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(申请人提供)：正常的，受控的细胞生长所必需的基因被称为肿瘤抑制基因，这些基因的失活会导致肿瘤的形成。大多数已知的肿瘤抑制基因是通过遗传易患癌症的生物体的基因图谱来定位的。然而，家族性癌症的易感性只占人类癌症的大约10%，而且对非家族性癌症中涉及的肿瘤抑制基因的识别一直比较缓慢。这项提议的目标是定义一组肿瘤抑制基因，当这些基因被删除时，有助于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，尽可能完全。这将通过逆转录病毒插入突变和化学突变相结合的方法来尝试，以灭活给定小鼠细胞中的两个等位基因。化学诱变雄性小鼠的后代会受到逆转录病毒的插入突变，这种逆转录病毒会诱导淋巴细胞源的肿瘤。病毒基因组破坏潜在的抑制基因，导致它们失活，同时创建一个标记来识别插入位点。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，将进一步确定它们中的一个子集的特征，并确定它们与其他癌基因(共突变)合作的性质。