Investigation of Gene Regulation by NF-kappaB Transcription factors

NF-kappaB 转录因子基因调控的研究

• 批准号: 8067860
• 负责人: GOURISANKAR GHOSH
• 金额: $ 29.74万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067860
• 关键词: Acetylation; Address; Adopted; Affect; Affinity; Binding; Biochemical; Bioinformatics; Cell Line; Cell Proliferation; Cell Survival; Cell physiology; Cells; Chromatin; Chronic; Complex; Cyclin D1; DNA; DNA Binding Domain; DNA Sequence; Disease; EP300 gene; Elements; Embryo; Event; Family; Family member; Fibroblasts; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomics; Goals; Immune; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Investigation; Knock-out; Laboratories; Location; Malignant Neoplasms; Maps; Measures; Microarray Analysis; Modeling; Modification; Molecular; NF-kappa B; NMR Spectroscopy; Normal Cell; Nuclear; Organogenesis; Phosphorylation; Physiological; Physiological Processes; Play; Positioning Attribute; Post-Translational Protein Processing; Protein Family; Publishing; Regulation; Reporter; Reporting; Role; SELP gene; Serine; Site; Specificity; Stimulus; Structure; System; TNFRSF5 gene; Testing; Transcription Coactivator; Transcriptional Regulation; base; cell type; combinatorial; design; dimer; genome-wide; human disease; in vivo; inhibitor/antagonist; insight; mutant; p65; preference; promoter; public health relevance; research study; response; three dimensional structure; transcription factor

DESCRIPTION (provided by applicant): The NF-kappaB (NF-?B) family of dimeric transcription factors regulates diverse physiological processes including immune and inflammatory responses, cell proliferation and survival. The combinatorial NF-?B dimers are formed from five family members; p50, p52, RelA (p65), cRel and RelB. These dimers regulate transcription by binding to specific DNA sequences of target genes known as ?B sites. The long term goals of our laboratories are to understand how NF-?B dimers function specifically in gene regulation. To achieve that goal, we have pursued a variety of approaches ranging from the biophysical to the genetic. Recent studies have emphasized the role of post-translational modifications of NF-?B dimers and the role of dimer-specific co-activators in regulating specific target genes. The focus of this proposal is to examine transcriptional regulation by phosphorylation and coactivator recognition events. We employ genetic, genomic, biochemical and biophysical approaches to investigate the two NF-?B family members that play the most prominent roles in human disease: RelA and p52. In aim 1 experiments are designed to investigate the mechanisms of transcriptional control by the RelA:CBP/p300 complex. Several reports have demonstrated the importance of RelA phosphorylation, and CBP/p300 binding in target gene regulation. Other studies have revealed that the effect of this modification/interaction is not global. Each modification/interaction affects the expression of only a subset of genes in stimulus and cell type specific manner. In this study we will investigate the role of RelA phosphorylation and CBP/p300 interaction mechanism and its impact on gene regulation. In aim 2 Biophysical and in vivo experiments are designed to study the transcriptional control by the cancer-associated p52:Bcl3 complex. As homodimers, NF-?B p52 and p50 have been reported to associate with Bcl3 to activate transcription, and as such they play critical roles in immune organogenesis and tolerance. The goal of this aim is to investigate the molecular basis of how p52 homodimer associates with Bcl3 and the specificity of the interaction, and if these complexes target a subset of ?B sequences. Public Health Relevance: The NF-?B family of dimeric transcription activators, which regulates a large number of genes, is critical for maintaining normal cell physiology. The focus of this proposal is to understand the regulation of promoter and transcriptional coactivator recognition by the NF-?B dimers.

描述（由申请人提供）：二聚体转录因子的 NF-κB (NF-κB) 家族调节多种生理过程，包括免疫和炎症反应、细胞增殖和存活。组合 NF-κB 二聚体由五个家族成员组成； p50、p52、RelA (p65)、cRel 和 RelB。这些二聚体通过与靶基因的特定 DNA 序列（称为 ?B 位点）结合来调节转录。我们实验室的长期目标是了解 NF-κB 二聚体如何在基因调控中发挥具体作用。为了实现这一目标，我们采取了从生物物理到遗传学的各种方法。最近的研究强调了 NF-κB 二聚体翻译后修饰的作用以及二聚体特异性共激活剂在调节特定靶基因中的作用。该提案的重点是检查磷酸化和共激活剂识别事件的转录调节。我们采用遗传、基因组、生物化学和生物物理方法来研究在人类疾病中发挥最重要作用的两个 NF-κB 家族成员：RelA 和 p52。目标 1 实验旨在研究 RelA:CBP/p300 复合物的转录控制机制。一些报告已经证明了 RelA 磷酸化和 CBP/p300 结合在靶基因调控中的重要性。其他研究表明，这种修改/相互作用的影响不是全局的。每个修饰/相互作用仅以刺激和细胞类型特定的方式影响一部分基因的表达。在本研究中，我们将研究 RelA 磷酸化和 CBP/p300 相互作用机制的作用及其对基因调控的影响。目标 2 生物物理和体内实验旨在研究癌症相关 p52:Bcl3 复合物的转录控制。据报道，作为同二聚体，NF-κB p52 和 p50 与 Bcl3 结合以激活转录，因此它们在免疫器官发生和耐受中发挥着关键作用。该目的的目的是研究 p52 同二聚体如何与 Bcl3 结合的分子基础以及相互作用的特异性，以及这些复合物是否靶向 ?B 序列的子集。公共健康相关性：二聚体转录激活因子 NF-κB 家族调节大量基因，对于维持正常细胞生理机能至关重要。该提案的重点是了解 NF-κB 二聚体对启动子和转录共激活子识别的调节。