NF-kappaB Regulation by Human Pirin

人 Pirin 对 NF-kappaB 的调节

基本信息

批准号：
9057580
负责人：
Jian-Dong Li
金额：
$ 23.78万
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 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9057580
关键词：
Active Sites Aging Apoptosis Binding 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 Health 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 Signal Transduction Staging 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 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（由适用提供）：诱导转录因子NF-κB是细胞内信号传导的关键介体。它与细胞反应有关促炎信号的反应以及控制了与免疫和胁迫反应，癌症和凋亡有关的大量基因表达的控制。虽然对细胞质中NF-κB激活的过程有充分的了解，但关于细胞核内NF-κB激活的机制以及NF-κB如何选择靶向特定基因的机制知之甚少。我们建议研究响应氧化应激而在细胞核中调节NF-κB的机制。在我们最近的研究中，我们证明了人类金属蛋白pirin是NF-κB的核调节剂。长期目标是阐明Pirin参与NF-κB的核调节的调节机制。 Pirin是在人类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之间的复杂形成中起着重要作用。 pirin pirin实质性设施的铁（但不是亚铁形式）的NF-κB蛋白与靶向κB基因的结合，这表明Pirin执行了氧化还原传感器蛋白，这是最后的要塞，可保护细胞免于通过NF-κB链接的免疫防御转移的实质氧化还原。因此，了解Pirin对诱导的转录因子的调节至关重要。我们将确定pirin蛋白与NF-κB蛋白的控制结合和解离的结构成分。我们将确定由人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-κB同二聚体和异二聚体蛋白之间的功能关系，以及这种关系如何因氧化应激而反应而变化。