Chfr is a newly identified early mitotic checkpoint protein that regulates entry into metaphase. Chfr is either mutated or more frequently down-regulated in human cancers. These observations suggest that Chfr may be associated with cancer development. To explore the potential role of Chfr in tumorigenesis, we have recently generated Chfr knockout mice. Our preliminary studies have demonstrate that 1) Chfr deficiency leads to increased tumor incidence, 2) Chfr is required for ubiquitination and degradation of a key mitotic kinase Aurora-A. Thus, we hypothesize that Chfr is a tumor suppressor and it elicits its tumor suppression function through its ability to regulate Aurora-A. In this study, we aim to establish a link between Chfr downregulation and Aurora-A overexpression in the development of human cancer. We will also determine whether Aurora is the key downstream effector of Chfr in tumorigenesis. Finally, we aim to delineate the regulation of Chfr in mitosis by focusing on the identification of Chfr-associated proteins. The knowledge gained here will allow us to better understand how dysregulation of Chfr is associated with tumorigenesis and will shed light on the mechanism by which chromosomal instability could contribute to tumorigenesis in humans.
