Dissecting eIF4E dependent mRNA export

描述（由申请人提供）：真核翻译起始因子eIF4E在约30%的癌症中升高。eIF4E通过协调上调参与这些途径的基因的表达来促进增殖和存活。eIF4E在细胞核和细胞质中都起作用。在细胞质中，它与mrna 5'端发现的7-甲基鸟苷（m7G）帽结合，从而允许翻译起始。重要的是，高达68%的eIF4E存在于细胞核中，在细胞核中，eIF4E促进mRNA输出编码存活和增殖相关蛋白质的转录本子集。这种mRNA输出活性在很大程度上促进了其致癌性。eIF4E必须绑定m7G上限，以便在翻译、导出和转换中起作用。我们发现，通过引入m7G帽的物理模拟物利巴韦林抑制eIF4E功能，可抑制eIF4E的存活和增殖活性，并与白血病患者的临床获益相关。虽然eIF4E在翻译中的作用已经被很好地理解，但其在mRNA输出中的分子作用尚不清楚。我们的研究表明，依赖eIF4E的mRNA输出不同于散装mRNA输出，依赖于CRM1。我们将研究eIF4E依赖性mRNA输出使用CRM1输出机制的程度。此外，我们在靶mrna的非翻译区鉴定了一个50个核苷酸的元件，称为eIF4E敏感元件（4E-SE）。4E-SE赋予eIF4E敏感性（允许优惠出口）。在随后的研究中，我们发现了一个因子，即富含亮氨酸的五肽重复蛋白LRP，它直接结合4E-SE元素。我们将研究LRP在这一出口过程中所起的作用。最后，我们将研究入侵蛋白IIp45抑制剂对eIF4E活性的影响。IIp45似乎以一种新的方式损害eIF4E的功能。我们提出三个具体目标来研究这些可能性：确定eIF4E依赖性mRNA输出的分子机制；2 .确定LRP在这一途径中所起的作用。研究IIp45蛋白控制eIF4E的新模式。我们相信，阐明eIF4E依赖性mRNA输出的分子基础将对eIF4E介导的转化机制产生新的见解。此外，这些发现可以为以eIF4E失调为特征的癌症提供新的治疗策略的基础。

DESCRIPTION (provided by applicant): The eukaryotic translation initiation factor eIF4E is elevated in about 30% of cancers. eIF4E promotes proliferation and survival by the coordinated upregulation of the expression of genes involved in these pathways. eIF4E functions in both the nucleus and cytoplasm. In the cytoplasm, it binds the 7-methyl guanosine (m7G) cap found on the 5' end of mRNAs thereby allowing translation initiation. Importantly, up to 68% of eIF4E is found in the nucleus, where it promotes mRNA export of a subset of transcripts coding for proteins involved in survival and proliferation. This mRNA export activity contributes substantially to its oncogenicity. eIF4E must bind the m7G cap to act in translation, export and transformation. We found that inhibition of eIF4E function by introduction of a physical mimic of the m7G cap, ribavirin, leads to inhibition of eIF4E's survival and proliferative activities, and is associated with clinical benefit in leukemia patients. Although eIF4E's role in translation is well understood, its molecular role in mRNA export is not. Our studies revealed that eIF4E dependent mRNA export is distinct from bulk mRNA export, being CRM1 dependent. We will examine the extent to which eIF4E dependent mRNA export uses the CRM1 export machinery. Further, we identified a 50-nucleotide element in the untranslated region of target mRNAs referred to as an eIF4E sensitivity element (4E-SE). The 4E-SE imparts sensitivity to eIF4E (allowing preferential export). In subsequent studies we identified a factor, the leucine-rich pentatricopeptide repeat protein LRP, which directly binds the 4E-SE element. We will examine the role LRP plays in this export process. Finally, we will examine the impact on eIF4E activity of a novel partner, the inhibitor of invasion protein IIp45. IIp45 appears to impair eIF4E function in a new manner. We propose three specific aims to investigate these possibilities: 1. Determine the molecular mechanism of eIF4E dependent mRNA export, 2. Define the role that LRP plays in this pathway and 3. Examine novel modes of control of eIF4E by the IIp45 protein. We believe that elucidation of the molecular underpinnings of eIF4E dependent mRNA export will yield new insights into the mechanics of eIF4E-mediated transformation. Further, these findings could provide the basis for novel therapeutic strategies for cancers characterized by dysregulated eIF4E.