FAT10与MAD2结合的破坏会抑制肿瘤进展。
Disruption of FAT10-MAD2 binding inhibits tumor progression.
作者信息
Theng Steven Setiawan, Wang Wei, Mah Way-Champ, Chan Cheryl, Zhuo Jingli, Gao Yun, Qin Haina, Lim Liangzhong, Chong Samuel S, Song Jianxing, Lee Caroline G
机构信息
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore; National University of Singapore Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore;
Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 119077, Singapore;
出版信息
Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):E5282-91. doi: 10.1073/pnas.1403383111. Epub 2014 Nov 24.
FAT10 (HLA-F-adjacent transcript 10) is a ubiquitin-like modifier that is commonly overexpressed in various tumors. It was found to play a role in mitotic regulation through its interaction with mitotic arrest-deficient 2 (MAD2). Overexpression of FAT10 promotes tumor growth and malignancy. Here, we identified the MAD2-binding interface of FAT10 to be located on its first ubiquitin-like domain whose NMR structure thus was determined. We further proceeded to demonstrate that disruption of the FAT10-MAD2 interaction through mutation of specific MAD2-binding residues did not interfere with the interaction of FAT10 with its other known interacting partners. Significantly, ablation of the FAT10-MAD2 interaction dramatically limited the promalignant capacity of FAT10, including promoting tumor growth in vivo and inducing aneuploidy, proliferation, migration, invasion, and resistance to apoptosis in vitro. Our results strongly suggest that the interaction of FAT10 with MAD2 is a key mechanism underlying the promalignant property of FAT10 and offer prospects for the development of anticancer strategies.
FAT10（HLA - F相邻转录本10）是一种类泛素修饰因子，在多种肿瘤中通常呈过表达状态。研究发现它通过与有丝分裂阻滞缺陷蛋白2（MAD2）相互作用，在有丝分裂调控中发挥作用。FAT10的过表达促进肿瘤生长和恶性进展。在此，我们确定FAT10与MAD2的结合界面位于其首个类泛素结构域，进而测定了该结构域的核磁共振结构。我们进一步证明，通过突变特定的MAD2结合残基破坏FAT10与MAD2的相互作用，并不影响FAT10与其其他已知相互作用伙伴的相互作用。值得注意的是，消除FAT10与MAD2的相互作用极大地限制了FAT10的促恶性能力，包括在体内促进肿瘤生长以及在体外诱导非整倍体形成、增殖、迁移、侵袭和抗凋亡。我们的结果强烈表明，FAT10与MAD2的相互作用是FAT10促恶性特性的关键机制，并为抗癌策略的开发提供了前景。
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