ROLE OF LIM PROTEINS IN REGULATING CELL GROWTH

描述：（改编自研究者的摘要）细胞外如何 环境影响调节细胞的细胞内信号通路 增长和差异化一直是过去十年的重大挑战。 控制这些过程的基因突变会导致细胞 转化和癌症发展。含有 LIM 的蛋白质家族 结构域已被认为在基因控制中发挥重要作用 表达、细胞命运决定、细胞骨架重塑等 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质 模块，能够在不同的细胞环境和多种 亚细胞区室。许多人已被证明直接参与 蛋白质-蛋白质相互作用。含有 LIM 结构域的蛋白质已被 根据 LIM 结构域之间的序列同源性和整体序列同源性进行分类 蛋白质结构。第 3 组蛋白是胞质蛋白，包含 3 至 4 个串联 LIM C 末端的结构域与不同的 N 末端结构域相关。一些 是源自染色体易位的融合蛋白的成分 存在于某些癌症中。一个主要的挑战是了解第 3 组 LIM 如何 蛋白质将细胞外刺激与特定的细胞反应结合起来。 PI 已鉴定并表征了一种新型 3 组 LIM 蛋白 Ajuba （印度方言乌尔都语中的“好奇心”）。 Ajuba 在细胞质之间穿梭 和细胞核。删除富含亮氨酸的核输出信号 Ajuba 导致 Ajuba 在细胞核中积累。在胚胎时期 Ajuba 的癌细胞核积聚导致细胞生长停滞 和自发分化。 Ajuba 与胞质接头结合 蛋白质 Grb2 导致丝裂原激活蛋白的 Ras 依赖性激活 激酶活性。当在爪蟾卵母细胞中表达时，Ajuba 促进减数分裂 成熟。因此，Ajuba 是一种胞质蛋白，可将信号转导至 细胞核对细胞外刺激作出反应。在此提案中，PI 已 设计实验来 1) 确定 Ajuba 如何改变 MAPK 信号通路； 2)确定Ajuba如何调节多能胚胎癌细胞 增殖和分化； 3）确定调节信号 Ajuba 的胞质-核胞质易位； 4) 识别细胞质和 与 Ajuba 相互作用的核蛋白并决定这些相互作用如何 影响特定亚细胞区室中的 Ajuba 功能。

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.