biology of PKC. The interactions of multiple elements of cellular signal transduction will be investigated at the same time. One of the goals is to combine these separate data to develop a better idea of the molecular apparatus in cells that integrates the transduced extracellular signals to yield a single outcome. It is probable that resistance of some cells and strains of mice to tumor promoting agents such as phorbol esters involves alterations in the integrative apparatus making study of such resistant cells useful. Lastly, somatic cell genetics system will be developed for investigating the transcytoplasmic phase of cellular signal transduction that begins with PKC and ends with activation of gene transcription. The latter study, together with the information that will be obtained about the interactions of signal transduction, will make it possible to obtain a more complete understanding of the process of cellular signal transduction and how it is involved in multistage carcinogenesis.

理解生物化学分子基础的实验方法 多阶段致癌作用的重点是解开细胞如何 调节发生在多种影响存在的情况下。因而 结果将独特地补充信号成分的研究 转导途径主要是在隔离的许多其他方面， 细胞调节本次调查的主要内容是 信号转导酶蛋白激酶C（PKC），也被称为 促进肿瘤的佛波醇酯的受体和由其编码的蛋白质 已证实在细胞内信号传导中起作用的癌基因 转导，如src，ras，raf，mye和jun。 将用于改造小鼠胚胎C3 H的信号转导装置 10 T1/2细胞，并分析这些细胞表型的影响。以来 本研究的主要主题是由 PKC的很大一部分工作是为了了解 PKC功能和调节的生物化学以及了解更多信息 PKC的分子和细胞生物学。多重的相互作用 细胞信号转导的元素将在同一时间进行研究， 时间目标之一是将这些独立的数据联合收割机组合起来， 更好的想法是细胞中的分子装置， 转导细胞外信号以产生单一结果。很可能 一些细胞和小鼠品系对肿瘤促进剂的抗性 例如佛波醇酯涉及整合器官的改变 使得对这种抗性细胞的研究变得有用。最后，体细胞遗传学 系统将被开发用于研究转胞质相的 以PKC开始并以激活结束的细胞信号转导 基因转录。后一项研究报告，以及 将获得关于信号转导的相互作用，将使 可以更全面地了解这个过程， 细胞信号传导及其如何参与多阶段 致癌作用