CHARACTERIZATION OF NAG EXPRESSION AND FUNCTIONS

NAG 表达和功能的表征

• 批准号: 7610256
• 负责人: CARLA J GUTHRIDGE
• 金额: $ 7.54万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610256
• 关键词: Address; COP9 protein; Cell physiology; Cells; Complex; Computer Retrieval of Information on Scientific Projects Database; Data; Epithelial Cells; Funding; Gene Expression; Gene Proteins; Grant; IL8 gene; Institution; Interleukin-1; Interleukin-6; Link; MYCN gene; Microarray Analysis; Molecular; Neuroblastoma; Pathway interactions; Phosphotransferases; Physiological Processes; Play; Protein Isoforms; Proteins; Regulation; Research; Research Personnel; Resources; Role; Signal Transduction; Source; System; United States National Institutes of Health; Yeasts; anakinra; design; human MAPK14 protein; inhibitor/antagonist; knock-down; mitogen-activated protein kinase p38; research study; signalosome subunit 3; tool; yeast two hybrid system

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Interleukin-1 receptor antagonists (IL-1Ra) are naturally occurring inhibitors of interleukin-1 (IL-1). Two intracellular forms of IL-1Ra (icIL-1Ra1 and icIL-1Ra3) have been described at the protein level. The precise function of these isoforms is unclear. Studies have demonstrated a role for icIL-1Ra1 as an inhibitor of IL-1-induced p38 MAP kinase activity, NFkB translocation, and IL-6 and IL-8 expression in epithelial cells. Previous data obtained from yeast two-hybrid analysis suggested that icIL-1Ra1 interacts with two intracellular proteins, COP9 signalosome subunit 3 (CSN3) and neuroblastoma amplified gene product (NAG). CSN3 is a component of the COP9 signalosome and its interaction with icIL-1Ra1 leads to an inhibition of CK2 and PKD kinases that associate with the signalosome complex. NAG is co-amplified along with MYCN in high grade neuroblastomas, however the normal function of the NAG protein is unknown. We hypothesize that icIL-1Ra1 and NAG play a crucial role in the regulation of cellular processes associated with IL-1 signaling. To address this hypothesis we initiated experiments examining the interaction of icIL-1Ra1 and NAG in relevant cell systems. Molecular tools were generated that allowed us to reconfirm the interaction of NAG and icIL-1Ra1 in relevant cell systems. Over-expression and knock-down expression systems have been designed and used to examine the effect of perturbing the expression of NAG and icIL-1Ra1 on global gene expression. Gene expression changes identified by microarray analysis have helped to identify candidate pathways linking NAG and icIL-1Ra1 to common physiological processes. The relevance of this linkage is currently under study.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 白介素1受体拮抗剂(IL-1ra)是白介素1(IL-1)的天然抑制剂。IL-1ra在细胞内的两种形式(icIL-1Ra1和icIL-1Ra3)已经在蛋白质水平上被描述。这些异构体的确切功能尚不清楚。研究表明，icIL-1Ra1可以抑制IL-1诱导的p38 MAP活性、NFkB易位以及IL-6和IL-8的表达。酵母双杂交分析表明，icIL-1Ra1与COP9信号小体亚单位3(CSN3)和神经母细胞瘤扩增基因产物(NAG)两种胞内蛋白相互作用。CSN3是COP9信号小体的一个组成部分，它与ICIL-1Ra1的相互作用导致与信号小体复合体相关的CK2和PKD激酶被抑制。在高级别神经母细胞瘤中，NAG与MYCN共扩增，但NAG蛋白的正常功能尚不清楚。我们假设icIL-1Ra1和NAG在与IL-1信号相关的细胞过程的调节中起关键作用。为了解决这一假设，我们启动了实验，检查icIL-1Ra1和NAG在相关细胞系统中的相互作用。分子工具的产生使我们能够再次确认NAG和icIL-1Ra1在相关细胞系统中的相互作用。已经设计了过表达和下调表达系统，并用来检测干扰NAG和icIL-1Ra1表达对整体基因表达的影响。微阵列分析确定的基因表达变化有助于确定将NAG和icIL-1Ra1与常见生理过程联系起来的候选途径。这种联系的相关性目前正在研究中。