NXF Proteins, Cofactors and Targets

NXF 蛋白质、辅因子和靶标

• 批准号: 7786965
• 负责人: MARIE-LOUISE HAMMARSKJOLD
• 金额: $ 30万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7786965
• 关键词: Adaptor Signaling Protein; Address; Be++ element; Beryllium; Binding; Brain; Cells; Data; Development; Diagnosis; Drosophila genus; Elements; Evolution; Functional RNA; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Goals; Hand; Hippocampus (Brain); Homeostasis; Human; Human body; Indium; Introns; Lead; Learning; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Mouse Strains; Mus; Mutate; Neurons; Nonsense-Mediated Decay; Organ; Organism; Play; Protein Family; Proteins; Publishing; RNA; RNA Binding; RNA Processing; RNA Splicing; RNA, Ribosomal, 5S; RNA-Binding Proteins; Regulation; Research; Retrotransposition; Retrotransposon; Ribosomal RNA; Rodent; Role; Small RNA; Synaptic plasticity; Syndrome; System; Translations; Uncertainty; Work; Zebrafish; base; cofactor; gene function; human disease; mouse development; protein function; public health relevance; receptor; relating to nervous system; research study; trafficking

DESCRIPTION (provided by applicant): The NXF family of proteins have emerged as playing important roles in post-transcriptional gene regulation. Most work has focused on NXF1 and we have recently demonstrated that the NXF1 protein regulates the expression of its own gene by binding to a Constitutive Transport Element (CTE). The CTE is present in an alternatively spliced intron and retention of this intron gives rise to a "small" NXF1 protein. This small protein appears to modulate NXF1 function. The current model held by many is that NXF1 functions as the major export receptor for mRNA in organisms from Drosophila to Humans. In this model, NXF1 acts together with an "essential" co-factor, NXT1. Direct RNA binding by NXF1 has been proposed to be the exception, rather than the rule. Thus NXF1 is supposed to interact only indirectly on most mRNAs, binding through RNA-binding protein adaptors, such as Aly/Ref and SR-proteins. However, data from several recent studies, including our own, cast some doubts on this model. The fact that NXF1 interacts directly with a "CTE" RNA element within the NXF1 gene itself demonstrates that NXF1 can interact directly with cellular mRNA. Other data suggests that the major function of adaptor proteins may be to serve in a "hand over" of NXF1 to the RNA, eventually resulting in a "lock-in" on the RNA. We also have preliminary evidence to indicate that NXF proteins also function in the export of certain non-coding RNAs (for example 5S rRNA and BC200 neuronal RNA). The overall goal of this application is to learn more about the interplay between the NXF proteins and their cofactors, and to elucidate how this is used to regulate expression of RNA. The proposal has 4 specific aims: Specific Aim 1: To investigate the regulation of expression and function of small NXF proteins. Specific Aim 2: To determine if CTE function and the small NXF1 protein, are essential for general development and/or brain development. Specific Aim 3: To analyze the function of NXF proteins in trafficking of non-coding small RNA. Specific Aim 4: To analyze the function of the MusD and Alu CTEs and the role of NXF proteins in retrotransposition. PUBLIC HEALTH RELEVANCE: This research will focus on the NXF family of proteins that control the process of RNA export in human cells. These proteins play a major role in the development and functioning of many cells and organs in the human body. Thus, the research has relevance for the diagnosis and treatment of several genetic syndromes, cancer and other human diseases.

描述（由申请人提供）：NXF 蛋白家族已在转录后基因调控中发挥着重要作用。大多数工作都集中在 NXF1 上，我们最近证明 NXF1 蛋白通过与组成型转运元件 (CTE) 结合来调节其自身基因的表达。 CTE 存在于可变剪接的内含子中，保留该内含子会产生“小”NXF1 蛋白。这种小蛋白质似乎可以调节 NXF1 功能。目前许多人持有的模型是，NXF1 在从果蝇到人类的生物体中充当 mRNA 的主要输出受体。在此模型中，NXF1 与“必需”辅助因子 NXT1 一起发挥作用。 NXF1 与 RNA 的直接结合被认为是例外，而不是规则。因此，NXF1 应该仅与大多数 mRNA 间接相互作用，通过 RNA 结合蛋白接头（例如 Aly/Ref 和 SR 蛋白）结合。然而，最近几项研究（包括我们自己的研究）的数据对这一模型提出了一些质疑。 NXF1 直接与 NXF1 基因内的“CTE”RNA 元件相互作用这一事实表明，NXF1 可以直接与细胞 mRNA 相互作用。其他数据表明，衔接蛋白的主要功能可能是将 NXF1“移交给”RNA，最终导致“锁定”RNA。我们还有初步证据表明 NXF 蛋白也在某些非编码 RNA（例如 5S rRNA 和 BC200 神经元 RNA）的输出中发挥作用。该应用的总体目标是更多地了解 NXF 蛋白及其辅助因子之间的相互作用，并阐明如何使用它来调节 RNA 的表达。该提案有 4 个具体目标： 具体目标 1：研究小 NXF 蛋白表达和功能的调控。具体目标 2：确定 CTE 功能和小 NXF1 蛋白是否对于一般发育和/或大脑发育至关重要。具体目标 3：分析 NXF 蛋白在非编码小 RNA 运输中的功能。具体目标 4：分析 MusD 和 Alu CTE 的功能以及 NXF 蛋白在逆转录转座中的作用。公共健康相关性：这项研究将重点关注控制人类细胞 RNA 输出过程的 NXF 蛋白质家族。这些蛋白质在人体许多细胞和器官的发育和功能中发挥着重要作用。因此，该研究与多种遗传综合征、癌症和其他人类疾病的诊断和治疗具有相关性。