ROLE OF LIM PROTEINS IN REGULATING CELL GROWTH

LIM 蛋白在调节细胞生长中的作用

• 批准号: 6732087
• 负责人: Gregory D. Longmore
• 金额: $ 26.55万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6732087
• 关键词: biological signal transduction; cell differentiation; cell growth regulation; cell proliferation; germ cell neoplasms; intermolecular interaction; intracellular transport; mitogen activated protein kinase; protein structure function; protein transport; yeast two hybrid system

DESCRIPTION: (Adapted from the investigator's abstract) How the extracellular environment influences intracellular signaling pathways that regulate cell growth and differentiation has been a major challenge over the past decade. Mutations in genes controlling these processes result in cellular transformation and cancer development. A family of proteins containing LIM domains has been recognized as playing important roles in the control of gene expression, cell fate determination, remodeling of the cytoskeleton, and as potential mediators of communication between the cytosol and the nucleus in response to extracellular signals. LIM domains function as versatile protein modules, capable of acting within diverse cellular contexts and in multiple subcellular compartments. Many have been shown to participate in direct protein-protein interactions. LIM domain-containing proteins have been classified according to sequence homologies among the LIM domains and overall protein structure. Group 3 proteins are cytosolic and contain 3 to 4 tandem LIM domains at the C-terminus in association with distinct N-terminal domains. Some are components of fusion proteins derived from chromosomal translocation present in some cancers. A major challenge is to understand how group 3 LIM proteins couple extracellular stimuli to specific cellular responses. The PI has identified and characterized a novel group 3 LIM protein, Ajuba ("curiosity" in Urdu, an Indian dialect). Ajuba shuttles between the cytoplasm and the nucleus of cells. Deletion of a leucine-rich nuclear export signal in Ajuba results in an accumulation of Ajuba in the cell nucleus. In embryonal carcinoma cells nuclear accumulation of Ajuba results in a cell growth arrest and spontaneous differentiation. Ajuba associates with the cytosolic adapter protein Grb2 leading to a Ras-dependent activation of mitogen-activated protein kinase activity. When expressed in Xenopus oocytes, Ajuba promotes meiotic maturation. Thus Ajuba is a cytosolic protein that transduces signals to the nucleus in response to extracellular stimuli. In this proposal the PI has designed experiments to 1) determine how Ajuba alters MAPK signaling pathways; 2) determine how Ajuba regulates multipotent embryonal carcinoma cell proliferation and differentiation; 3) determine the signals regulating cytosolic-nuclear cytosolic translocation of Ajuba; 4) identify cytosolic and nuclear proteins that interact with Ajuba and determine how these interactions affect Ajuba function in specific subcellular compartments.

描述：(改编自研究人员的摘要)细胞外如何 环境影响调节细胞的细胞内信号通路 在过去的十年里，增长和差异化一直是一个重大挑战。 控制这些过程的基因突变导致细胞 转化和癌症的发展。一个含有LiM的蛋白质家族 结构域在基因调控中发挥着重要作用 表达、细胞命运的决定、细胞骨架的重塑和AS 胞浆和胞核之间潜在的通讯媒介 对细胞外信号的反应。LIM结构域是一种多功能蛋白质 模块，能够在不同的蜂窝环境和多个 亚细胞隔间。许多人被证明参与了直接的 蛋白质之间的相互作用。含有LIM结构域的蛋白质已经被 根据LIM结构域之间的序列同源性进行分类，并总体 蛋白质结构。第3组蛋白是胞浆蛋白，含有3-4个串联LIM C-末端的结构域与不同的N-末端结构域相关联。一些人 是来自染色体易位的融合蛋白的组成部分 存在于某些癌症中。一个主要的挑战是了解第三组LIM 蛋白质将细胞外刺激与特定的细胞反应相结合。《少年派》 已经鉴定并鉴定了一种新的第3族LIM蛋白Ajuba (印度方言乌尔都语中的“好奇心”)。Ajuba穿梭于细胞质之间 以及细胞的核。一个富含亮氨酸的核出口信号在 Ajuba导致Ajuba在细胞核内积聚。在胚胎中 癌细胞核聚积Ajuba导致细胞生长停滞 和自发分化。Ajuba与胞浆适配器相关 Grb2蛋白导致丝裂原激活蛋白的RAS依赖激活 激活酶活性。当在非洲爪哇卵母细胞中表达时，Ajuba促进减数分裂 成熟。因此，Ajuba是一种胞浆蛋白，它将信号传导到 细胞核对细胞外刺激的反应。在这项提案中，PI具有 设计实验1)确定Ajuba如何改变MAPK信号通路； 2)确定Ajuba如何调节多潜能胚胎癌细胞 增殖与分化；3)确定信号调控 胞质-核胞质易位；4)鉴定胞质和胞质 与Ajuba相互作用的核蛋白，并决定这些相互作用如何 影响特定亚细胞隔间的Ajuba功能。