Physiological roles of Ewings Sarcoma gene product EWS

尤文氏肉瘤基因产物 EWS 的生理作用

• 批准号: 8553549
• 负责人: Sean Lee
• 金额: $ 38.62万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8553549
• 关键词: C-terminal; Cells; Chromosomal translocation; Defect; Development; Ewings sarcoma; Family; Gene Fusion; Gene Targeting; Genes; Genetic Transcription; Goals; Human; Knockout Mice; Knowledge; Lead; Malignant Neoplasms; Mus; Physiological; Play; Proteins; RNA Polymerase II; RNA Recognition Motif; RNA Splicing; Role; Solid; TBP-Associated Factor 15 kDa; base; effective therapy; embryonic stem cell; gene function; in vivo; sarcoma; tumor; tumorigenesis

Ewing's sarcoma gene (EWS) belongs to a family of TET proteins, which include TLS/FUS and TAFII15. These proteins encode RNA binding domain at the C-terminal end and a large repeats of SYGOO motif at their N-terminus. Based on the physical interactions with RNA polymerase II and splicing factors, TET proteins are thought to play roles in basic transcription and splicing. However, in vivo role of EWS and other TET proteins has not been demonstrated. Thus, the goal of this project is to understand the in vivo function of EWS and to relate that function in the context of the chromosomal translocation found in Ewing's sarcoma and other EWS-fusion sarcomas. Aim 1. We will generate EWS knockout mouse by gene targeting approach. We have already generated the knockout mouse derived from the targeted mouse ES cells. Aim 2. To characterize the defects caused by EWS deficiency in the knockout mouse. Aim 3. To characterize the EWS deficiency at the cellular level to identify the mechanisms by which EWS functions. The knowledge gained from this study will help to better understand about EWS and other TET proteins in general. This will further elucidate how EWS or TLS related fusion products will lead to tumorigenesis.

尤文氏肉瘤基因（EWS）属于泰特蛋白家族，其包括TLS/FUS和TAFII 15。这些蛋白质在C末端编码RNA结合结构域，在N末端编码SYGOO基序的大重复序列。基于与RNA聚合酶II和剪接因子的物理相互作用，泰特蛋白被认为在基本的转录和剪接中发挥作用。然而，EWS和其他泰特蛋白的体内作用尚未得到证实。因此，本项目的目标是了解EWS的体内功能，并将其与尤文氏肉瘤和其他EWS融合肉瘤中发现的染色体易位相关。目标1.我们将通过基因打靶的方法建立EWS基因敲除小鼠。我们已经从靶向小鼠ES细胞中产生了敲除小鼠。目标2.鉴定EWS基因敲除小鼠中EWS缺陷引起的缺陷。目标3.在细胞水平上表征EWS缺陷，以确定EWS功能的机制。从这项研究中获得的知识将有助于更好地了解EWS和其他泰特蛋白。这将进一步阐明EWS或TLS相关融合产物如何导致肿瘤发生。