Degree Granting Department
Pathology and Cell Biology
Jin Q. Cheng, Ph.D.
Santo V. Nicosia, M.D.
Domenico Coppola, M.D.
Patricia A. Kruk, Ph.D.
Jie Wu, Ph.D.
E2F3, CHFR, CNTD2, Centrosome, Cell cycle, cancer
Aurora-A is a mitotic kinase, which regulates cell cycle progression through modulating centrosome function. Aurora-A expression is frequently altered in human malignancies. The discrepancy between overexpression and amplification suggests that elevated Aurora-A level is likely to be regulated also by transcriptional and/or translational modifications. In this study, we have demonstrated: 1) transcriptional regulation of Aurora-A by E2F3; 2) feedback regulation between tumor suppressor CHFR and Aurora-A; 3) CNTD2 as a novel Aurora-A partner and oncogene to activate Aurora-A and induce transformation.
Aurora-A expression and activity are cell cycle regulated. The mechanism of Aurora-A upregulation at onset of mitosis is largely unknown. We demonstrated, for the first time, that transcription factor E2F3 directly binds to Aurora-A promoter and tightly regulates Aurora-A expression during G2/M phase. Moreover, expression of E2F3 considerably correlates with Aurora-A level in human ovarian cancer, indicates that E2F3 is a causal factor for Aurora-A overexpression. Thus, E2F3-Aurora-A axis could be an important target for cancer intervention. The frequent inactivation of prophase checkpoint CHFR caused by DNA methylation or mutation has been reported in human cancers. We showed that CHFR is hypermethylated in ovarian carcinoma. Aurora-A phosphorylates CHFR on Ser-218 and Ser-337 in vivo and in vitro, which inhibits CHFR ubiquitin ligase activity. The feedback regulation loop between Aurora-A and CHFR could play a critical role in regulation of cell cycle progression, imbalance of which may contribute to human oncogenesis. Using yeast 2-hybrid screening, we identified a splicing form of CNTD2 as Aurora-A interacting protein. CNTD2 locates to chromosome 19q13.2 AKT2 amplicon. CNTD2 is amplified and overexpressed in human ovarian, pancreatic and lung cancer cell lines and primary tumors. CNTD2 colocalizes and interacts with Aurora-A in the centrosome. CNTD2 expression induces Aurora-A and cdc2 kinase activity, G2/M progression, and malignant transformation. These data indicate that CNTD2 is an oncogene and could play a pivotal role in Aurora-A activation during the cell cycle and that disruption of CNTD2-Aurora-A axis may represent a potential means to antitumor drug discovery.
Scholar Commons Citation
He, Lili, "Molecular Mechanism of Aurora-A Kinase in Human Oncogenesis" (2008). Graduate Theses and Dissertations.