Oncogenic impact of eIF4E-dependent RNA export in cancer

eIF4E 依赖性 RNA 输出对癌症的致癌影响

• 批准号: 10582921
• 负责人: KATHERINE L B BORDEN
• 金额: $ 25.88万
• 依托单位: UNIVERSITY OF MONTREAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2028-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582921
• 关键词: Actins; Acute Myelocytic Leukemia; Acute monocytic leukemia; Adherence; Antiviral Agents; Binding; Binding Sites; Biochemical; Biological; Bone Marrow; CD44 Antigens; CD44 gene; Cancer Patient; Cell Line; Cell membrane; Cells; Clinic; Complex; Cytoskeleton; DNA; Development; Disease; Disease remission; Encapsulated; Engraftment; Eukaryotic Initiation Factors; Event; Extramedullary; Genetic; Glycosaminoglycans; Head Cancer; Homing; Hyaluronan; Impairment; In Vitro; Invaded; Knowledge; Link; Liver; Malignant Neoplasms; Mechanics; Membrane; Molecular; Monitor; Morphology; Neck Cancer; Neoplasm Metastasis; Newly Diagnosed; Normal Cell; Nuclear Export; Nuclear RNA; Oncogenic; Outcome; Patients; Phase I Clinical Trials; Phosphorylation; Physiological; Process; Production; Proliferating; Property; Prostate; Proteins; RNA; RNA Caps; RNA Processing; Regulon; Ribavirin; Role; Signal Transduction; Site; Solid; Specimen; Spleen; Surveys; Therapeutically Targetable; Tissues; Transcript; Translations; acute myeloid leukemia cell; cancer cell; cell motility; ezrin; in vivo; leukemia; link protein; lymph nodes; migration; mouse model; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; overexpression; pharmacologic; programs; protein function; receptor; response; tumor

Abstract This renewal application investigates the impact of dysregulated RNA processing in cancer. Dysregulation of these events can elevate the production of proteins that function in all facets of malignancy, without altering their transcript levels. The eukaryotic translation initiation factor eIF4E, dysregulated in many cancers including in acute myeloid leukemia (AML), governs the RNA processing of networks of transcripts that ultimately underpin its oncogenic activities. Its ability to govern these regulons has been attributed to its well-established roles in nuclear export and translation of specific RNAs. eIF4E elevation in cancer patients is correlated with aggressive disease and poor outcomes. Here, we discovered that eIF4E reprograms various facets of cell motility including adherence, migration, and invasion through its effects on RNA processing. Indeed, we identified eIF4E-dependent RNA export targets that encode factors which are key modulators of cell motility including hyaluronan, its main receptor CD44 and ezrin. Ezrin is an intracellular protein that links CD44 signalling to cytoskeletal changes that alter adherence, migration, and invasion. Furthermore, eIF4E directly interacts with ezrin. Three aims are proposed to dissect the mechanistic principles and biological impacts related to these novel findings. We will uncover the requirements for eIF4E to drive cell movement, determine the role of the ezrin- eIF4E complex in translation and motility, and examine the role of the HA/CD44/ezrin axis in eIF4E-dependent AML cell motility in mouse models. Our studies provide a unique opportunity to identify novel biochemical mechanisms that underpin aggressive disease associated with dysregulated eIF4E.

摘要 这个更新的应用程序研究了癌症中RNA加工失调的影响。 这些事件的失调可以提高蛋白质的产生，这些蛋白质在细胞的各个方面发挥作用。 恶性肿瘤，而不改变其转录水平。真核生物翻译起始因子 eIF 4 E在包括急性髓细胞白血病（AML）在内的许多癌症中失调， RNA处理最终支持其致癌活性的转录物网络。其 能够控制这些调节子，是因为它在核出口中发挥了重要作用 和特定RNA的翻译。癌症患者中eIF 4 E升高与侵袭性 疾病和不良后果。在这里，我们发现eIF 4 E重新编程细胞的各个方面， 运动，包括粘附，迁移和入侵通过其对RNA加工的影响。 事实上，我们确定了eIF 4 E依赖的RNA输出靶点，这些靶点编码的因子是关键的 细胞运动调节剂，包括透明质酸、其主要受体CD 44和埃兹蛋白。埃兹林是一个 将CD 44信号传导与改变粘附的细胞骨架变化联系起来的细胞内蛋白， 迁徙和入侵此外，eIF 4 E直接与ezrin相互作用。提出了三个目标 剖析与这些新发现相关的机械原理和生物学影响。我们 将揭示eIF 4 E驱动细胞运动的要求，确定ezrin的作用， eIF 4 E复合物在翻译和运动中的作用，并检查HA/CD 44/ezrin轴在 小鼠模型中eIF 4 E依赖性AML细胞运动性。我们的研究提供了一个独特的机会， 确定支持与以下疾病相关的侵袭性疾病的新的生化机制 eIF 4 E失调。