Molecular Mechanisms of eIF4E mediated transformation.

eIF4E 介导转化的分子机制。

• 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
• 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

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(申请人提供)：真核翻译起始因子eIF4E，一种细胞生长的关键调节因子，在包括一些白血病和乳腺癌在内的几种癌症中升高。EIF4E在细胞中过表达可促进细胞增殖和随后的转化。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生存。EIF4E在胞核和胞浆中均有功能。在细胞质中，它与mRNAs 5‘端的7甲基鸟苷(M7G)帽结合，从而允许翻译启动。重要的是，高达68%的eIF4E存在于细胞核中，在那里它促进了一组促生长转录子的mRNA输出，包括细胞周期蛋白D1、A2、B1、MDM2、c-myc等。这种mRNA输出活性对其转化活性有很大贡献。我们在靶mRNAs的非翻译区发现了一个50个核苷酸的元件，它对eIF4E(允许优先出口)具有敏感性，并将其称为eIF4E敏感性元件(4E-SE)。因此，eIF4E可以协同上调含有4E-SE的基因的表达。在一组白血病中，eIF4E至少有三个水平失调：eIF4E高度升高，其在细胞核中聚集的亚细胞分布发生改变，以及结合伙伴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，我们还将确定这种失调对eIF4E功能的影响。我们发现了一种新的方法来提高eIF4E水平，通过与mRNA稳定因子Hur的相互作用来提高eIF4E mRNA的稳定性。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定位和功能的方法，以及这是否在这些癌症中调节失调。最后，我们将研究eIF4E的一个新的核伙伴对其活动的影响。我们提出了三个特定的目标来研究这些可能性：1.确定Hur是否调控eIF4E的活性；2.确定eIF4E转运蛋白4E-T是否调控eIF4E的功能及其定位；3.研究eIF4E结合蛋白BP1控制核eIF4E的新模式。我们相信，对这个调控网络的阐明将对eIF4E介导的转化产生新的见解。此外，这些发现可能为以eIF4E基因异常为特征的癌症提供新的治疗策略。公共卫生相关性：真核翻译启动因子eIF4E在许多人类癌症中表达失调，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。