RETROVIRUSES AND CANCER GENES

基因损伤似乎是肿瘤发生的核心。损害 有两种类型：显性，具有被称为原癌基因的靶点； 隐性，以肿瘤抑制基因为靶点。这项工作 在这笔赠款的支持下，他们寻求受损基因的身份，他们的 在肿瘤发生中的贡献，它们所通过的生化机制 行为，以及它们在正常细胞和有机体中的作用。在这些方面取得成功 目标可能会提供新的、更合理的战略 癌症的预防、诊断和治疗；它还应该揭示 细胞正常增殖和分化所依据的原则 都是受控制的。寻找更多的癌症基因将会进行 在细胞培养和转基因小鼠中，特别是使用新的策略 为了检测肿瘤抑制基因，特别要注意 肿瘤进展的独特步骤，重点是神经学 肿瘤和白血病。到目前为止发现的癌症基因的作用机制之一是 三种方式：蛋白质磷酸化、GTP酶信号转导和控制 抄写。每一项都将被研究，重点是在哪里 它们的行为以及它们在正常细胞中是如何被控制的，它们是如何 整合到细胞的信号通路中，它们是如何在 细胞增殖或分化，它们如何在 生物发育，以及它们如何对肿瘤做出贡献 转型。最受关注的将是蛋白质-酪氨酸 原癌基因SRC和HCK编码的激酶及其转录 由MYB和MYC编码的因子。但HRAS的产物，肿瘤 人乳头瘤病毒抑癌基因Rb、P53与E7癌基因 也将进行研究。这项工作将依靠不同的实验方法， 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的诱变、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，通过将其蛋白质的活性 小行星激素控制下的产品，遗传分析 果蝇、黑腹果蝇及其同源基因在小鼠体内的调控 重组-所有设计都是为了识别基因的正常功能 一种发育中的有机体，并绘制出这些生物 执行函数。

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.