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: 3079703
• 负责人: ROBERT J PELLEY
• 金额: $ 6.43万
• 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/3079703
• 关键词: DNA; Retroviridae disease; avian leukosis virus; complementary DNA; cytogenetics; epidermal growth factor; hematopoietic growth factor; leukemia; molecular cloning; mutagens; neoplasm /cancer genetics; oncogenes; protein kinase

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.

许多细胞基因在突变后能够 诱导细胞转化（原癌基因）最近 已被鉴定为参与正常细胞的成分 成长途径。 最近，负责禽类的致癌基因 成红细胞增多症，erb B，已被证明代表截短的 表皮生长因子受体（EGF-R）的版本。 这 癌基因提供了研究这种关系的独特机会 生长因子受体与白血病之间的关系及其过程 正常细胞基因的致癌转化。 它一直 证明 c-erb B 基因在 由非急性逆转录病毒引起的白血病。 病毒突变 DNA 插入是非常特异且可重复的结果 生产截短的 c-erb B/EGF-R 基因产物，其中包含 仅蛋白激酶结构域。 大概这个过程 组成型激活 EGF-R 受体功能，导致 靶细胞的生长不受控制。 为了更好地 了解这一过程的分子基础，c-DNA 克隆 对应于激活的c-erb B/EGF-R基因已被 从白血病细胞中分离出来。 使用这些克隆，我们有 通过插入激活的c-构建了禽白血病模型 erb B 基因转化为感受态逆转录病毒载体。 劳斯/erb B 病毒 (REB) 在鸡中具有致白血病作用，并且似乎具有组织 特异性。 在本研究中，我们计划：1）进一步表征 REB 病毒并定义其 c-erb 的致癌决定因素 采用位点特异性体外诱变技术的B基因产物； 2) 表征c-erb B基因的生化特性 活性形式和原癌基因形式的产品； 3） 确定激活的 c-erb B 表达对 消除造血细胞对生长因子的依赖性。