EFFECTORS AND REGULATORS OF NORMAL AND ONCOGENIC RAS

正常和致癌 RAS 的效应器和调节器

• 批准号: 2667940
• 负责人: JOHN J. COLICELLI
• 金额: $ 20.49万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-02 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2667940
• 关键词: 3T3 cells; PC12 cells; animal genetic material tag; carcinogenesis; enzyme activity; guanine nucleotide binding protein; intermolecular interaction; mitogen activated protein kinase; neoplasm /cancer genetics; oncogenes; oncoproteins; protein tyrosine kinase; reporter genes; site directed mutagenesis

DESCRIPTION: (adapted from the investigator's abstract) Ras proteins serve as critical control elements in the response of cells to external signals. The stimulation of some plasma membrane receptors can lead to activation of Ras and a mitogenic response. Mutant, constitutively active, forms of Ras can lead to a persistent mitotic signal that is independent of receptor stimulation. Such Ras mutations are among the most common causative events in human tumors. In some specialized mammalian cell types, however, Ras activation leads to cell cycle arrest and differentiation. This suggests that cell type differences provide a context for the interpretation of Ras signals which may lead to either cell cycle progression or arrest and differentiation. One downstream pathway directly connecting Ras activation to changes in gene expression that are required for cell division has been uncovered. The key first step is activation of the protein kinase Raf1. This is initiated by a physical interaction between Raf1 and Ras. There are however, other Ras-mediated events that appear to be required for a full transformation or differentiation response, suggesting the involvement of additional Ras interaction partners. They have isolated and are continuing to study Rin1, a human protein that binds specifically to activated Ras and can compete with Raf1. There are additional parallels between Rin 1 and Raf1 behavior, including their interactions with 14-3-3 proteins. Tissue type expression of Rin1 is regulated over a wide range. In addition, some splice variant forms of Rin1 have altered properties. Their findings are consistent with Rin1 functioning as a regulated Ras effector, as a Raf1 competitor or as both. Interestingly, the rin 1 gene has been mapped to 11q13.2, a chromosomal position that is frequently amplified in squamous cell carcinomas and breast tumors. This proposal includes an analysis of Rin1 binding properties and function. The focus is on interactions that occur in mammalian cells (co-immunoprecipitations and co-immunofluorescence) and on the biological consequences of those interactions (effects on Ras-mediated transformation and differentiation). They will take advantage of both artificial and naturally occurring variants of Rin1 that have different binding properties. These studies, directed at the role of Rin1 function in Ras-mediated signal transduction, should facilitate their understanding of normal cellular processes including differentiation and mitosis as well as cancer pathologies.

描述：（改编自研究者的摘要）Ras蛋白 作为细胞对外部信号反应的关键控制元件。 一些质膜受体的刺激可导致细胞膜的激活。 Ras和促有丝分裂反应。 Ras的组成型活性突变形式 可以导致不依赖于受体的持续的有丝分裂信号 刺激. 这种Ras突变是最常见的致病事件之一， in human人tumors肿瘤. 然而，在某些特殊的哺乳动物细胞类型中，Ras 活化导致细胞周期停滞和分化。 这表明 细胞类型的差异为Ras的解释提供了背景， 可能导致细胞周期进展或停滞的信号， 分化 一条下游通路直接将Ras激活与基因改变联系起来， 细胞分裂所需的表达已经被发现。 关键 第一步是激活蛋白激酶Raf 1。 这是由一个 Raf 1和Ras之间的物理相互作用。然而，其他 Ras介导的事件似乎是完全转化所必需的， 分化反应，表明参与额外的Ras 互动伙伴。 他们已经分离并继续研究Rin 1， 一种与激活的Ras特异性结合并可以竞争的人类蛋白质 关于Raf 1 Rin 1和Raf 1行为之间还有其他相似之处， 包括它们与14-3-3蛋白的相互作用。 Rin 1的组织类型表达在宽范围内调节。 此外，本发明还提供了一种方法， Rin 1的一些剪接变体形式具有改变的性质。 他们的发现 与Rin 1作为受调节的Ras效应子起作用一致，Rin 1作为Raf 1 竞争对手或两者。 有趣的是，rin 1基因已经被定位到 11q13.2，在鳞状细胞癌中经常扩增的染色体位置 细胞癌和乳腺肿瘤。 该建议包括Rin 1结合特性和功能的分析。 重点是发生在哺乳动物细胞中的相互作用 （共免疫沉淀和共免疫荧光）和生物学 这些相互作用的后果（对Ras介导的转化的影响 差异化）。 他们将利用人工和 Rin 1的天然变体具有不同的结合特性。 这些研究针对Rin 1功能在Ras介导的信号传导中的作用， 转导，应该有助于他们理解正常细胞 包括分化和有丝分裂以及癌症 病理学