Proepithelin is a secreted pluripotent growth factor that plays a significant role in cell proliferation and cell cycle progression in many cellular systems. Proepithelin is highly expressed in several aggressive tumors and it is also promoting cell migration, wound healing and tissue repair. Despite the strong connections with growth control and cancer, proepithelin 's mode of action is not well understood. Furthermore, the proepithelin receptor and/or proteins that mediate the early stages of proepithelin signaling from the plasma membrane have not been identified. The objective of this grant proposal is to elucidate the molecular mechanism(s) by which proepithelin promotes proliferation and migration of bladder cells. The central hypothesis of this application is that proepithelin plays a critical role in cell growth, migration and transformation of bladder cells. Our hypothesis is based on our preliminary findings, which indicates that proepithelin promotes proliferation and migration of bladder cells. We have also identified a novel proepithelin-interacting transmembrane protein that we hypothesized is the proepithelin receptor. We will test our hypothesis and accomplish the objectives of this application through the following specific aims: ?Characterize the mechanism(s) that regulates proepithelin signaling in bladder cells ?Investigate how the proepithelin receptor affects proepithelin signaling in bladder cells ?Investigate the role of proepithelin in human bladder cancer. To address these specific aims this grant application proposes experiments focusing on normal and cancer urothelial cells. We will use small interfering RNA (siRNA), over-expression and dominant negative approaches to investigate the function of proepithelin and the proepithelin receptor in urothelial cells. A combination of assays for proliferation and migration and assays for proepithelin-dependent signal transduction will be employed. The significance of this grant proposal is not only in terms of a better knowledge of proepithelin action in the biology of bladder cells, but in the long range this studies could yield valuable information for translational research. Given the critical role of proepithelin in malignant transformation, it may prove a useful clinical target for prognosis and therapy. Furthermore, the identification of novel proteins and novel mechanism(s) that regulate proepithelin action will help us in designing novel therapeutic agents to target malignant cells in bladder tumors.
