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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Etiology Study Section (CE)
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Mietz, Judy
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University of Texas MD Anderson Cancer Center
Other Domestic Higher Education
United States
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Sorokin, Alexey V; Nair, Binoj C; Wei, Yongkun et al. (2015) Aberrant Expression of proPTPRN2 in Cancer Cells Confers Resistance to Apoptosis. Cancer Res 75:1846-58
Fong, Ka-wing; Leung, Justin Wai-chung; Li, Yujing et al. (2013) MTR120/KIAA1383, a novel microtubule-associated protein, promotes microtubule stability and ensures cytokinesis. J Cell Sci 126:825-37
Fong, Ka-Wing; Li, Yujing; Wang, Wenqi et al. (2013) Whole-genome screening identifies proteins localized to distinct nuclear bodies. J Cell Biol 203:149-64
Huen, Michael S Y; Sy, Shirley M H; Leung, Ka Man et al. (2010) SON is a spliceosome-associated factor required for mitotic progression. Cell Cycle 9:2679-85
Maddika, Subbareddy; Chen, Junjie (2009) Protein kinase DYRK2 is a scaffold that facilitates assembly of an E3 ligase. Nat Cell Biol 11:409-19
Fu, Zheng; Regan, Kevin; Zhang, Lizhi et al. (2009) Deficiencies in Chfr and Mlh1 synergistically enhance tumor susceptibility in mice. J Clin Invest 119:2714-24
Maddika, Subbareddy; Sy, Shirley M-H; Chen, Junjie (2009) Functional interaction between Chfr and Kif22 controls genomic stability. J Biol Chem 284:12998-3003
Lu, Lin-Yu; Wood, Jamie L; Ye, Lin et al. (2008) Aurora A is essential for early embryonic development and tumor suppression. J Biol Chem 283:31785-90
Lu, Lin-Yu; Wood, Jamie L; Minter-Dykhouse, Katherine et al. (2008) Polo-like kinase 1 is essential for early embryonic development and tumor suppression. Mol Cell Biol 28:6870-6
Fu, Zheng; Malureanu, Liviu; Huang, Jun et al. (2008) Plk1-dependent phosphorylation of FoxM1 regulates a transcriptional programme required for mitotic progression. Nat Cell Biol 10:1076-82

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