Components of Translation in Signal Transduction

信号转导翻译的组成部分

• 批准号: 6757990
• 负责人: PAUL R SCHIMMEL
• 金额: $ 30.74万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6757990
• 关键词: IP 10 protein; aminoacid tRNA ligase; angiogenesis; apoptosis; biological signal transduction; chimeric proteins; cytokine receptors; genetic translation; interferon gamma; interleukin 8; laboratory mouse; mutant; receptor binding; retina; transfection /expression vector

This project focuses on novel activities of two essential components of the translation apparatus in human cells. These components are aminoacyl tRNA synthetases. In their canonical role, aminoacyl tRNA synthetases catalyze aminoacylation of transfer RNAs in the first step of protein synthesis, and thereby establish the rules of the genetic code. Each of the 20 amino acids that make up proteins has a separate, distinct aminoacyl tRNA synthetase. In recent work we reported that one specific tRNA synthetase-for the amino acid tyrosine-could be split into two distinct cytokines. While the full-length protein is inactive, the two fragments are potent cytokines with distinct biological activities. The protein is secreted during apoptosis in cell culture and then can be cleaved by a protease such as leukocyte elastase. In further unpublished work, we found that the aforementioned fragments of this synthetase, and fragments of its close homolog that acts on the amino acid tryptophan, are active in angiogenesis or angiostasis. (Proteolysis or alternative splicing produces fragments of the latter enzyme.) The purpose of this project is to expand upon and further validate the initial observations of the activities of these fragments in angiogenesis or angiostasis, using several different assays for angiogenesis in vivo. The receptors involved in the angiogenic pathways, the specific motifs within the proteins responsible for the activities, the mechanism of secretion, and the cell signals responsible for secretion will investigated. These investigation will clarify how these components of the translation apparatus link protein synthesis to signal transduction pathways. The results of these studies can provide one kind of foundation for treating human diseases where cytokine activities and angiogenesis play an important role.

该项目着重于人类细胞中翻译设备的两个基本组成部分的新活动。这些成分是氨基酰基TRNA合成酶。在其规范的作用中，氨基酰基TRNA合酶在蛋白质合成的第一步中催化转移RNA的氨基酰化，从而确定了遗传密码的规则。构成蛋白质的20种氨基酸中的每一个都有一个独立的，不同的氨基酰基TRNA合成酶。在最近的工作中，我们报道了一种特定的tRNA合成酶 - 氨基酸酪氨酸 - 蛋白可以分为两种不同的细胞因子。尽管全长蛋白质不活跃，但两个片段是具有不同生物学活性的有效细胞因子。该蛋白在细胞培养的凋亡过程中分泌，然后可以被白细胞弹性酶等蛋白酶裂解。在进一步的未发表的工作中，我们发现该合成酶的上述片段及其作用于氨基酸色氨酸的紧密同源物的片段在血管生成或血管生成中活跃。 （蛋白水解或替代剪接产生后一种酶的片段。）该项目的目的是使用几种不同的在体内血管生成的测定法，在血管生成或血管生成中扩展并进一步验证这些片段的初始观察结果。将研究参与血管生成途径的受体，负责活性的蛋白质中的特定基序，分泌机理以及负责分泌的细胞信号。这些研究将阐明这些翻译设备的这些成分如何将蛋白质合成与信号转导途径联系起来。这些研究的结果可以为治疗细胞因子活性和血管生成起着重要作用的人类疾病提供一种基础。