Mechanistic and Functional Dissection of mTOR-Mediated Translational Control in Prostate Cancer
Abstract
My long-term career goal is to become an outstanding independent prostate cancer investigator with my own research group at a respected academic institute. This fellowship will provide me the technical training, conceptual knowledge, and salary support during my postdoctoral training at the University of California, San Francisco Helen Diller Cancer Center. Importantly, the research outlined in this proposal will greatly help us understand how key oncogenic signaling pathways specifically regulate protein synthesis and contribute to prostate cancer development and progression. The proposed work will not only help me to generate the preliminary data necessary to apply for future grants, but will also lay the foundation for my independent research career in the field of translational control and prostate cancer, in which I will specifically focus on the development of novel therapeutics and overcoming drug resistance. The role of mutations at the genomic level in cancer has been well described, but very little is known about how modifications during protein synthesis promote cancer. In order to further understand the implications of changes during critical cellular processes such as protein synthesis, we chose to focus on the mTOR pathway, as it is deregulated in nearly 100% of advanced human prostate cancer cases and has been linked to tumor formation and resistance to drug therapy in prostate cancer. The major function of the mTOR kinase is to regulate the process of protein synthesis. Strikingly, recent work from our lab suggests that mTOR may specifically regulate the translation of distinct sets of mRNAs that contribute to prostate cancer initiation, motility, and invasiveness. However, two outstanding questions remain to be answered. First, how does mTOR control the specificity of translation? Second, how do translational targets downstream mTOR contribute to prostate cancer development? In this proposal, I will answer these two questions by mechanistically (Aim 1) and functionally (Aim 2) dissecting mTOR-mediated translational control in prostate cancer. By analyzing the sequence of the five prime untranslated regions of mTOR-sensitive mRNAs, we found that there is a "code" in the mRNA sequence that can impart translational sensitivity to critical mTOR translational targets. The majority of mTOR translationally sensitive mRNAs contain an element (distinct sequence) termed the Pyrimidine Rich Translational Element (PRTE). In Aim 1, I will define the mechanism by which this PRTE guides the translational specificity of these mRNAs downstream mTOR. My preliminary data also suggest that the PRTE recruits other factors to control the translational specificity. Therefore, I will use an unbiased proteomics assay to identify all the PRTE-binding proteins. I will further functionally validate the PRTE-binding proteins by studying their roles in prostate cancer development. Using a new technology called ribosome profiling, we previously identified a translationally controlled four-gene pro-invasion signature (YB1, MTA1, CD44, and vimentin) that directs prostate cancer invasion and metastasis downstream of oncogenic mTOR signaling. Other studies have suggested that these invasive genes also have multiple other functions, including promoting cell proliferation and cell survival, in which case these genes may also play roles in cellular transformation and tumor formation. In Aim 2, I will use in vitro assays and a novel mouse model that simultaneously expresses all four genes in mouse prostate epithelial cells to determine whether these four genes, collectively, are sufficient to drive prostate cancer tumorigenesis and metastasis. Upon completion of this proposal, I will have delineated the mechanism underlying the ability of a novel RNA cis-element (PRTE) to direct a specialized mTOR translational program that drives prostate cancer, as well as identify translational regulators, which could be potential biom
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510398
Entities
People
- Xiaming Pang
Organizations
- United States Army
- University of California, San Francisco