Role of Deregulated Cyclin E Proteolysis in Breast Cancer Development

摘要

In breast cancer, the regulatory mechanisms that operate to control proper progression of the cell through each cell cycle are perturberd, leading to uncontrolled cell division. A key regulator of cell cycle passage is the G1 cyclin, cyclin E, which regulates the transition from G1 phase into S phase where replication of the DNA occurs. Cyclin E is synthesized and associates periodically with its catalytic subunit, the cyclin-dependent kinase CDK2, followed by its rapid destruction in early S phase. Abnormal accumulation of cyclin E is frequently observed in breast cancer. The levels of cyclin S correlate with the advanced stage and grade of the tumor and with a poor prognosis for breast cancer patients. Previous work has suggested that defects in the proteolytic destruction of cyclin E may account for its accumulation in these tumors. In the first year of this study, we have shown that the turnover of cyclin S is controlled by the ubiquitin-dependent SCF pathway. We have also isolated a novel human F-box protein, designated hCdc4, that specifically directs ubiquitination of cyclin E in a phosphorylation-dependent manner. In the second year of this proposal, we have extended the characterization of this newly identified pathway and we have addressed the question whether mutations to components of the pathway might account for accumulation of cyclin E in tumor cells.