title: Ewing sarcoma EWS protein regulates midzone formation by recruiting Aurora B kinase to the midzone.
abstract: Ewing sarcoma is a malignant bone cancer that primarily occurs in children and adolescents. Eighty-five percent of Ewing sarcoma is characterized by the presence of the aberrant chimeric EWS/FLI1 fusion gene. Previously, we demonstrated that an interaction between EWS/FLI1 and wild-type EWS led to the inhibition of EWS activity and mitotic dysfunction. Although defective mitosis is considered to be a critical step in cancer initiation, it is unknown how interference with EWS contributes to Ewing sarcoma formation. Here, we demonstrate that EWS/FLI1- and EWS-knockdown cells display a high incidence of defects in the midzone, a midline structure located between segregating chromatids during anaphase. Defects in the midzone can lead to the failure of cytokinesis and can result in the induction of aneuploidy. The similarity among the phenotypes of EWS/FLI1- and EWS siRNA-transfected HeLa cells points to the inhibition of EWS as the key mechanism for the induction of midzone defects. Supporting this observation, the ectopic expression of EWS rescues the high incidence of midzone defects observed in Ewing sarcoma A673 cells. We discovered that EWS interacts with Aurora B kinase, and that EWS is also required for recruiting Aurora B to the midzone. A domain analysis revealed that the R565 in the RGG3 domain of EWS is essential for both Aurora B interaction and the recruitment of Aurora B to the midzone. Here, we propose that the impairment of EWS-dependent midzone formation via the recruitment of Aurora B is a potential mechanism of Ewing sarcoma development.
authors.affiliation: a Department of Molecular Biosciences; University of Kansas; Lawrence, KS USA.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Park
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Turkalo
authors.forename: Kayla
authors.initials: K
authors.lastname: Nelson
authors.forename: Stephen Sai
authors.initials: SS
authors.lastname: Folmsbee
authors.forename: Caroline
authors.initials: C
authors.lastname: Robb
authors.forename: Brittany
authors.initials: B
authors.lastname: Roper
authors.forename: Mizuki
authors.initials: M
authors.lastname: Azuma
mesh_terms: D000705:Anaphase / Q000502:physiology; D000782:Aneuploidy; D064107:Aurora Kinase B / Q000378:metabolism*; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D020090:Chromosome Segregation / Q000502:physiology; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D022101:Microtubule-Organizing Center / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D034802:RNA-Binding Protein EWS / Q000235:genetics / Q000378:metabolism*; D012512:Sarcoma, Ewing / Q000378:metabolism* / Q000473:pathology
chemical_list: C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034741:RNA, Small Interfering; D034802:RNA-Binding Protein EWS; D064107:Aurora Kinase B
keywords: Aurora B; CIN; EWS; Ewing sarcoma; midzone