Molecular Mechanisms of eIF4E mediated transformation.

抽象的。 真核细胞翻译起始因子eIF4E是细胞生长的关键调节因子，是 在几种癌症中升高，包括一些白血病和乳腺癌。EIF4E 细胞中的过度表达促进了细胞的增殖和随后的转化。EIF4E是 RNA调节子中的一个网络节点通过协调 上调参与这些途径的基因的表达。中的eIF4E函数 胞核和胞浆都有。在细胞质中，它与7甲基鸟苷(M7G)结合。 在mRNAs的5‘端发现帽，从而允许翻译起始。重要的是，向上 到68%的eIF4E存在于细胞核中，在那里它促进了一个子集的mRNA输出 促生长转录本包括细胞周期蛋白D1、A2、B1、MDM2、c-myc等。 出口活动对其转型活动有很大贡献。我们确认了一个50 靶向mRNAs非翻译区的核苷酸元件，使其对 EIF4E(允许优先出口)，并将其称为eIF4E敏感元件(4E- Se)。因此，eIF4E可以协同上调含有 4E-SE。在白血病的一个子集中，eIF4E至少有三个水平失调：eIF4E是 高度升高时，它在细胞核内积累的亚细胞分布会发生变化 而结合伙伴对其活动的调节也发生了变化。在这里，我们将研究 这种失调的分子基础。此外，我们将确定这一点的影响 EIF4E功能失调。我们发现了一种提高eIF4E水平的新方法， 通过与信使核糖核酸稳定因子的相互作用提高eIF4E信使核糖核酸的稳定性 胡尔。与eIF4E一样，HUR也是一种强有力的原癌基因。接下来，我们将研究 细胞用来调节eIF4E的定位和功能，以及这是否 在这些癌症中调节失调。最后，我们将考察一种新型核技术的影响。 EIF4E的合作伙伴的活动。我们提出了三个具体目标来调查这些 可能性：1.确定HUR是否调节eIF4E的活动2.确定是否 EIF4E转运蛋白4E-T调节eIF4E的功能及其定位 以及3.检测eIF4E结合蛋白控制核eIF4E的新模式 BP1。我们相信，对这一监管网络的阐明将为 EIF4E介导的转化。此外，这些发现可能提供新的治疗方法。 以eIF4E异常表达为特征的癌症的治疗策略。

Abstract. The eukaryotic translation initiation factor eIF4E, a key modulator of cellular growth, is elevated in several cancers including some leukemias and breast cancer. eIF4E overexpression in cells promotes proliferation and subsequently transformation. eIF4E is a network node in a RNA regulon promoting 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 growth promoting transcripts including cyclins D1, A2, B1, mdm2, c-myc etc. This mRNA export activity contributes substantially to its transformation activity. We identified a 50 nucleotide element in the untranslated region of target mRNAs which impart sensitivity to eIF4E (allowing preferential export) and refer to this as an eIF4E sensitivity element (4E- SE). Thus, eIF4E can coordinately upregulate expression of genes which contain the 4E-SE. eIF4E is dysregulated at (least) three levels in a subset of leukemias: eIF4E is highly elevated, its subcellular distribution is altered where it accumulates in the nucleus and regulation of its activity by binding partners is altered. Here, we will examine the molecular basis for this dysregulation. Further we will determine the effects of this dysregulation on eIF4E function. We identified a novel means to elevate eIF4E levels, through increased eIF4E mRNA stability via interactions with the mRNA stability factor HuR. Like eIF4E, HuR is a potent proto-oncogene. Next, we will examine the means the cell uses to regulate localization and thus function of eIF4E and whether this is dysregulated in these cancers. Finally, we will examine the impact of a novel nuclear partner of eIF4E on its activities. We propose three specific aims to investigate these possibilities: 1. Establish whether HuR modulates eIF4E's activity 2. Establish whether the eIF4E transporter protein, 4E-T, modulates eIF4E function as well as its localization and 3. Examine novel modes of control of nuclear eIF4E by the eIF4E binding protein BP1. We believe that elucidation of this regulatory network will yield new insights into eIF4E mediated transformation. Further, these findings could provide novel therapeutic strategies for cancers characterized by dysregulated eIF4E.