RETROVIRUSES AND CANCER GENES

遗传损伤似乎是肿瘤发生的核心。 的损害 有两种类型：显性的，靶基因是原癌基因; 隐性的，其靶基因被称为肿瘤抑制基因。 工作 在这项资助的支持下，他们寻求受损基因的身份， 对肿瘤发生的贡献，它们的生化机制， 行为，以及它们在正常细胞和生物体中的作用。 成功与这些 这些目标可能会提供新的和更合理的战略， 癌症的预防、诊断和治疗;它还应该揭示 细胞的正常增殖和分化 都是被控制的 寻找更多的癌症基因将在 在细胞培养和转基因小鼠中，特别是使用新的策略， 用于检测肿瘤抑制基因，特别注意 肿瘤进展的独特步骤，并重点关注神经系统 肿瘤和白血病。 迄今为止发现的癌症基因通过以下方式之一起作用： 三种方法：蛋白磷酸化，GT3信号传导和控制 转录。 每一个都将被研究，重点是在哪里 它们在正常细胞中的作用以及它们是如何被控制的 整合到细胞的信号通路中， 细胞增殖或分化，它们如何在 生物体发育，以及它们如何有助于肿瘤 转型 大多数注意力将给予蛋白质酪氨酸 由原癌基因SRC和HCK编码的激酶，以及 由MYB和MYC编码的因子。 但是HRAS的产物肿瘤 抑制基因RB和P53，以及人乳头瘤病毒的E7癌基因 也将被研究。 这项工作将依赖于不同的实验方法， 包括：分子克隆、DNA介导的基因转移、逆转录病毒 载体，免疫化学，体外生化分析，定点 重组DNA诱变，核苷酸测序，蛋白质 纯化，专门的细胞培养，分子筛选程序， 酵母，基因通过将其蛋白质的活性 产品根据小行星激素的控制，基因分析 黑腹果蝇，以及小鼠基因操作的同源 重组-所有这些都是为了确定基因的正常功能， 一个发展中的有机体，并绘制这些信号通路， 功能被执行。

Genetic damage appears to lie at the heart of tumorigenesis. The damage is of two sorts: dominant, with targets known as proto-oncogenes; and recessive, with targets known as tumor suppressor genes. The work supported by this grant seeks the identity of the damaged genes, their contributions to tumorigenesis, the biochemical mechanisms by which they act, and their roles in the normal cell and organism. Success with these objectives might provide new and more rational strategies for the prevention, diagnosis and therapy of cancer; and it should also reveal principles by which the normal proliferation and differentiation of cells are controlled. The search for additional cancer genes will be conducted in cell culture and transgenic mice, using in particular new strategies for the detection of tumor suppressor genes, with special attention to the distinctive steps in tumor progression, and with a focus on neurological tumors and leukemia. The cancer genes identified to date act by one of three means: protein phosphorylation, signalling by GTPase's, and control of transcription. Each of these will be studied, with emphasis on where they act and how they are controlled in normal cells, how they are integrated into the signalling pathways of the cell, how they figure in cellular proliferation or differentiation, how they serve during organismal development, and how they can contribute to neoplastic transformation. Most attention will be given to the protein-tyrosine kinases encoded by the proto-oncogenes SRC and HCK, and the transcription factors encoded by MYB and MYC. But the products of HRAS, the tumor suppressor genes RB and P53, and the E7 oncogene of Human Papilloma Virus will also be studied. The work will rely on diverse experimental methods, including: molecular cloning, DNA-mediated gene-transfer, retroviral vectors, immunochemistry, biochemical analysis in vitro, site-directed mutagenesis of recombinant DNA, nucleotide sequencing, protein purification, specialized cell culture, molecular screening procedures in yeast, genes made conditional by placing the activity of their protein products under the control of asteroid hormone, genetic analysis in Drosophila melanogaster, and manipulation of genes in mice by homologous recombination - all designed to identify the normal functions of genes in a developing organism and to map the signalling pathways by which these functions are executed.