Molecular Mechanisms of eIF4E mediated transformation.

eIF4E 介导转化的分子机制。

• 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
• 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

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。 真核生物翻译起始因子eIF 4 E是细胞生长的关键调节因子， 在几种癌症中升高，包括一些白血病和乳腺癌。eIF4E 细胞中的过表达促进增殖和随后的转化。eif 4 e是 RNA调节子中的一个网络节点，通过协调 参与这些途径的基因表达的上调。eIF 4 E功能 细胞核和细胞质。在细胞质中，它结合7甲基鸟苷（m7 G） 在mRNA的5'端发现的帽，从而允许翻译起始。重要的是，up 至68%的eIF 4 E存在于细胞核中，在那里它促进一个亚群的mRNA输出。 促生长转录物包括细胞周期蛋白D1、A2、B1、mdm 2、c-myc等。 出口活动大大促进了其转型活动。我们确认了一个50 靶mRNA的非翻译区中的核苷酸元件，其赋予对 eIF 4 E（允许优先出口），并将其称为eIF 4 E敏感元件（4 E- SE）。因此，eIF 4 E可以协同上调含有eIF 4 E的基因的表达。 4E-SE。eIF 4 E在白血病的一个亚组中在（至少）三个水平上失调： 当浓度升高时，其亚细胞分布发生改变，在细胞核中积聚 并且改变了结合配偶体对其活性的调节。在这里，我们将研究 这种失调的分子基础。我们将进一步确定这一影响 eIF 4 E功能失调。我们确定了一种提高eIF 4 E水平的新方法， 通过与mRNA稳定性因子相互作用增加eIF 4 E mRNA稳定性 呵呵。与eIF 4 E一样，HuR是一种有效的原癌基因。接下来，我们将研究 细胞用于调节eIF 4 E的定位和功能，以及这是否是 在这些癌症中失调。最后，我们将研究一种新型核武器的影响。 eIF 4 E的合作伙伴。我们提出了三个具体的目标，以调查这些 可能性：1.确定HuR是否调节eIF 4 E的活性2.确定是否 eIF 4 E转运蛋白4 E-T调节eIF 4 E功能及其定位 和3.检查通过eIF 4 E结合蛋白控制核eIF 4 E的新模式 BP1.我们相信，阐明这一监管网络将产生新的见解， eIF 4 E介导的转化。此外，这些发现可以提供新的治疗方法， 针对以eIF 4 E失调为特征的癌症的策略。