Translational Control by eIF3f in Pancreatic Cancer

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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.