NF-kappaB Regulation by Human Pirin

人 Pirin 对 NF-kappaB 的调节

• 批准号: 8760952
• 负责人: Jian-Dong Li
• 金额: $ 28.12万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8760952
• 关键词: Active Sites; Address; Aging; Apoptosis; Binding; Biological Models; Biological Process; C-terminal; Cartoons; Cell Nucleus; Cells; Chemicals; Communication; Complex; Cytoplasm; DNA Sequence; Data; Development; Disease; Dissociation; Drops; Future; Gene Expression Regulation; Gene Targeting; Genes; Homeostasis; Human; Human body; Immune; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Intervention; Iron; Iron-Binding Proteins; Lead; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical; Metabolic syndrome; Metalloproteins; Metals; Modification; Molecular; Molecular Conformation; NF-kappa B; Nonheme Iron Proteins; Nuclear; Outcome; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pharmacologic Substance; Physiological; Play; Process; Protein Family; Proteins; Reactive Nitrogen Species; Regulation; Role; Shapes; Signal Transduction; Staging; Stimulus; Stress; Structure; Sulfur; System; Testing; Transcriptional Regulation; Work; base; bindin; biological adaptation to stress; cytokine; human tissue; in vivo; inhibitor/antagonist; innovation; mouse model; novel; novel therapeutics; oxidation; p65; protein B; public health relevance; response; sensor; transcription factor

DESCRIPTION (provided by applicant): The inducible transcriptional factor NF-?B is a critical mediator of intracellular signaling. It has been linked with cellular response to pro-inflammatory signals and control of the expression of a vast array of genes involved in immune and stress responses, cancer, and apoptosis. While the process of NF-?B activation in the cytoplasm is well understood, little is known regarding the mechanism of NF-?B activation inside the cell nucleus and how NF-?B selectively targets specific genes. We propose to study the mechanisms by which NF-?B is regulated in the cell nucleus in response to oxidative stress. In our recent study, we demonstrated that a human metalloprotein pirin is a nuclear regulator of NF-?B. The long-term objective is to elucidate the regulatory mechanisms by which pirin participates in nuclear regulation of NF-?B. Pirin is a non-heme iron protein expressed in human tissues. We have found that the pirin metal center plays an important role in complex formation between pirin and NF-?B. The ferric, but not ferrous, form of pirin substantially facilities bindin of NF-?B proteins to target ?B genes, which suggests that pirin performs a redox sensing role in NF- ?B regulation. We hypothesize that pirin is a nuclear redox sensor protein, the last fortress protecting cells from substantial redox shifting through NF-?B-linked immune defense. Understanding regulation of the inducible transcriptional factor by pirin is thus fundamentally important. We will determine the structural components that control association and dissociation of pirin protein to the NF-?B proteins. We will identify the target signaling genes triggered by human pirin, finally we will perform cellular and in vivo studies to further test the functional relationship between pirin and NF-?B homodimer and heterodimer proteins and how this relationship changes in response to oxidative stress.

描述（申请人提供）：诱导型转录因子NF-？B是细胞内信号传导的关键介质。它与细胞对促炎信号的反应以及控制参与免疫和应激反应、癌症和细胞凋亡的大量基因的表达有关。而NF-？B在细胞质中的激活是很清楚的，关于NF-？B活化细胞核内的NF-？B选择性地靶向特定基因。我们建议研究NF-？B在细胞核中响应于氧化应激而被调节。在我们最近的研究中，我们证明了人类金属蛋白pirin是NF-？B。长期的目标是阐明的监管机制，吡林参与核调节NF-？B。Pirin是一种在人体组织中表达的非血红素铁蛋白。我们已经发现，pirin金属中心起着重要的作用，在复杂的形成pirin和NF-？B。铁，但不是亚铁，形式的pirin基本设施结合NF-？靶向B蛋白？B基因，这表明，pirin执行的氧化还原传感NF-？B法规。我们假设，pirin是一个核氧化还原传感器蛋白，最后的堡垒保护细胞从大量的氧化还原转变通过NF-？B连锁免疫防御因此，理解pirin对诱导型转录因子的调节是非常重要的。我们将确定的结构组成部分，控制协会和解离的pirin蛋白的NF-？B蛋白。我们将鉴定人pirin触发的靶信号基因，最后我们将进行细胞和体内研究，以进一步测试pirin和NF-？B同源二聚体和异源二聚体蛋白以及这种关系如何在氧化应激反应中变化。