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）：翻译不正常是人类癌症发展中最重要的因素之一。因此，对翻译调节的更好理解对于破译癌症发展的分子基础以及为制定新的抗癌策略提供基础是必不可少的。翻译起始因子EIF3在翻译中起重要作用。但是，其各个亚基的功能尚未在哺乳动物中完全定义。 EIF3F是EIF3复合物的亚基，在物种之间是高度保守的。我们是第一个报告人类胰腺癌中EIF3F表达显着降低的组。 EIF3F蛋白表达的增加抑制了肿瘤细胞的生长并诱导的凋亡，而EIF3F表达的敲低也相反。因此，EIF3F是翻译控制中的关键要素，它在胰腺癌的发展中起着重要作用。但是，EIF3F调节翻译的基本机制知之甚少。我们已经证明了EIF3F是一种翻译抑制剂。肿瘤细胞中EIF3F表达的恢复诱导的核糖体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，将追求以下特定目标：（1）eIF3F表征核糖体RNA稳态的调节。我们将测试EIF3F与核糖体RNA降解结合并调节的假设。我们将使用遗传和分子生​​物学技术调查由EIF3F调控的28S和18S rRNA降解。 （2）定义EIF3F和HNRNP K之间的相互作用及其在rRNA降解中的作用。我们将测试EIF3F与HNRNP K坐标以调节RRNA稳定性的假设。我们的初步数据表明，HNRNP K与RRNA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。这两个特定的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独立测试，但是它们高度相互关联并相互支持。从这些研究中得出的知识将在理解涉及转化控制的分子机制和EIF3F在翻译中的重要功能方面取得重大突破。这些将成为进一步鉴定新的分子信号通路和胰腺癌诊断和治疗目标的基础。 公共卫生相关性：EIF3F在胰腺癌项目叙事中进行的转化控制，我们将研究EIF3F调节翻译的分子机制。翻译错误是人类癌症发展中最重要的因素之一。因此，对翻译调节的更好理解对于破译胰腺癌发展的分子基础以及为制定新的抗癌策略提供基础是必不可少的。