NF-kappaB Regulation by Human Pirin

描述(申请人提供)：可诱导转录因子NF-κB是细胞内信号转导的关键介体。它与细胞对促炎信号的反应以及控制大量基因的表达有关，这些基因涉及免疫和应激反应、癌症和细胞凋亡。虽然核转录因子κB在细胞质中的激活过程已被人们所熟知，但对于核内核因子κB激活的机制以及核因子-κB如何选择性地靶向特定基因却知之甚少。我们建议研究核转录因子-κB在细胞核内对氧化应激反应的调节机制。在我们最近的研究中，我们证实了一种人类金属蛋白Pirin是一种核转录因子κB的核调节因子。我们的长期目标是阐明Pirin参与核转录因子κB核调节的调控机制。我们发现Pirin的金属中心在Pirin和NF-κB之间的复合体的形成中起着重要的作用。Pirin的铁的形式，而不是铁的形式，大大方便了NF-κB蛋白与靶κB基因的结合，这表明Pirin在NF-κB的调节中起着氧化还原敏感的作用。我们假设Pirin是一种核氧化还原感受器蛋白，是通过NF-κB连接的免疫防御来保护细胞免受实质性氧化还原转移的最后堡垒。因此，了解Pirin对可诱导转录因子的调节是非常重要的。我们将确定控制海豚蛋白与NF-κB蛋白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与NF-κB同源二聚体和异源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反应中发生变化。

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.