Tumor Suppressors in Lymphocytes

淋巴细胞中的肿瘤抑制因子

• 批准号: 7027215
• 负责人: MATTHIAS R WABL
• 金额: $ 27.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-05 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027215
• 关键词: chemical carcinogenesis; functional /structural genomics; fusion gene; gene deletion mutation; gene interaction; laboratory mouse; lymphocyte; lymphoma; murine leukemia virus; neoplasm /cancer genetics; nitrosourea; polymerase chain reaction; protooncogene; site directed mutagenesis; tumor suppressor genes; viral carcinogenesis

DESCRIPTION (provided by applicant): The genes that are necessary for normal, controlled cell growth are called tumor suppressor genes, and inactivation of these genes can lead to tumor formation. The majority of known tumor suppressors were located by the genetic mapping of organisms with an inherited predisposition for cancer. However, familial predisposition to cancer is responsible for only approximately 10% of human cancers and identification of tumor suppressors involved in non-familial cancers has been slower. The goal of this proposal is to define the set of tumor suppressors that when deleted contribute to the formation of lymphocyte tumors in mice; and their interactions with protooncogenes, as completely as possible. This will be attempted by retroviral insertional mutagenesis, combined with chemical mutagenesis, to inactivate both alleles in cells of a given mouse. The offspring of chemically mutagenized male mice are subjected to insertional mutagenesis by retrovirus that induces tumors of lymphocyte origin. The viral genome disrupts potential suppressor genes, leading to their inactivation, and at the same time creates a marker for identifying the insertion loci. The tagged cancer genes will be cloned and sequenced by a high throughput PCR based technique. Subsequently, a subset of them will be further characterized and the nature of their cooperation with other oncogenes (co-mutations) will be determined.

描述（由申请人提供）：正常、受控细胞生长所必需的基因称为肿瘤抑制基因，这些基因的失活可导致肿瘤形成。大多数已知的肿瘤抑制因子是通过具有遗传性癌症倾向的生物体的基因图谱定位的。然而，家族性癌症倾向仅导致约 10% 的人类癌症，并且非家族性癌症中涉及的肿瘤抑制因子的识别速度较慢。该提案的目标是定义一组肿瘤抑制因子，当它们被删除时，会导致小鼠淋巴细胞肿瘤的形成；以及它们与原癌基因的相互作用，尽可能完整。这将通过逆转录病毒插入诱变与化学诱变相结合来尝试，以使给定小鼠细胞中的两个等位基因失活。化学诱变的雄性小鼠的后代受到逆转录病毒的插入诱变，诱导淋巴细胞来源的肿瘤。病毒基因组破坏潜在的抑制基因，导致其失活，同时创建用于识别插入位点的标记。标记的癌症基因将通过基于高通量 PCR 的技术进行克隆和测序。随后，将进一步表征其中的一个子集，并确定它们与其他癌基因（共突变）合作的性质。