Role of Phosphorylation in the Regulation of p27 Function in Breast Cancer

摘要

Breast Cancer is a tragic disease that affects an increasing number of North American women each year. Although much is known about the disease, it appears this knowledge merely touches the surface of the mechanisms which underlie disease progression, often leading to patient death. Loss of the cell cycle inhibitor p27 in Breast Cancer Cells is known to be associated with advanced stage disease progression and poor patient prognosis. However, the mechanisms regulating the loss of p27 are only beginning to be understood. This proposal addresses the role of p27 phosphorylation on regulating p27 degradation. We find that the mitogen activated protein kinase (MAPK) pathway can lead to accelerated p27 degradation and a reduced protein half-life. Furthermore, MAPK activation alters p27 phosphorylation and increases p27 nuclear export. Opposite effects on p27 are observed when the MAPK pathway is inhibited by the drug U0l26. This indicates the importance of this pathway in mediating p27 loss. Further work is being conducted to precisely determine the sites on p27 which are phosphorylated by MAPK which will lead to a better understanding of the potential mechanisms mediating p27 loss in Breast Cancer. The hope is that these results will lead to new therapeutic drug discovery.