Loss of the tumor suppressor protein APC is the main cause of colorectal cancer. APC has a well-known role in regulating the transcription factor beta-catenin. However, other functions of APC, independent of beta-catenin, also contribute to tumorigenesis. These functions are likely linked to a subpopulation of APC found in clusters at the distal tips of microtubules both in interphase protrusions and on the mitotic spindle. I recently discovered that APC clusters at protrusions have an unanticipated role in localizing there a large group of RNAs. During my proposed research, I will determine whether this novel APC role also occurs on the mitotic spindle. I will identify RNAs associated with APC during mitosis and determine how APC-RNA interactions are regulated during the cell-cycle. I will additionally devise a new FRET-based assay to image RNA translation in vivo, in order to determine whether the function of these localized RNAs is related to their translation or whether they have other structural roles. I will further address how oncogenic APC mutations affect RNA localization and I will dissect the molecular composition of the APC-RNA complexes in order to specifically disrupt their localization and determine their contribution to tumorigenesis induced upon APC mutation. To successfully carry out these studies, during the mentored phase, I will be trained in FRET methodology and have access to state-of-the-art imaging facilities to develop the FRET-based translation reporter. I will also undertake training in cancer biology through courses and workshops. This training will allow me to expand my expertise with the goal of setting up an independent research group that will study the involvement of RNA localization in cancer, ranging from basic molecular mechanisms to functional analyses in animal models. The stimulating research environment and the available facilities at UVa provide an optimal place for the proposed training. Specifically, Dr. Macara's lab has significant expertise in studying cell polarity mechanisms and their relation to cancer progression in various model systems and is, therefore, uniquely suited to assist me in achieving my goals.
Colorectal cancer is the second leading cause of death among cancer patients and is caused by loss of the tumor suppressor protein APC. Despite its importance, however, the molecular functions of APC are not fully understood. This work will explore a novel APC role and its connection to tumor progression, and could thus provide valuable information towards prevention or treatment of colorectal cancers.
| Yasuda, Kyota; Zhang, Huaye; Loiselle, David et al. (2013) The RNA-binding protein Fus directs translation of localized mRNAs in APC-RNP granules. J Cell Biol 203:737-46 |
