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Disruption of FAT10–MAD2 binding inhibits tumour progression Steven Setiawan Theng, Wei Wang, Way-Champ Mah, Cheryl Chan, Jingli Zhuo, Yun Gao, Haina Qin, Liangzhong Lim, Samuel S. Chong, Jianxing Song, and Caroline G. Lee FAT10 is a molecule that is found at low levels in various tissues of the body. Its expression level is significantly increased during inflammation and in various inflammation-associated cancers including hepatocellular carcinoma (HCC) and colorectal cancer (CRC). Our laboratory previously found that over-expression of FAT10 promotes tumor formation, growth and progression. We also discovered that FAT10 interacts with a protein called MAD2, which serves as a gatekeeper of cell-division to ensure that each cell receives the same number of chromosomes. When FAT10 binds to MAD2, it pulls MAD2 away from its gate-keeping function, causing many cells to carry abnormal number of chromosomes leading to cancer. In this study, in collaboration with A/Prof Song Jianxing, we determined the three-dimensional structures of FAT10 using the state-of-the-art nuclear magnetic resonance (NMR) spectroscopy, and further examined the relationship between the two proteins. Using genetic mutation manipulation, we discovered that when the binding between FAT10 and MAD2 is specifically disrupted without affecting FAT10’s interaction with its other known key interaction partners, the number of chromosomes in the affected cells is restored and tumour progression is curtailed. Our findings present a new paradigm for drug targeting and pave the way for the development of a novel small-molecule anti-cancer inhibitor targeting the specific interaction between FAT10 and MAD2. Many current strategies target over-expressed genes to inhibit their expression. As many of these cellular genes also perform other physiological functions in addition to causing cancer, inhibiting their expression in a blanket fashion may result in undesirable side effects as the physiological function of these genes may be affected as well. Our strategy works differently as it targets a specific pathological function of the ‘culprit’ molecule without affecting its other physiological functions. This is especially important for a molecule like FAT10 which is not only over-expressed during cancer formation but is also over-expressed during immune response. ------------------------------------------------------------------------------------------------------------------------The full paper can be accessed via: http://www.pnas.org/content/111/49/E5282.abstract For NUS staffs and students, you can access to the full manuscript via http://www.pnas.org.libproxy1.nus.edu.sg/content/111/49/E5282.abstract