Translational Control by eIF3f in Pancreatic Cancer

eIF3f 在胰腺癌中的翻译控制

• 批准号: 8231276
• 负责人: EUGENE W GERNER
• 金额: $ 7.58万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231276
• 关键词: Alleles; Apoptosis; Binding; Cancerous; Cell Survival; Cells; Complex; Data; Development; Diagnosis; Essential Genes; Foundations; Genes; Genetic; Growth; Heterogeneous-Nuclear Ribonucleoprotein K; Homeostasis; Human; Immunofluorescence Immunologic; Indium; Individual; Knowledge; Malignant Neoplasms; Malignant neoplasm of pancreas; Mammals; Molecular; Molecular Biology; Peptide Initiation Factors; Play; Protein Biosynthesis; RNA Degradation; Regulation; Reporting; Research; Resources; Reverse Transcriptase Polymerase Chain Reaction; Ribosomal RNA; Role; Signal Pathway; Specimen; Technology; Testing; Tissues; Translational Regulation; Translations; base; cell growth; inhibitor/antagonist; neoplastic cell; novel; protein expression; public health relevance; restoration; tumorigenesis

DESCRIPTION (provided by applicant): Misregulated translation is one of the most important factors in cancer development in humans. Thus, a better understanding of translational regulation is essential in deciphering the molecular basis underlying cancer development, as well as providing a foundation for developing new anti- cancer strategies. Translation initiation factor eIF3 plays an important role in translation. However, the functions of its individual subunits have not yet been fully defined in mammals. eIF3f is a subunit of eIF3 complex and is highly conserved among species. We were the first group to report that the expression of eIF3f is significantly decreased in human pancreatic cancer. Increased eIF3f protein expression suppressed tumor cell growth and induced apoptosis, whereas knockdown of eIF3f expression did the opposite. Therefore, eIF3f is a critical element in translational control and it plays an important role in the development of pancreatic cancer. However, the underlying mechanisms by which eIF3f regulates translation are poorly understood. We have demonstrated that eIF3f is a translation inhibitor. Restoration of eIF3f expression in tumor cells induced ribosomal RNA degradation. Therefore, we hypothesize that eIF3f controls translation by regulating rRNA degradation. To test our hypothesis, the following specific aims will be pursued: (1) To characterize the regulation of ribosomal RNA homeostasis by eIF3f. We will test the hypothesis that eIF3f binds to and regulates ribosomal RNA degradation. We will investigate both 28S and 18S rRNA degradation regulated by eIF3f using genetic and molecular biology technologies. (2) To define the interaction between eIF3f and hnRNP K and their role in rRNA degradation. We will test the hypothesis that eIF3f coordinates with hnRNP K to regulate rRNA stability. Our preliminary data showed that hnRNP K binds to and stabilizes rRNAs, and eIF3f directly interacts with hnRNP K. Immunofluorescence, RIP and RT-PCR studies will be used. These two specific aims are supported by our novel preliminary data and can be tested independently using our unique research resources, yet they are highly interrelated and support one another. The knowledge derived from these studies will make a major breakthrough in the understanding of the molecular mechanisms implicated in translational control and the important function of eIF3f in translation. These will serve as a foundation for the further identification of novel molecular signaling pathways and targets for the diagnosis and treatment of pancreatic cancer. PUBLIC HEALTH RELEVANCE: Translational Control by eIF3f in Pancreatic Cancer Project Narrative In this proposal we will investigate the molecular mechanisms by which eIF3f regulates translation. Misregulated translation is one of the most important factors in cancer development in humans. Thus, a better understanding of translational regulation is essential in deciphering the molecular basis underlying pancreatic cancer development, as well as providing a foundation for developing new anti-cancer strategies.

描述（由申请人提供）：翻译失调是人类癌症发展中最重要的因素之一。因此，更好地理解翻译调控对于破译癌症发展的分子基础以及为开发新的抗癌策略提供基础至关重要。翻译起始因子eIF3在翻译中发挥着重要作用。然而，哺乳动物中其各个亚基的功能尚未完全确定。 eIF3f 是 eIF3 复合物的一个亚基，在物种间高度保守。我们是第一个报告 eIF3f 表达在人类胰腺癌中显着降低的研究组。 eIF3f 蛋白表达的增加抑制肿瘤细胞生长并诱导细胞凋亡，而 eIF3f 表达的敲低则起到相反的作用。因此，eIF3f是翻译控制的关键元件，在胰腺癌的发生发展中发挥着重要作用。然而，人们对 eIF3f 调节翻译的基本机制知之甚少。我们已经证明 eIF3f 是一种翻译抑制剂。肿瘤细胞中 eIF3f 表达的恢复诱导核糖体 RNA 降解。因此，我们假设 eIF3f 通过调节 rRNA 降解来控制翻译。为了检验我们的假设，我们将追求以下具体目标：（1）表征eIF3f对核糖体RNA稳态的调节。我们将测试 eIF3f 结合并调节核糖体 RNA 降解的假设。我们将利用遗传和分子生​​物学技术研究 eIF3f 调控的 28S 和 18S rRNA 降解。 (2) 明确eIF3f和hnRNP K之间的相互作用及其在rRNA降解中的作用。我们将检验 eIF3f 与 hnRNP K 协调调节 rRNA 稳定性的假设。我们的初步数据表明，hnRNP K 结合并稳定 rRNA，eIF3f 直接与 hnRNP K 相互作用。将使用免疫荧光、RIP 和 RT-PCR 研究。这两个具体目标得到了我们新颖的初步数据的支持，并且可以使用我们独特的研究资源进行独立测试，但它们高度相关并相互支持。从这些研究中获得的知识将在理解翻译控制所涉及的分子机制以及 eIF3f 在翻译中的重要功能方面取得重大突破。这些将为进一步鉴定用于诊断和治疗胰腺癌的新型分子信号通路和靶点奠定基础。 公共健康相关性：胰腺癌项目叙述中 eIF3f 的翻译控制 在本提案中，我们将研究 eIF3f 调节翻译的分子机制。翻译失调是人类癌症发展的最重要因素之一。因此，更好地理解翻译调控对于破译胰腺癌发展的分子基础以及为开发新的抗癌策略提供基础至关重要。