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: 6619874
• 负责人: Gregory D. Longmore
• 金额: $ 26.53万
• 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 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6619874
• 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：（改编自研究者摘要）细胞外 环境影响细胞内信号通路， 增长和分化是过去十年的一个重大挑战。 控制这些过程的基因突变会导致细胞 转化和癌症发展。含LIM的蛋白质家族 结构域在基因调控中起着重要的作用 表达，细胞命运决定，细胞骨架重塑，以及作为 细胞质和细胞核之间通讯的潜在介质， 对细胞外信号的反应。LIM结构域作为多功能蛋白的功能 模块，能够在不同的细胞环境中和在多个 亚细胞区室许多人被证明参与了直接 蛋白质相互作用含有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， 蛋白质结构第3组蛋白质是胞质的，含有3至4个串联的LIM C-末端的结构域与不同的N-末端结构域相关联。一些 是源自染色体易位的融合蛋白的组分 存在于某些癌症中。一个主要的挑战是了解第3组LIM 蛋白质将细胞外刺激与特定的细胞反应偶联。的PI 鉴定并鉴定了一种新的第3组LIM蛋白，Ajuba （乌尔都语中的“好奇心”，一种印度方言）。筋骨草穿梭于细胞质之间 和细胞核。缺失富含亮氨酸的核输出信号， 筋骨草导致筋骨草在细胞核中的积累。在胚胎期 癌细胞核积累的筋骨草导致细胞生长停滞 自发分化。筋骨草与胞质适配器 Grb 2蛋白导致促分裂原活化蛋白的Ras依赖性活化 激酶活性当在非洲爪蟾卵母细胞中表达时，筋骨草促进减数分裂， 成熟因此，Ajuba是一种细胞溶质蛋白，其将信号转导至细胞内的细胞。 细胞核对细胞外刺激的反应。在本提案中，PI 设计实验以1）确定筋骨草如何改变MAPK信号通路; 2)确定筋骨草如何调节多能胚胎癌细胞 3）确定细胞增殖和分化的调控信号 筋骨草胞质-核胞质易位; 4）鉴定胞质和 与筋骨草相互作用的核蛋白， 影响特定亚细胞区室中的筋骨草功能。