Molecular Mechanisms of eIF4E mediated transformation.

eIF4E 介导转化的分子机制。

基本信息

批准号：
7890484
负责人：
KATHERINE L B BORDEN
金额：
$ 22.16万
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 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7890484
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 arm base c-myc Genes cell growth combinatorial design insight leukemia mRNA Export mRNA Stability malignant breast neoplasm novel novel therapeutics overexpression public health relevance

项目摘要

DESCRIPTION (provided by applicant): 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. 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.

描述（由申请人提供）：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表达升高。 eIF4E 在细胞中过度表达可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发挥作用。在细胞质中，它结合 mRNA 5' 端的 7 甲基鸟苷 (m7G) 帽，从而允许翻译起始。重要的是，高达 68% 的 eIF4E 存在于细胞核中，它促进生长促进转录物子集的 mRNA 输出，包括细胞周期蛋白 D1、A2、B1、mdm2、c-myc 等。这种 mRNA 输出活性对其转化有重大贡献活动。我们在目标 mRNA 的非翻译区域中鉴定了一个 50 个核苷酸元件，该元件赋予 eIF4E 敏感性（允许优先输出），并将其称为 eIF4E 敏感性元件 (4E-SE)。因此，eIF4E 可以协调上调含有 4E-SE 的基因的表达。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，并且结合配偶体对其活性的调节发生改变。在这里，我们将研究这种失调的分子基础。此外，我们将确定这种失调对 eIF4E 功能的影响。我们发现了一种提高 eIF4E 水平的新方法，即通过与 mRNA 稳定因子 HuR 的相互作用来增加 eIF4E mRNA 的稳定性。与 eIF4E 一样，HuR 是一种有效的原癌基因。接下来，我们将检查细胞用于调节 eIF4E 定位和功能的方法，以及其在这些癌症中是否失调。最后，我们将研究 eIF4E 的新型核合作伙伴对其活动的影响。我们提出了三个具体目标来研究这些可能性： 1. 确定 HuR 是否调节 eIF4E 的活性 2. 确定 eIF4E 转运蛋白 4E-T 是否调节 eIF4E 功能及其定位 3. 检查核 eIF4E 控制的新模式通过 eIF4E 结合蛋白 BP1。我们相信，阐明这一调控网络将为 eIF4E 介导的转化带来新的见解。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。公共健康相关性：真核翻译起始因子 eIF4E 在许多人类癌症中失调，包括乳腺癌、头颈癌、结肠癌、前列腺癌和血液癌。我们的项目旨在了解这种失调的机制和治疗意义。