Novel Subunit of NF-kB Confers Gene Regulatory Specificity

转录因子核因子-kB广泛调节过多的基因，并参与癌症和 炎症性疾病。核因子-kB的异常结构性激活已被认为是一种重要的致病因素 癌症和炎症性疾病。我们的长期目标是阐明控制特定基因的机制 核因子-kB靶基因的表达。具体的假设是，核因子-kB DNA结合复合体包含 除了Rel二聚体和这些介导特定基因调控的新成分。我们基于这一点 对观察结果的假设1)核提取液中天然核因子-kB的初始大小估计为200 KD，但当由纯化的p50和p65蛋白重组时，估计为115 kD，这将是 适用于简单的杂二聚体，2)从纯化的蛋白质中重组的杂二聚体具有100倍 核糖体蛋白S3(RPS3)是一种新的成分 在介导选择性基因调控的核因子-kB DNA结合复合体中。这个实验的重点是 建议鉴定新的亚基fNFTkB，并确定Rion-Rg1的生化功能。 郊区。其具体目的是：1.阐明rps3介导的核因子-kB靶标的特异性机制。 基因调控；2.鉴定核因子-kB DNA结合复合体中的新成分(S)，以介导特异性 基因表达。我们将提纯CD25kB DNA结合复合体中的新成分，阐明 新成分在核因子-kB信号转导中的作用意义及机制 病理环境；3、建立体内模型，设计新型靶向RPS3的小肽和新型 核因子-kB DNA结合复合体中的成分与虹膜抑制因子核因子-kB基因的特异性结合。我们将绘制最小的地图 P65、RPS3和用于物理相互作用和核因子-kB功能的新组件，并评估 针对这些最小部分的细胞通透性多肽的抑制能力。该项目将提供新的 深入了解核因子-kB，更好地理解核因子-kB的调控特异性。这些结果也将 为癌症和炎症性疾病的治疗提供潜在的新治疗靶点，并可能 对核因子-kB相关疾病有普遍意义。

The transcription factor NF-kB extensively regulates a plethora of genes and is involved in cancer and inflammatory disease. Aberrant constitutive NF-kB activation has been recognized as a critical pathogenetic in cancer and inflammatory disease. Our long-term goal is to elucidate the mechanism controlling specific expression of NF-kB target genes. The specific hypothesis is that NF-kB DNA binding complexes contain novel components, besides the Rel dimer and these mediate specific gene regulation. We based that hypothesis on the observations 1) the original size estimate of native NF-kB in nuclear extracts was > 200 kD, but when reconstituted from purified p50 and p65 proteins, it was estimated to be 115 kD which would be appropriate for a simple heterodimer, 2) reconstituted heterodimers from purified proteins have a > 100 fold lower affinity than native NF-kB, 3) our recent finding that ribosomal protein S3 (RPS3) is a novel component in NF-kB DNA binding complexes that mediates selective gene regulation. The experimental focus of this proposal is to identify the novel subupjtsgfNFTkB andsto define the biochemical function of rion-Rgl ^ suburiits. The specific aims are: 1. to elucidate the mechanism of RPS3-mediated specificity in NF-kB target gene regulation; 2. to identify novel component(s) in NF-kB DNA binding complexes that mediated specific gene expression. We will purify the novel components in CD25 kB DNA binding complex, elucidate the functional significance and mechanism of novel components in NF-kB signaling under normal and pathological settings; 3, to develop in vivo models and design novel small peptides targeting RPS3 and novel components in NF-kB DNA binding complexes to specifically irihibitor NF-kB genes. We will map the minimal parts in p65, RPS3 and novel components for physical interaction and NF-kB function and assess the inhibitory capability of cell-permeable peptides targeting at these minimal parts. This project will provide new insight into NF-kB and better our understanding of the regulatory specificity of NF-kB. These results will also provide potential novel therapeutic targets for the treatment of cancer and inflammatory disease, and may have implication for NF-kB-related diseases in general.