Cell Adhesion Control by the Proto-Oncoprotein SYT

原癌蛋白 SYT 控制细胞粘附

• 批准号: 6788759
• 负责人: JOSIANE E EID
• 金额: $ 15.33万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-08 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6788759
• 关键词: RNA interference; biological signal transduction; cadherins; cell adhesion; cell line; chimeric proteins; chromatin; connective tissue neoplasm; contact inhibition; cytoplasm; gene targeting; genetically modified animals; laboratory mouse; oncogenes; protein localization; protein protein interaction; protein purification; protein structure function; sarcoma

DESCRIPTION (provided by applicant): Synovial sarcoma is a soft tissue cancer of the joints that affects young adults. It is characterized by a chromosomal rearrangement between the SYT gene on chromosome 18 and the SSX gene on chromosome x, which results in a fusion product, SYT/SSX. In synovial sarcomas, wt SYT expression from the intact allele is suppressed, and therefore, with the other allele engaged in expressing SYT/SSX, the tumor almost entirely lacks intact SYT function. This could mean that SYT contributes to maintaining normal homeostasis, and losing its function could, at least in part, contribute to tumor formation. Elucidating SYT in vivo function, therefore, is of great importance to the understanding of synovial sarcoma development. One biological event SYT appears to contribute to, is proper cell adhesion, by sending a nuclear to cytoplasm signal. The ability of the cell to adhere to its extracellular matrix is crucial for normal growth and other cellular functions, and loss of such property is one of the prominent features of tumorigenesis and invasiveness. The objective of this application is to gain an in-depth knowledge about the mechanism of cell adhesion control by SYT. One important approach toward this goal is to study the biological consequences in development and adult tissue formation when the SYT gene is targeted in a mouse model. SYT will also be deleted in vitro, by RNAi, in primary and immortalized cell lines, where the integrity of proper adhesion will be investigated. Such events normally involve the ability of the cells to migrate in the wounds for repair, to form polarized epithelial layers, to differentiate on basement membranes, and to adhere to the extracellular matrix for normal division. The recent finding that SYT regulates (-catenin function is of particular interest, since beta-catenin is a major component of cell adhesion-related processes. One of the objectives of this application is to elucidate the biological significance of the SYT/beta-catenin interaction and whether such association is part of SYT nuclear signaling in cell adhesion control. Finally, in order to decipher the basic mechanism of SYT function, protein purification experiments will be conducted in order to isolate and characterize the total cellular complexes in which SYT exists, and through which it sends its efferent signal to mediate proper cell adhesion.

描述（由申请人提供）：滑膜肉瘤是影响年轻人的关节的软组织癌。 它的特征是染色体上的SYT基因与X染色体上的SSX基因之间的染色体重排，从而导致融合产物Syt/SSX。 在滑膜肉瘤中，来自完整等位基因的WT SYT表达被抑制，因此，由于其他等位基因参与表达SYT/SSX，肿瘤几乎完全缺乏完整的SYT功能。 这可能意味着SYT有助于维持正常的稳态，并且失去其功能至少可能部分导致肿瘤形成。 因此，阐明体内功能的SYT对于理解滑膜肉瘤发育至关重要。 一个生物事件SYT似乎是通过发送核向细胞质信号来促成适当的细胞粘附。 细胞粘附于其细胞外基质的能力对于正常生长和其他细胞功能至关重要，而这种特性的丧失是肿瘤发生和侵入性的重要特征之一。 该应用的目的是获得有关SYT细胞粘附控制机制的深入知识。 实现此目标的一种重要方法是研究小鼠模型中SYT基因的发育和成人组织形成中的生物学后果。 SYT还将在体外，RNAi，在原发性和永生的细胞系中删除，其中将研究适当的粘附的完整性。 这些事件通常涉及细胞在伤口中迁移的能力进行修复，形成偏振上皮层，区分基底膜，并粘附于正常分裂的细胞外基质。 最近的发现，SYT调节（ - 蛋白酶功能特别有趣，因为β-catenin是细胞粘附相关过程的主要组成部分。本应用程序的目标之一是阐明SYT/beta-catenin的生物学意义相互作用以及这种关联是否是细胞粘附控制中SYT核信号的一部分，为了破译SYT功能的基本机制，将进行蛋白质纯化实验，以隔离和表征Syt存在的总细胞复合物并通过它发送其传出信号以介导适当的细胞粘附。