TUMOR SUPPRESSOR GENETICS OF MOUSE CHRMOSOME 11

小鼠 11 号染色体的肿瘤抑制基因

• 批准号: 6453010
• 负责人: ALLAN BRADLEY
• 金额: $ 14.57万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-11 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6453010
• 关键词: cell line; cell transformation; chromosome deletion; chromosomes; fibroblasts; gene mutation; genetic mapping; genetic screening; genome; genotype; laboratory mouse; loss of heterozygosity; molecular cloning; neoplasm /cancer genetics; neoplastic process; tumor suppressor genes

Cancer is a genetic disease. Identifying genes which are playing a causal role in cancer and elucidating their function will enhance our understanding of the neoplastic process. This information will improve our ability to modulate the disease by providing therapeutic opportunities based on knowledge of the genetic changes in tumor cell. Ultimately this will improve both prognostic outcomes and treatment of regimens. A novel technology, based on the Cre-loxP recombinase system which enables large regions of the mouse genome to be deleted has been developed. A series of mice with deletions (each several megabases) which in sum cover the entire distal half of mouse chromosome 11, will be generated by the Deletion Core. This region of the mouse genome, containing an estimated 2,000 genes, is syntenic with human chromosome 17. Although three tumor suppressor genes have been localized to this chromosome (NF1, p53 and BRCA1), loss of heterozygosity studies strongly suggest that there are several other tumor suppressor genes on this chromosome which are mutated at a high frequency in sporadic tumors. Tumors suppressor genes are difficult to identify because two mutational events are required to disrupt the function of the gene in a diploid cell. Fibroblasts isolated from mice with these deficiencies have a single copy of each gene in the region of the deficiency. A genetic screen will be employed to identify these tumor suppressor genes, based on the hypothesis that cells which loose the remaining copy of the tumor suppressor gene can be identified in a large pool of cells since they transform in vitro. Transformation foci will be induced by pro-viral tagging in primary embryonic fibroblasts isolated from mice with these deficiencies. The pro-viral tag will facilitate the direct molecular identification of the tumor suppressor gene which causes transformation in these cell lines.

癌症是一种遗传疾病。识别正在发挥因果的基因 在癌症中的作用并阐明其功能将增强我们的 了解肿瘤过程。这些信息将改善我们的 通过提供治疗机会来调节疾病的能力 基于对肿瘤细胞遗传变化的了解。最终 将改善预后结局和治疗方案。 一种基于CRE-LoxP重组酶系统的新技术 已经开发了要删除的小鼠基因组的大区域。一个 一系列具有删除的小鼠（每几个巨蛋） 鼠标11的整个远端半远端将由 删除核心。小鼠基因组的这个区域，包含估计的 2,000个基因，与人类染色体17。尽管三个肿瘤 抑制基因已定位在该染色体上（NF1，p53和 BRCA1），杂合性研究的丧失强烈表明存在 该染色体上的其他几个肿瘤抑制基因突变 在零星肿瘤的高频下。肿瘤抑制基因是 很难识别，因为需要两个突变事件才能 破坏基因在二倍体细胞中的功能。成纤维细胞分离 从这些缺陷的小鼠中，每个基因都有一个副本 缺陷的区域。将使用遗传屏幕来识别 这些肿瘤抑制基因，基于以下假设 可以在肿瘤抑制基因的剩余副本中识别 大量细胞自从体外转化。转换焦点 将通过原代胚胎成纤维细胞中的促病毒标记诱导 与这些缺陷的小鼠分离。亲病毒标签将 促进肿瘤抑制剂的直接分子鉴定 在这些细胞系中引起转化的基因。