Disruption of FAT10-MAD2 binding inhibits tumor progression
#MMPMID25422469
Theng SS
; Wang W
; Mah WC
; Chan C
; Zhuo J
; Gao Y
; Qin H
; Lim L
; Chong SS
; Song J
; Lee CG
Proc Natl Acad Sci U S A
2014[Dec]; 111
(49
): E5282-91
PMID25422469
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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.
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