ONCOGENES IN HUMAN CANCER INDUCTION

家族性癌症综合征提供了一个独特的机会，检查 癌症的遗传易感性机制，以及更多 与恶性肿瘤的发展有关的一般过程。 我们 一个实验室正在研究一个患有Li-Fraumeni综合征的家庭， 以多种肿瘤的发展为特征的多原发性肿瘤 单个个体内的肿瘤。 特别强调了 癌基因在这些肿瘤发展中的作用。 致癌基因是 参与恶性肿瘤发展的基因。 癌基因来源于 正常的细胞基因，称为原癌基因，当后者被改变时 通过点突变、缺失、重排或扩增。 证据 癌基因参与非遗传性人类恶性肿瘤，以及 在遗传的癌症易感性中，继续积累。 正常 已经阐明了几种原癌基因的功能;它们是 参与正常细胞生长、分裂、代谢，和/或 分化 原癌基因产物作为生长因子或 酪氨酸特异性或丝氨酸/苏氨酸特异性生长因子受体 蛋白激酶，表现出GT3活性的G蛋白，或核 参与DNA合成的蛋白质。 在本申请中，我们建议研究 易感性中的原癌基因、癌基因和抑制基因 一个有癌症倾向的家庭的成员。 我们的目标是识别和 描述这个家庭中共有的主要遗传缺陷;然而，在 在这个过程中，我们可能发现了某些致癌基因， 二级和三级遗传缺陷。 我们将（1）继续分析 两个转化基因来源于两个正常皮肤成纤维细胞， 受影响的家庭成员，先证者和他的兄弟，（2）试图 鉴定其他人正常皮肤成纤维细胞中的转化基因 家庭成员，以及（3）评估抑制者的可能参与 Rb基因在家族遗传缺陷中的作用 癌基因将在分子水平上 克隆并与正常的同类进行比较。 基因缺陷会 通过DNA序列分析和定点诱变来定义。 特异性抗体将产生合成肽， 癌基因产物的生物合成和亚细胞定位将是 考察 将尝试表征癌基因产物， 探索它的功能。 正常皮肤Rb基因的RNA表达谱 通过北方分析检测家族成员的成纤维细胞。 通过Southern杂交检测Rb DNA RFLP。

Familial cancer syndromes provide a unique opportunity to examine the mechanism of inherited susceptibility to cancer, as well as the more general processes involved in the development of malignancy. Our laboratory is studying a family with Li-Fraumeni syndrome, which is characterized by the development of diverse neoplasms as multiple primary tumors within single individuals. Particular emphasis has been placed on the role of oncogenes in the development of these tumors. Oncogenes are genes involved in the development of malignancy. Oncogenes derive from normal cellular genes, termed proto-oncogenes, when the latter are altered by point mutation, deletion, rearrangement, or amplification. Evidence for the involvement of oncogenes in non-inherited human malignancy, as well as in inherited predisposition to cancer, continues to accumulate. The normal functions of several proto-oncogenes have been elucidated; they are involved in normal cell growth, division, metabolism, and/or differentiation. Proto-oncogene products functions as growth factors or growth factor receptors, tyrosine-specific or serine/threonine-specific protein kinases, G-proteins exhibiting GTPase activities, or nuclear proteins participating in DNA synthesis. In this application, we propose to study the involvement of proto-oncogene(s), oncogene(s), and suppressor genes in the predisposition of the members of a cancer-prone family. Our goal is to identify and characterize the primary genetic defect shared in this family; however, in this process, we may have uncovered certain oncogenes which may represent secondary and tertiary genetic defects. We will (1) continue to analyse two transforming genes derived from the normal skin fibroblasts of two affected family members, the proband, and his brother, (2) attempt to identify the transforming gene(s) in normal skin fibroblasts of other family members, and (3) assess the possible involvement of a suppressor gene, Rb, in the family genetic defect. The oncogene will be molecularly cloned and compared to their normal counterparts. The genetic defect will be defined by DNA sequence analysis and site-directed mutagenesis. Specific antibodies will be raised to synthetic peptides and the biosynthesis and subcellular localization of the oncogene product will be examined. Attempts will be made to characterize the oncogene product and to explore its function. RNA profile of the Rb gene in normal skin fibroblasts of the family members will be examined by Northern analysis. Rb DNA RFLPs will be detected by Southern hybridization.