NXF Proteins, Cofactors and Targets

描述(由申请人提供)：NXF蛋白家族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，我们最近证明了Nxf1蛋白通过与一个结构性运输元件(CTE)结合来调节自己基因的表达。CTE存在于一个选择性剪接的内含子中，该内含子的保留导致了一个“小”的Nxf1蛋白。这种小蛋白似乎能调节Nxf1的功能。目前许多人持有的模型是，在从果蝇到人类的有机体中，Nxf1是mRNA的主要出口受体。在这个模型中，Nxf1和一个“必要的”辅助因子Nxt1一起起作用。Nxf1直接与RNA结合被认为是例外，而不是规则。因此，Nxf1被认为只与大多数mRNAs间接相互作用，通过RNA结合蛋白适配器结合，如Aly/Ref和SR-蛋白。然而，最近几项研究的数据，包括我们自己的，对这一模型提出了一些质疑。Nxf1与Nxf1基因中的“CTE”RNA元件直接相互作用的事实表明，Nxf1可以直接与细胞mRNA相互作用。其他数据表明，接头蛋白的主要功能可能是将Nxf1“移交”给RNA，最终导致对RNA的“锁定”。我们也有初步证据表明，NXF蛋白也在某些非编码RNA的输出中发挥作用(例如5S rRNA和BC200神经元RNA)。这项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，并阐明这是如何被用来调节RNA的表达的。该提案有4个特定目标：特定目标1：研究小NXF蛋白的表达和功能调节。具体目标2：确定CTE功能和小的Nxf1蛋白是否对一般发育和/或脑发育是必需的。具体目的3：分析NXF蛋白在非编码小RNA运输中的作用。具体目的4：分析MU.S.和Alu CTE的功能以及NXF蛋白在逆转录转座中的作用。公共卫生相关性：这项研究将重点放在控制人类细胞中RNA输出过程的NXF家族蛋白质上。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，这项研究对几种遗传综合征、癌症和其他人类疾病的诊断和治疗具有重要意义。

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.