| Dysregulation of signaling pathways required for stem cell maintenance are frequently found in cancer. Melanoma, and their stem cell precursors, melanoblasts, are of peculiar interest as they develop from a neural crest lineage, yet are associated with the skin. Therefore, evaluation of proteins and signaling pathways that are frequently dysregulated in melanoma but involved in neurogenesis may provide further understanding to melanomagenesis. Indeed, the Notch signaling pathway is a vital pathway involved in neurogenesis and is a driving component in melanoma progression from early to advanced disease. Additionally, recent research has shown that the Drosophila mitotic protein, dPolo plays a critical role in neuronal cell fate determination through regulating the localization of the dNotch inhibitor, dNumb. Therefore, this thesis work was aimed at exploring changes in the human neurogenesis related proteins (PIk1, Numb and Notch) that may contribute to melanoma development and how these changes may be exploited for the treatment of this disease. The thesis details the expression pattern of PIk1 in melanoma versus normal skin tissues and cells. This also includes an evaluation into the use of PIk1 inhibition to cause melanoma cell death, suggesting it may be a useful target in the management of melanoma. This thesis also investigates the mechanism of PIk1 and Numb regulation in the melanoma cell cycle and shows that Numb is required for proper PIk1 stability and localization. Without Numb expression, PIk1 protein half-life is decreased and PIk1 mislocalizes during mitosis resulting in immature centrosome formation, which could potentially lead to aneuploidy, and possibly cancer. |
