Abstract
Aurora B kinase is an integral regulator of cytokinesis, as it stabilizes the intercellular canal within the midbody to ensure proper chromosomal segregation during cell division. Here we identified that the ubiquitin E3 ligase complex SCFFBXL2 mediates Aurora B ubiquitination and degradation within the midbody, which is sufficient to induce mitotic arrest and apoptosis. Three molecular acceptor sites (K102, K103 and K207) within Aurora B protein were identified as important sites for its ubiquitination. A triple Lys mutant of Aurora B (K102/103/207R) exhibited optimal resistance to SCFFBXL2-directed polyubiquitination, and overexpression of this variant resulted in a significant delay in anaphase onset, resulting in apoptosis. A unique small molecule F-box/LRR-repeat protein 2 (FBXL2) activator, BC-1258, stabilized and increased levels of FBXL2 protein that promoted Aurora B degradation, resulting in tetraploidy, mitotic arrest and apoptosis of tumorigenic cells, and profoundly inhibiting tumor formation in athymic nude mice. These findings uncover a new proteolytic mechanism targeting a key regulator of cell replication that may serve as a basis for chemotherapeutic intervention in neoplasia.
Highlights
B ubiquitination and degradation within the midbody, which is sufficient to induce mitotic arrest and apoptosis
We demonstrated that the Skp-Cullin-F box (SCF) subunit, F-box/LRR-repeat protein 2 (FBXL2), targets Aurora B for its ubiquitination to mediate its disposal in cells, an effect antagonized by the calcium sensor, calmodulin.[25]
Aurora B is the key regulator of abscission timing, which responds to chromosome bridge formation by delaying abscission to stabilize the intercellular canal until the chromosome bridge is resolved.[36]
Summary
B ubiquitination and degradation within the midbody, which is sufficient to induce mitotic arrest and apoptosis. A unique small molecule F-box/LRR-repeat protein 2 (FBXL2) activator, BC-1258, stabilized and increased levels of FBXL2 protein that promoted Aurora B degradation, resulting in tetraploidy, mitotic arrest and apoptosis of tumorigenic cells, and profoundly inhibiting tumor formation in athymic nude mice. These findings uncover a new proteolytic mechanism targeting a key regulator of cell replication that may serve as a basis for chemotherapeutic intervention in neoplasia. This study provides a new strategy for degrading Aurora B protein as a potential means to modulate tumorogenesis
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