Skp-cullin-F box E3 ligase component FBXL2 ubiquitinates Aurora B to inhibit tumorigenesis.
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 SCF(FBXL2) 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 SCF(FBXL2)-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.
Department of Medicine, Pulmonary, Allergy and Critical Care Medicine, UPMC Montefiore, University of Pittsburgh, Pittsburgh, PA 15213, USA. chenb@upmc.edu
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Chen
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Mallampalli
D000818:Animals; D017209:Apoptosis; D064107:Aurora Kinase B / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics*; D044783:F-Box Proteins / Q000378:metabolism / Q000502:physiology*; D059565:G2 Phase Cell Cycle Checkpoints; D051379:Mice; D008819:Mice, Nude; D011123:Polyploidy; D054875:Ubiquitination
D044783:F-Box Proteins; C558726:FBXL2 protein, mouse; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B