ERB-B ACTIVATION: FROM EGF-RECEPTOR TO LEUKEMIA ONCOGENE

ERB-B 激活：从 EGF 受体到白血病癌基因

• 批准号: 3079704
• 负责人: ROBERT J PELLEY
• 金额: $ 6.44万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3079704
• 关键词: DNA; Retroviridae disease; avian leukosis virus; chickens; complementary DNA; cytogenetics; enzyme mechanism; epidermal growth factor; growth factor receptors; hematopoietic growth factor; leukemia; molecular cloning; mutagens; neoplasm /cancer genetics; oncogenes; protein kinase; protooncogene

A number of the cellular genes which upon mutation are capable of inducing cellular transformation (proto-oncogenes) have recently been identified as components involved in the normal cellular growth pathways. Recently, the oncogene responsible for avian erythroblastosis, erb B, has been shown to represent a truncated version of the epidermal growth factor receptor (EGF-R). This oncogene offers a unique opportunity to study the relationship between growth factor receptors and leukemia, and the process of oncogenic conversion of a normal cellular gene. It has been demonstrated that the c-erb B gene is mutated consistently in leukemia induced by a non-acute retrovirus. The mutation by viral DNA insertion is very specific and reproducible results in the production of a truncated c-erb B/EGF-R gene product that contains only the protein kinase domain. Presumably, this process constitutively activates the EGF-R receptor function leading to the uncontrolled growth of the target cell. In an effort to better understand the molecular basis for this process, the c-DNA clones corresponding to the activated c-erb B/EGF-R gene have been isolated from leukemic cells. Using these clones, we have constructed an avian leukemia model by inserting an activated c- erb B gene into a competent retroviral vector. The Rous/erb B virus (REB) is leukemogenic in chickens and appears to have tissue specificity. In this study we plan to: 1) Further characterize the REB virus and define the oncogenic determinants of its c-erb B gene product using site specific in vitro mutagenesis techniques; 2) Characterize the biochemical properties of the c-erb B gene product in its activated form and in its proto-oncogene form; 3) Determine the effect of activated c-erb B expression on the abrogation of growth factor dependence of hematopoietic cells.

一些细胞基因突变后能够 诱导细胞转化（原癌基因）最近 被鉴定为参与正常细胞 增长途径。 最近，负责鸟类的癌基因 成红细胞增多症，erB B，已被证明是一个截短的 表皮生长因子受体（EGF-R）。 这 癌基因提供了一个独特的机会来研究 生长因子受体和白血病之间的联系， 正常细胞基因的致癌转化。 已经 证明了c-er B B基因的突变一致， 由非急性逆转录病毒引起的白血病。 病毒引起的变异 DNA插入是非常具体的和可重复的结果， 产生截短的c-er B B/EGF-R基因产物，所述产物含有 只有蛋白激酶结构域。 据推测，这个过程 组成型激活EGF-R受体功能，导致 靶细胞不受控制的生长。 为了更好 了解这个过程的分子基础，c-DNA克隆 与激活的c-er B B/EGF-R基因相对应的基因已经被 分离自白血病细胞。 利用这些克隆体， 通过插入激活的c- erB B基因导入感受态逆转录病毒载体。 Rous/er B B 病毒（REB）在鸡中是致白血病的， 的特异性 在这项研究中，我们计划：1）进一步表征 REB病毒并确定其c-erb的致癌决定簇 使用位点特异性体外诱变技术的B基因产物; 2)表征c-er B B基因的生化特性 以其活化形式和以其原癌基因形式的产物; 3） 确定活化的c-er B B表达对细胞凋亡的影响。 消除造血细胞的生长因子依赖性。