The genetic material DNA is packaged and organized into chromosomes in cells. Abnormal numbers of chromosomes or changes in chromosomal structures or organizations will cause human diseases including cancers. Many mitotic checkpoint pathways are evolved in the cell to maintain chromosomal stability. Studies in the last decade have highlighted the importance of spindle assembly checkpoint in the maintenance of chromosomal stability. While spindle checkpoint clearly plays a critical role in this process, mutations or dysregulations of spindle checkpoint components are not frequently observed in cancers, suggesting that tumor-associated instability could result from other deficiencies. One of these deficiencies is likely to be Chfr downregulation, which has been repeatedly observed in many types of cancers. Checkpoint protein with FHA and RING domains (Chfr) is involved in early mitotic checkpoint. It comprises of a RING domain and functions as an E3 ubiquitin ligase. During the last funding period, we have established Chfr knockout mice and demonstrated directly that Chfr acts as tumor suppressor. In addition, we showed that the major function of Chfr is to regulate the stability of several key mitotic proteins including Aurora A and PLK1. Our current working hypothesis is that Chfr normally acts throughout G1, S and G2 phases, but is specifically downregulated in mitosis. The function of Chfr is to prevent premature accumulation of many key mitotic regulators before the entry of mitosis. In the absence of Chfr and probably due to untimely upregulation of these Chfr substrates, cells would undergo abnormal mitotic transitions, which result in low frequency of chromosomal instability and thus promote tumorigenesis. Therefore, the identification of Chfr substrates and the understanding of Chfr downregulation in mitosis will reveal how Chfr normally act to prevent tumor initiation in vivo. We recently identified a potential mitotic kinase TOPK as a Chfr substrate. In addition, we demonstrated that Chfr deficiency greatly promoted tumorigenesis in MLH1-deficient mice, suggesting that chromosomal instability caused by Chfr deficiency may synergize with microsatellite instability caused by mismatch repair deficiency to facilitate tumorigenesis. Based on these preliminary studies, we propose to: (1) Study the functional interaction between Chfr and TOPK in mitosis;(2) Explore whether balanced regulation of TOPK expression is critical for the maintenance of chromosomal stability and tumor suppression;(3) Determine whether chromosomal instability caused by Chfr downregulation cooperates with mismatch repair deficiency in tumor initiation.
Chfr (Checkpoint with FHA and RING domains) is frequently downregulated in human cancers and specific deletion of Chfr in mice promotes tumorigenesis, suggesting that Chfr functions as a tumor suppressor. As E3 ubiquitin ligase, Chfr regulates the stability of several key mitotic regulators and thus assures proper mitotic transitions. Further study the regulation and function of Chfr will reveal mechanistically how Chfr deficiency in humans contributes to cancer development.
|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; Sy, Shirley M-H; Chen, Junjie (2009) Functional interaction between Chfr and Kif22 controls genomic stability. J Biol Chem 284:12998-3003|
|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; Chen, Junjie (2009) Protein kinase DYRK2 is a scaffold that facilitates assembly of an E3 ligase. Nat Cell Biol 11:409-19|
|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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