Chromosomal instability is a common feature of human cancers. Chromosomal instability allows the accumulation of multiple genetic alterations that ultimately leads to the development of cancer. Increasing evidence in the last decade suggest that mitotic checkpoint controls are essential for the maintenance of chromosomal stability. Chfr (checkpoint with FHA and ring finger domains) is a newly identified checkpoint protein involved in mitotic transitions. Studies of human primary tumors and tumor cell lines suggest that Chfr downregulation is associated with human cancer development. However, it remains to be determined whether Chfr downregulation directly contributes to tumorigenesis. We recently generated Chfr knockout mice. Using these mice, we have demonstrated that Chfr-deficient mice have an increased incidence of spontaneous and carcinogen-induced tumors, suggesting that loss or downregulation of Chfr expression contributes to tumorigenesis. Here, we propose to study mechanistically how Chfr controls mitotic progression and suppress tumor formation. Chfr contains a RING domain and has E3 ubiquitin ligase activity in vitro. We have shown that one of the physiological substrates of Chfr is a key mitotic kinase Aurora-A.
In Specific Aim 1, we will determine the structure of Chfr/Aurora A complex and study at molecular level how Chfr interacts with and regulates Aurora A.
In Specific Aim 2, we will explore whether Aurora A overexpression and/or p53 mutation are critical for tumor development in the absence of Chfr. These studies will reveal the mechanisms by which Chfr deficiency promotes tumorigenesis. We and others have shown that Chfr is frequently downregulated in colorectal cancers, suggesting that Chfr deficiency may contribute to colorectal cancer development in humans. This possibility will be explored in Specific Aim 3. In conclusion, studies outlined here will elucidate the precise molecular role of Chfr in the control of mitotic transition, and provide insights into the function of this newly defined early mitotic checkpoint in the maintenance of genomic stability and cancer prevention. ? ? ?
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