Molecular Mechanisms of eIF4E mediated transformation.

eIF4E 介导转化的分子机制。

基本信息

批准号：
8465821
负责人：
KATHERINE L B BORDEN
金额：
$ 20.21万
依托单位：
UNIVERSITY OF MONTREAL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8465821
关键词：
Animal Model Binding Binding Proteins Biochemical Blood Cancer cell line Carrier Proteins Cell Cycle Progression Cell Nucleus Cells Colon Cultured Tumor Cells Cyclin D1 Cytoplasm Elements Eukaryotic Initiation Factors Gene Expression Gene Order Gene Targeting Growth Guanosine Head and neck structure Human Indium Lead Link Malignant Neoplasms Mediating Messenger RNA Molecular Mus Nuclear Nuclear Export Nucleotides Oncogenic Pathway interactions Positioning Attribute Process Prostate Proteins Proto-Oncogenes RNA Regulation Regulon Relative (related person)Specimen Therapeutic Transcript Translation Initiation Translations Untranslated Regions Up-Regulation abstracting arm base c-myc Genes cell growth combinatorial design insight leukemia mRNA Export mRNA Stability malignant breast neoplasm novel novel therapeutics overexpression

项目摘要

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.

抽象的。真核翻译起始因子 eIF4E 是细胞生长的关键调节剂，在包括某些白血病和乳腺癌在内的多种癌症中升高。 eIF4E 细胞中的过度表达促进增殖和随后的转化。 eIF4E 是 RNA 调节子中的一个网络节点，通过协调促进增殖和生存上调参与这些途径的基因的表达。 eIF4E 的功能细胞核和细胞质。在细胞质中，它结合 7 甲基鸟苷 (m7G) mRNA 5'端有帽，从而允许翻译起始。重要的是，向上 68% 的 eIF4E 存在于细胞核中，它促进一部分基因的 mRNA 输出促生长转录本包括cyclins D1、A2、B1、mdm2、c-myc等。该mRNA 出口活动对其转型活动做出了重大贡献。我们确定了 50 目标 mRNA 非翻译区的核苷酸元件赋予对 eIF4E（允许优先导出）并将其称为 eIF4E 敏感元素（4E- 东南）。因此，eIF4E 可以协调上调包含以下基因的表达： 4E-SE。在白血病的一个子集中，eIF4E 在（至少）三个水平上失调：eIF4E 高度升高，其在细胞核中积累的亚细胞分布发生改变结合伙伴对其活动的监管也发生了变化。在这里，我们将检查这种失调的分子基础。进一步我们将确定这的影响 eIF4E 功能失调。我们找到了一种提高 eIF4E 水平的新方法，通过与 mRNA 稳定因子相互作用增加 eIF4E mRNA 稳定性胡尔。与 eIF4E 一样，HuR 是一种有效的原癌基因。接下来，我们将检查该方法细胞用来调节 eIF4E 的定位和功能，以及这是否是这些癌症中失调。最后，我们将研究新型核能的影响 eIF4E 活动的合作伙伴。我们提出三个具体目标来调查这些问题可能性： 1. 确定 HuR 是否调节 eIF4E 的活性 2. 确定是否 eIF4E 转运蛋白 4E-T 调节 eIF4E 功能及其定位 3. 检查 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我们带来新的见解 eIF4E 介导的转化。此外，这些发现可以提供新的治疗方法针对以 eIF4E 失调为特征的癌症的策略。