Dissecting eIF4E dependent mRNA export

描述（由申请人提供）：真核翻译起始因子eIF 4 E在约30%的癌症中升高。eIF 4 E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。eIF 4 E在细胞核和细胞质中均起作用。在细胞质中，它结合在mRNA的5'端上发现的7-甲基鸟苷（m7 G）帽，从而允许翻译起始。重要的是，高达68%的eIF 4 E存在于细胞核中，在那里它促进编码参与存活和增殖的蛋白质的转录物子集的mRNA输出。这种mRNA输出活性实质上有助于其致癌性。eIF 4 E必须结合m7 G帽以在翻译、输出和转化中起作用。我们发现，通过引入m7 G帽的物理模拟物利巴韦林来抑制eIF 4 E功能，导致抑制eIF 4 E的存活和增殖活性，并且与白血病患者的临床益处相关。虽然eIF 4 E在翻译中的作用已经被很好地理解，但它在mRNA输出中的分子作用还没有。我们的研究表明，eIF 4 E依赖的mRNA输出不同于大量mRNA输出，是CRM 1依赖的。我们将研究eIF 4 E依赖性mRNA输出使用CRM 1输出机制的程度。此外，我们在靶mRNA的非翻译区中鉴定了一个50个核苷酸的元件，称为eIF 4 E敏感性元件（4 E-SE）。4 E-SE赋予eIF 4 E敏感性（允许优先出口）。在随后的研究中，我们确定了一个因子，富含亮氨酸的五肽重复蛋白LRP，它直接结合4 E-SE元件。我们将研究LRP在这一出口过程中所扮演的角色。最后，我们将研究对eIF 4 E活性的一种新的合作伙伴，侵袭蛋白IIp 45的抑制剂的影响。IIp 45似乎以一种新的方式损害eIF 4 E功能。我们提出了三个具体的目标来研究这些可能性：1。确定eIF 4 E依赖性mRNA输出的分子机制。定义LRP在此途径中发挥的作用，3。检查IIp 45蛋白控制eIF 4 E的新模式。我们相信，阐明eIF 4 E依赖的mRNA输出的分子基础将产生新的见解eIF 4 E介导的转化机制。此外，这些发现可以为以eIF 4 E失调为特征的癌症的新治疗策略提供基础。 公共卫生相关性：真核翻译起始因子eIF 4 E在许多人类癌症中失调，包括乳腺癌、头颈癌、结肠癌、前列腺癌和血癌。我们的项目旨在了解这种失调的机制和治疗意义。

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. PUBLIC HEALTH RELEVANCE: The eukaryotic translation initiation factor eIF4E is dysregulated in many human cancers including cancers of the breast, head & neck, colon, prostate and blood. Our project is designed to understand the mechanisms and therapeutic implications of this dysregulation.