Function of QKI RNA-binding Protein in CNS Myelination

描述(申请人提供)：不断积累的证据表明 RNA结合蛋白在细胞功能和发育中发挥着重要作用。这个 本应用程序的目标是了解RNA结合的功能 髓鞘形成中的蛋白QKT。髓鞘生成细胞中QKI的表达减弱 导致震颤存活(Qkv)小鼠严重的髓鞘障碍。QKI是以下组织的成员 RNA的信号转导激活物(STAR)，它携带一个单一的 RNA结合域以及几个Src同源3(SH3)结合域 可以与RNA和信号分子相互作用。恒星蛋白，On 信号级联反应中的磷酸化被认为是 调节对细胞RNA的影响。与这种观点一致的是，我们有 发现QKI选择性地与编码髓鞘碱性的mRNA相互作用 蛋白质(MBP)，QK1的酪氨酸磷酸化显著降低了这一点 互动。这种互动的功能重要性得到了我们的 最近的研究发现，MBP的mRNA严重失稳和错位定位于 QKV少突胶质细胞，其中QKI几乎完全消失。这些发现 提示MBP mRNA是QKI在髓鞘形成过程中的功能靶点。 QKI与MBP信使核糖核酸的相互作用对控制正常 MBP基因转录后的命运。此应用程序侧重于 QKI调控细胞代谢的分子机制研究进展 MBP基因的表达。提出了三个具体目标：1)确定是否 MBP信使核糖核酸在qkt细胞质中加速降解。 少突胶质细胞，以及高表达的QKI是否延长半衰期 MBP信使核糖核酸；2)定义与之相互作用所需的MBP信使核糖核酸元件 QKI及其是否介导秋S对基因表达的影响 稳定性；3)检测QKI酪氨酸磷酸化是否调节其 结合和稳定信使核糖核酸的能力。这些问题的答案应该是 显著提高我们对基本管理机制的了解 并提供了关于mRNA代谢如何的特殊见解。 受蛋白质-RNA相互作用控制。这最终可能导致新的 针对髓鞘疾病的治疗策略。此外，了解如何 QKI在髓鞘形成过程中调节其RNA靶标可能阐明共同的 其他恒星在细胞生长和肿瘤形成中的机制。

DESCRIPTION (provided by applicant): Accumulating evidence suggests that RNA-binding proteins play important roles in cell function and development. The goal of this application is to understand the function of the RNA-binding protein QKT in myelination. Diminished QKI expression in myelin-producing cells leads to severe dysmyelination in quakingviable (qkv) mice. QKI is a member of the Signal Transduction Activators of RNA (STARs), which carries a single RNA-binding domain as well as several Src-Homology 3 (SH3)-binding domains thus can interact with both RNA and signaling molecules. STAR proteins, upon phosphorylation in response to signaling cascades, are postulated to exert regulatory influences on cellular RNAs. Consistent with this view, we have found that QKI selectively interacts with the mRNA encoding the myelin basic protein (MBP), and tyrosine phosphorylation of QK1 dramatically reduces this interaction. The functional importance of this interaction is reinforced by our recent finding that MBP mRNA is severely destabilized and mislocalized in the qkv oligodendrocytes in which QKI is almost completely lost. These findings suggest that MBP mRNA is a functional target for QKI in myelination, and the interaction between QKI and the MBP mRNA is critical in controlling the normal posttranscriptional fate of the MBP mRNA. This application focuses on delineating the molecular mechanisms by which QKI regulates the metabolism of the MBP mRNA. Three specific aims are proposed: 1) To determine whether accelerated degradation of MBP mRNA occurs in the cytoplasm of qkt about/qkv oligodendrocytes, and whether elevated QKI expression prolongs the half-life of the MBP mRNA; 2) To define the MBP mRNA element required for interaction with QKI and to determine whether this element mediates QIU' s effect on mRNA stability; 3) To test whether tyrosine-phosphorylation of QKI regulates its ability to bind and to stabilize mRNA. Answers to these questions should significantly advance our knowledge of fundamental mechanisms governing myelination and provide particular insights into how mRNA metabolism is controlled by protein-RNA interaction. This may ultimately lead to new therapeutic strategies against myelin disorders. In addition, understanding how QKI regulates its RNA targets during myelination may elucidate common mechanisms for other STARs in cell growth and tumorigenesis.