Linking PRP4K Cytoplasmic Functions to Tumour Suppression
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Breast cancer is one of the most common cancers faced by Canadian women today. These carcinomas arise from epithelial cells in mammary tissue, and therefore processes and signaling pathways that regulate tissue homeostasis are important in tumour suppression, including: Hippo-YAP signaling that plays a role in epithelial-to-mesenchymal (EMT) transition; epidermal growth factor receptor (EGFR) signaling; and programmed cell death triggered by cell detachment, a process known as anoikis. In addition, induction of EMT is associated in some cancers with autophagy, or “self-eating”, by which organelles and macromolecules are recycled to overcome cellular stress from nutrient and oxygen deprivation. Autophagy is also known to affect cancer cell migration and invasiveness, which are the hallmarks of EMT. PRP4K is a multifunctional protein that is implicated in several cellular processes that play a role in tumour suppression, including pre-mRNA splicing and transcriptional regulation, epidermal growth factor signaling and sensitivity to both anoikis and taxane-based chemotherapy, and more recently loss of PRP4K has been shown to promote YAP signaling. However, how induction of EMT affects PRP4K expression and a possible role for PRP4K in stress-induced autophagy remained to be studied. This thesis focuses on examining the relationship between PRP4K and EMT, as well as PRP4K’s role in the cell's response to cellular stress that induces autophagy. Using MDA-MB-231, HMLE and MCF10A cell lines, I demonstrated that loss of PRP4K causes a state of partial EMT, which is associated with cells traits that provide cancers with several advantages including collective cell migration and resistance to anoikis. Additionally, I demonstrated that PRP4K responds to stress by shuttling from the nucleus to the cytoplasm following both nutrient deprivation and oxidative cell stress, as well as inhibition or activation of autophagy using chloroquine and rapamycin (respectively). When PRP4K translocates to the cytoplasm, it does so in a CRM1-dependent manner and colocalizes with markers of autophagy, oxidative stress, and endosomal trafficking. Taken together, this thesis demonstrates a novel potential role of PRP4K in the cellular stress response.