NF-kappaB Regulation by Human Pirin

描述（由申请人提供）：诱导转录因子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与免疫和应激反应、癌症和细胞凋亡有关的大量基因表达的控制有关。虽然我们对细胞质中NF-κB的活化过程已经很清楚，但对细胞核内NF-κB活化的机制以及NF-κB如何选择性靶向特定基因的机制却知之甚少。我们拟研究细胞核中NF-κB在氧化应激反应中的调控机制。在我们最近的研究中，我们证明了人类金属蛋白pirin是NF-κB的核调节因子。长期目标是阐明pirin参与NF-κB核调控的调控机制。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与NF-κB复合物的形成中起着重要的作用。以铁而非铁的形式存在的pirin，在很大程度上促进了NF-κB蛋白与κB基因的结合，这表明pirin在NF-κB调控中发挥了氧化还原传感作用。我们假设pirin是一种核氧化还原传感器蛋白，通过NF-κ b相关的免疫防御保护细胞免受实质性氧化还原转移的最后堡垒。因此，了解匹林对诱导转录因子的调控是非常重要的。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。我们将确定人类pirin触发的靶信号基因，最后我们将进行细胞和体内研究，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，以及这种关系如何在氧化应激下发生变化。

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.