RETROVIRUSES AND CANCER GENES
逆转录病毒和癌症基因
基本信息
- 批准号:2091417
- 负责人:
- 金额:$ 139.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1987
- 资助国家:美国
- 起止时间:1987-07-01 至 2001-04-30
- 项目状态:已结题
- 来源:
- 关键词:Drosophilidae Retroviridae biological signal transduction cell differentiation cell growth regulation genetic manipulation genetic transcription genetically modified animals guanosinetriphosphatases immunocytochemistry laboratory mouse molecular cloning neoplasm /cancer genetics neoplastic transformation phosphorylation protein tyrosine kinase protooncogene tissue /cell culture transcription factor tumor suppressor genes viral carcinogenesis virus related neoplasm /cancer yeasts
项目摘要
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.
遗传损伤似乎是肿瘤发生的核心。 损害
有两种类型:显性的,其目标称为原癌基因;和
隐性,其目标称为肿瘤抑制基因。 工作
在这笔赠款的支持下,我们寻求受损基因的身份、它们的
对肿瘤发生的贡献及其生化机制
行为,以及它们在正常细胞和有机体中的作用。 有了这些就成功了
目标可能会提供新的、更合理的策略
癌症的预防、诊断和治疗;它也应该揭示
细胞正常增殖和分化的原理
被控制。 将寻找其他癌症基因
在细胞培养和转基因小鼠中,特别使用新策略
用于检测抑癌基因,特别关注
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之一发挥作用
三种方式:蛋白质磷酸化、GTPase 信号传导和控制
的转录。 每一个都将被研究,重点是在哪里
它们的行为以及它们在正常细胞中如何被控制,它们是如何的
整合到细胞的信号传导途径中,它们如何参与
细胞增殖或分化,它们如何在细胞增殖或分化过程中发挥作用
有机体发育,以及它们如何促进肿瘤
转变。 最受关注的是蛋白质酪氨酸
原癌基因 SRC 和 HCK 编码的激酶及其转录
MYB 和 MYC 编码的因子。 但是HRAS的产物,肿瘤
人乳头瘤病毒的抑制基因 RB 和 P53 以及 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,通过将其蛋白质的活性置于条件下的基因
小行星激素控制下的产品,基因分析
果蝇,以及通过同源基因操纵小鼠基因
重组 - 全部旨在识别基因的正常功能
发育中的有机体并绘制这些信号通路的图谱
函数被执行。
项目成果
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