Regulation of Nucleoporins by Interferon

干扰素对核孔蛋白的调节

• 批准号: 7256488
• 负责人: Beatriz MA Fontoura
• 金额: $ 26.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-05 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256488
• 关键词: Antiviral Response; Binding; Biochemical Genetics; Biological Assay; Cell Nucleus; Cell Proliferation; Cells; Chromosomal Rearrangement; Chromosomal translocation; Confocal Microscopy; Cytoplasm; Dextrans; Diffusion; Disruption; Electron Microscopy; Eukaryotic Cell; Exclusion; Genes; Goals; Immunofluorescence Immunologic; In Situ Hybridization; In Vitro; Interferons; Knock-out; Luciferases; Malignant Neoplasms; Mediating; Messenger RNA; Microscopy; Molecular; Movement; Mutagenesis; Natural Immunity; Nuclear; Nuclear Envelope; Nuclear Export; Nuclear Import; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Nucleic Acids; Oligonucleotide Probes; Pathway interactions; Phosphotransferases; Play; Process; Protein Binding; Protein Overexpression; Proteins; RNA Interference; Range; Regulation; Reporter Genes; Research; Resolution; Role; Signal Pathway; Signal Transduction; Site; Structure; Transcriptional Activation; Transfection; Up-Regulation; Vesicular stomatitis Indiana virus; Viral; Viral Proteins; cell growth; cell type; dextran; extracellular; in vivo; innovation; intracellular protein transport; knock-down; leukemia; mRNA Export; multiple myeloma M Protein; novel; nuclear pore complex protein 96; nucleocytoplasmic transport; particle; passive transport; protein localization location; protein protein interaction; receptor; tandem mass spectrometry; transcription factor; yeast two hybrid system

DESCRIPTION (provided by applicant): The movement of molecules between the nucleus and the cytoplasm of eukaryotic cells is mediated by, the nuclear transport machinery. In general, to be imported or exported from the nucleus, molecules 1) bind to transport receptors, 2) are transported through nuclear pore complexes (NPCs) present in the nuclear envelope, 3) and translocate from the NPCs to intranuclear or cytoplasmic target sites. These are crucial steps for controlling nuclear entry and exit of molecules such as transcription factors, RNAs, kinases and viral particles. Disruption of this machinery has been involved in cancer. NPC proteins (nucleoporins or Nups) are associated with chromosomal rearrangements in leukemia. Nups are also targets of viral proteins. Our recent findings show that up-regulation of two major Nups, Nup98 and Nup96, by interferon (IFN) reverts mRNA nuclear export inhibition mediated by a viral protein. These results indicate a role for Nups in antiviral response and in other IFN-mediates processes such as innate immunity and cell proliferation. Our long-range goal is to understand the molecular mechanisms of the nuclear transport machinery and how they are, regulated by different signaling pathways. The central hypothesis is that a subset of Nups are highly regulated by extracellular signals, facilitate nuclear import and export of molecules, and are also target of viral proteins and other pathogenic factors. We will pursue the following specific aims: 1. To characterize Sec 13 and novel constituents of the Nup98 and Nup96-mediated nuclear transport pathway(s). 2. To determine the role of Secl3 and novel constituents of the Nup98 and Nup96-mediated pathway(s) on the structure, active and passive transport at the NPC. 3. Determine the molecular mechanisms involved in the disruption of Nup98 and Nup96 function by a viral protein and their regulation by the IFN pathway. High-resolution microscopies, biochemical and genetic approaches will be used. Thus, our research proposes innovative findings on Nup function and regulation, which are crucial to advance the nuclear transport field and are also essential for understanding the role of Nups in leukemia and IFN-mediated processes, such as antiviral response, innate immunity and cell proliferation.

描述（由申请人提供）：真核细胞的细胞核和细胞质之间的分子运动是由核转运机制介导的。一般来说，要从细胞核输入或输出，分子1)与转运受体结合，2)通过存在于核膜中的核孔复合物（NPCs）运输，3)从NPCs转运到核内或细胞质目标位点。这是控制转录因子、rna、激酶和病毒颗粒等分子进入和退出核的关键步骤。这种机制的破坏与癌症有关。NPC蛋白（核孔蛋白或Nups）与白血病的染色体重排有关。糖蛋白也是病毒蛋白的目标。我们最近的研究结果表明，干扰素（IFN）上调Nup98和Nup96这两个主要的Nup98和Nup96，可以逆转由病毒蛋白介导的mRNA核输出抑制。这些结果表明，Nups在抗病毒反应和其他ifn介导的过程（如先天免疫和细胞增殖）中发挥作用。我们的长期目标是了解核转运机制的分子机制，以及它们是如何被不同的信号通路调节的。核心假设是Nups的一个子集受到细胞外信号的高度调节，促进分子的核进出口，也是病毒蛋白和其他致病因子的靶点。具体目标是：表征Sec 13和Nup98和nup96介导的核转运途径的新成分。2. 目的：确定Nup98和nup96介导通路的新组分和隐居3在鼻咽癌的结构、主动和被动转运中的作用。3. 确定病毒蛋白破坏Nup98和Nup96功能的分子机制及其通过IFN途径的调控。将使用高分辨率显微镜、生化和遗传方法。因此，我们的研究提出了关于Nup功能和调控的创新发现，这对推进核转运领域至关重要，也对理解Nup在白血病和ifn介导的过程中的作用至关重要，如抗病毒反应、先天免疫和细胞增殖。