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（由申请人提供）：在包括某些白血病和乳腺癌在内的几种癌症中，真核翻译起始因子EIF4E是细胞生长的关键调节剂EIF4E。 EIF4E细胞中的过表达促进了增殖和随后转化。 EIF4E是RNA调节子中的网络节点，该节点通过协调这些途径的基因表达的上调促进增殖和存活。 EIF4E在核和细胞质中均起作用。在细胞质中，它结合了在mRNA的5'末端发现的7甲基鸟嘌呤（M7G）盖，从而允许翻译起始。重要的是，在核中发现了多达68％的EIF4E，在该细胞核中，它促进了一个促进细胞周期蛋白D1，A2，B1，MDM2，C-MYC等生长的子集的mRNA导出。这种mRNA输出活性对其转化活性做出了重大贡献。我们在目标mRNA的未翻译区域中鉴定了一个50个核苷酸元件，该核苷酸元件对EIF4E（允许优先导出）赋予了敏感性，并将其称为EIF4E敏感性元素（4E-SE）。因此，EIF4E可以协同上调包含4E-SE的基因的表达。在白血病的一部分中，EIF4E在（至少）三个水平上失调：EIF4E高度升高，其亚细胞分布在其在细胞核中积聚并通过结合伙伴的调节而改变了其亚细胞分布。在这里，我们将检查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。我们通过与mRNA稳定性因子HUR的相互作用来确定了一种新颖的方法来提高EIF4E水平，从而提高了EIF4E mRNA稳定性。像EIF4E一样，Hur是一种有效的原型癌基因。接下来，我们将研究单元格在调节本地化以及eIF4E的功能以及在这些癌症中是否失调的手段。最后，我们将研究EIF4E新型核合作伙伴对其活动的影响。我们提出了三个具体目的来研究这些可能性：1。确定HUR是否调节EIF4E的活性2。确定EIF4E转运蛋白4E-T是否可以调节EIF4E功能以及其本地化和3。检查EIF4E结合蛋白BP1的新型核EIF4E控制模式。我们认为，阐明这种监管网络将产生对EIF4E介导的转换的新见解。此外，这些发现可以为以EIF4E失调为特征的癌症提供新颖的治疗策略。公共卫生相关性：在许多人类癌症中，包括乳腺癌，头颈，结肠，前列腺和血液在内的许多人类癌症中，真核翻译起始因子EIF4E失调。我们的项目旨在了解这种失调的机制和治疗意义。