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: 3079707
• 负责人: ROBERT J PELLEY
• 金额: $ 8.83万
• 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/3079707
• 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.

一些细胞基因在发生突变后能够 诱导细胞转化(原癌基因)最近已经 已被鉴定为参与正常细胞的成分 成长路径。近年来，与禽类相关的癌基因 红细胞增多症，erb B，已被证明代表一种截短的 表皮生长因子受体(EGF-R)的版本。这 癌基因为研究两者之间的关系提供了一个独特的机会 生长因子受体与白血病之间的关系，以及 正常细胞基因的致癌转化。一直以来 证明c-erb B基因在 由非急性逆转录病毒引起的白血病。由病毒引起的突变 DNA插入是非常特异和可重复性的结果 截短型c-erb B/EGF-R基因产物的制备 只有蛋白激酶结构域。据推测，这一过程 结构性地激活EGF-R受体功能，导致 目标细胞不受控制的生长。为了更好地 了解这一过程的分子基础，即c-DNA克隆 与激活的c-erb B/EGF-R基因相对应 从白血病细胞中分离出来。使用这些克隆人，我们拥有 通过插入活化的c-干扰素构建禽类白血病模型 将Erb B基因插入到一个有能力的逆转录病毒载体中。劳资关系组/雇员代表B 病毒(REB)在鸡中是白血病原性的，似乎有组织 专一性。在这项研究中，我们计划：1)进一步表征 REB病毒及其c-erb癌基因决定簇的确定 B基因产物采用体外定点突变技术； 2)鉴定c-erb B基因的生化特性 具有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 减少造血细胞对生长因子的依赖。