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NF-kappaB Regulation by Human Pirin

人 Pirin 对 NF-kappaB 的调节

基本信息

批准号：
9279172
负责人：
Jian-Dong Li
金额：
$ 22.6万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9279172
关键词：
Active Sites Aging Apoptosis Binding Binding Proteins Biological Models Biological Process C-terminal Cell Nucleus Cells Chemicals Communication Complex Cytoplasm DNA Sequence Data Development Disease Dissociation Drops Future Gene Expression Regulation Gene Targeting Genes Genetic Transcription Homeostasis Human Human body Immune Immune response Immune signaling In Vitro Inflammation Inflammatory Inflammatory Response Intervention Iron Iron-Binding Proteins Link Malignant Neoplasms Mediating Mediator of activation protein Medical Metabolic syndrome Metalloproteins Metals Modification Molecular Molecular Conformation Mutation Analysis 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 Signal Transduction Stimulus Stress Structure Sulfur System Testing Transcriptional Regulation Work alpha helix base bindin biological adaptation to stress cytokine human tissue in vivo inhibitor/antagonist innovation mouse model novel novel therapeutics oxidation p65 public health relevance response sensor transcription factor

项目摘要

DESCRIPTION (provided by applicant): The inducible transcriptional factor NF-κB 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-κB activation in the cytoplasm is well understood, little is known regarding the mechanism of NF-κB activation inside the cell nucleus and how NF-κB selectively targets specific genes. We propose to study the mechanisms by which NF-κB 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-κB. The long-term objective is to elucidate the regulatory mechanisms by which pirin participates in nuclear regulation of NF-κB. 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-κB. The ferric, but not ferrous, form of pirin substantially facilities bindin of NF-κB proteins to target κB genes, which suggests that pirin performs a redox sensing role in NF-κB regulation. We hypothesize that pirin is a nuclear redox sensor protein, the last fortress protecting cells from substantial redox shifting through NF-κB-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-κB 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-κB homodimer and heterodimer proteins and how this relationship changes in response to oxidative stress.

描述（由申请人提供）：诱导型转录因子 NF-κB 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对涉及免疫和应激反应、癌症和细胞凋亡的大量基因的表达的控制有关。虽然细胞质中 NF-κB 激活的过程已广为人知，但对于细胞核内 NF-κB 激活的机制以及 NF-κB 如何选择性地靶向特定基因却知之甚少。我们建议研究细胞核中 NF-κB 响应氧化应激的调节机制。在我们最近的研究中，我们证明人类金属蛋白 Pirin 是 NF-κB 的核调节因子。长期目标是阐明pirin参与NF-κB核调节的调节机制。 Pirin 是一种在人体组织中表达的非血红素铁蛋白。我们发现pirin金属中心在pirin和NF-κB之间的复合物形成中起着重要作用。 pirin 的铁（而非亚铁）形式显着促进 NF-κB 蛋白与靶 κB 基因的结合，这表明 Pirin 在 NF-κB 调节中发挥氧化还原传感作用。我们假设 Pirin 是一种核氧化还原传感器蛋白，是通过 NF-κB 相关免疫防御保护细胞免受大量氧化还原变化的最后堡垒。因此，了解吡林对诱导转录因子的调节至关重要。我们将确定控制 Pirin 蛋白与 NF-κB 蛋白结合和解离的结构成分。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与NF-κB同二聚体和异二聚体蛋白之间的功能关系以及这种关系如何响应氧化应激而变化。