REGULATION OF RAS FUNCTION

RAS功能的调节

• 批准号: 2376838
• 负责人: DANIEL L BROEK
• 金额: $ 26.17万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-07-01 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2376838
• 关键词: 3T3 cells; cell growth regulation; chimeric proteins; cytogenetics; gel electrophoresis; gene expression; genetic mapping; genetic regulation; genetically modified animals; guanine nucleotide binding protein; human genetic material tag; in situ hybridization; laboratory mouse; laboratory rabbit; neurons; nucleic acid probes; nucleic acid sequence; phenotype; polymerase chain reaction; posttranslational modifications; protein purification; protein structure function; protooncogene; radionuclides; reagent /indicator

Mutations in the ras proto-oncogenes have been implicated in the development of greater than 20% of all human cancers. The elucidation of the biochemical pathways which regulate the activity of the normal ras proteins as well as the pathways which the activated ras proteins stimulate is critical to our understanding of normal cell growth as well as of the defective regulation of biochemical pathway in ras-induced tumors. While the normal ras proteins regulate growth and cell division for most cell types, ras protein can also induce terminal differentiation of certain cell types. Ras proteins are highly expressed in the non-dividing cells of the brain. There is evidence suggesting ras is critical for the maintenance of the neuronal phenotype. However, ras proteins could have additional biological role(s) in the biology of the neuronal cell. The understanding of the regulation of ras function in the brain is key to defining more precisely the biological role of ras protein in neurons. One aim of this proposal is to examine the mechanism by which the recently-identified vertebrate ras-specific nucleotide-exchange factors regulate ras function. We will employ in vitro biochemical and molecular genetic techniques to address this aim. Another aim is to characterize the brain-specific NEF (cdc25). We will examine the oncogenic potential of cdc25 and investigate how cdc25-NEF is regulated, using biochemical techniques as well as the NIH-3T3 cell oncogenicity assay. Another aim is to identify novel NEFs which regulate ras and ras-related proteins. We will use biochemical means to purify known NEFs; we will also employ molecular genetic screens to discover novel NEFs. The identification of novel NEFs and the understanding of how they regulate the function of ras or ras-related proteins is all-important to an understanding of the complexity of ras pathway signaling. Further, because ras is implicated in a large percent of human tumors, it is a potential target for chemotherapeutic agents. it is critical to understand the function of ras in neurons (and other non- proliferating tissues) before anti-ras chemotherapeutic agents can be successfully developed.

ras 原癌基因的突变与 超过 20% 的人类癌症发生。 的阐明 调节正常 ras 活性的生化途径 蛋白质以及激活的 ras 蛋白质刺激的途径 对于我们理解正常细胞生长以及 ras 诱导的肿瘤中生化途径的调节有缺陷。 尽管 正常的 ras 蛋白调节大多数细胞的生长和细胞分裂 类型，ras蛋白还可以诱导某些细胞的终末分化 类型。 Ras 蛋白在非分裂细胞中高表达 脑。 有证据表明 ras 对于维持 神经元表型。 然而，ras 蛋白可能还有额外的 在神经元细胞生物学中的生物学作用。 的理解 大脑中 ras 功能的调节是定义更多功能的关键 正是 ras 蛋白在神经元中的生物学作用。 这样做的目的之一 提案的目的是审查最近确定的机制 脊椎动物 ras 特异性核苷酸交换因子调节 ras 功能。 我们将采用体外生化和分子遗传学技术 解决这一目标。 另一个目标是表征大脑特异性 NEF （疾病预防控制中心25）。 我们将检查 cdc25 的致癌潜力并研究 如何使用生化技术以及 NIH-3T3 细胞致癌性测定。 另一个目标是识别新的 NEF 调节 ras 和 ras 相关蛋白。 我们将使用生化手段 纯化已知的 NEF；我们还将采用分子遗传筛选 发现新颖的 NEF。 新型 NEF 的鉴定和 了解它们如何调节 ras 或 ras 相关的功能 蛋白质对于理解 ras 的复杂性至关重要 通路信号传导。 此外，因为 ras 涉及很大比例 人类肿瘤，它是化疗药物的潜在靶点。 它 对于理解 ras 在神经元（和其他非神经元）中的功能至关重要 增殖组织）之前可以使用抗ras化疗药物 开发成功。