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重要作用。大多数工作都集中在NXF 1和我们最近证明，NXF 1蛋白质调节其自身基因的表达，通过结合到一个组成型转运元件（CTE）。CTE存在于选择性剪接的内含子中，保留该内含子产生“小”NXF 1蛋白。这种小蛋白似乎调节NXF 1功能。目前许多人认为NXF 1是从果蝇到人类的生物体中mRNA的主要输出受体。在这个模型中，NXF 1与一个“必需的”辅因子NXT 1一起起作用。NXF 1与RNA的直接结合被认为是例外，而不是规则。因此，NXF 1被认为仅间接地与大多数mRNA相互作用，通过RNA结合蛋白衔接子（如Aly/Ref和SR蛋白）结合。然而，最近的几项研究（包括我们自己的研究）的数据对这个模型提出了一些质疑。NXF 1直接与NXF 1基因本身内的“CTE”RNA元件相互作用的事实表明，NXF 1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NXF 1“移交”给RNA，最终导致RNA上的“锁定”。我们也有初步的证据表明，NXF蛋白也在某些非编码RNA（例如5S rRNA和BC 200神经元RNA）的输出中起作用。本申请的总体目标是更多地了解NXF蛋白及其辅因子之间的相互作用，并阐明其如何用于调节RNA的表达。该提案有4个具体目标：具体目标1：研究小NXF蛋白的表达和功能的调节。具体目标2：确定CTE功能和小NXF 1蛋白是否对一般发育和/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。具体目的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。公共卫生相关性：这项研究将集中在控制人类细胞中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起着重要作用。因此，该研究与几种遗传综合征、癌症和其他人类疾病的诊断和治疗有关。

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.