MUTATION AND DEREPRESSION OF GENES IN CARCINOGENESIS

基因和染色体突变的潜在作用，以及 正常基因的转座和改变表达，在复杂的 最近一些戏剧性的证据支持了致癌过程 实验 在实验致癌作用，以及流行病学 癌症研究中，启动/促进模型似乎能够，在许多情况下， 例，以解释致癌作用的多阶段性质。 这个项目 建议继续进行诱变机制的基础研究， 哺乳动物细胞以及突变如何与 致癌起始 此外，还对间隙的机制进行了研究， 哺乳动物细胞中连接介导的细胞间通讯将是 持续期间内的 为了实现这两个主要目标，影响DNA的遗传突变体 修复和DNA复制酶将被分离和表征， 遗传的 使用高温抑制DNA聚合酶β， 阿非迪霉素抑制DNA聚合酶α和3-氨基苯甲酰胺抑制 ADP-（核糖基）-聚合酶，这些酶在DNA复制中的作用， 修复，细胞毒性，核内复制和诱变将在 中国仓鼠和体外人细胞。 影响代谢的突变体 合作将用于研究缝隙连接的潜在作用， 调节基因表达。 此外，在体外和体内研究， 将人类肿瘤细胞的代谢能力与 将进行与它们在裸鼠中生长的能力的协同作用。 最后，重组DNA技术将被用来检验假设， 可以转化NIH-3 T3细胞的sarc基因通过干扰 间隙连接介导的细胞间通讯。

The potential roles of gene and chromosomal mutations, as well as transposition and altered expression of normal genes, during the complex carcinogenic process has been supported by some recent dramatic experiments. In experimental carcinogenesis, as well as epidemiological cancer studies, the initiation/promotion model appears to be able, in many cases, to explain the multistage nature of carcinogenesis. This project proposes to continue basic studies on the mechanisms of mutagenesis in mammalian cells and how mutations might relate to the mechanism of carcinogenic initiation. In addition, studies on the mechanisms of gap junction-mediated intercellular communication in mammalian cells will be continued. To achieve these two major goals, genetic mutants affecting DNA repair and DNA replication enzymes will be isolated and characterized, genetically. Using hyperthermia to inhibit DNA polymerase Beta, aphidicolin to inhibit DNA polymerase Alpha and 3-aminobenzamide to inhibit ADP-(ribosyl)-polymerase, the roles of these enzymes in DNA replication, repair, cytotoxicity, endoreduplication and mutagenesis will be studied in Chinese hamster and human cells in vitro. Mutants affecting metabolic cooperation will be used to study the potential role of gap junctions in modulating gene expression. In addition, in vitro and in vivo studies on correlating the ability of cells from human tumors to metabolically cooperative with their ability to grow in nude mice will be performed. Lastly, recombinant DNA techniques will be used to test the hypothesis that the sarc gene, which can transform NIH-3T3 cells, does so by interfering with gap junction-mediated intercellular communication.