Ewing sarcoma EWS protein regulates midzone formation by recruiting Aurora B kinase to the midzone

Park, Hyewon; Turkalo, Timothy K.; Nelson, Kayla; Folmsbee, Stephen Sai; Robb, Caroline M.; Roper, Brittany; Mizuki, Akira

doi:10.4161/cc.29337

Cited by 16 publications

(27 citation statements)

References 44 publications

(58 reference statements)

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“…16 Recently, Park et al demonstrated that EWSR1 interacts with Aurora B kinase, a component of the chromosome passenger complex (CPC) which is critical for checkpoint control in mitosis, through its RGG3 domain, recruiting Aurora B to the midzone. 17 EWS-deficient mice were born at normal Mendelian ratios; however, the size of neonates was smaller than those of the wild type, and a high frequency of postnatal mortality was observed. 18 Detailed analysis of surviving mice showed that loss of EWSR1 led to a defect in pre-B lymphocyte development, significantly reduced cellularity in major haematopoietic organs, and deficient gametogenesis in both sexes.…”

Section: Introductionmentioning

confidence: 99%

“…Others have reported that EWSR1 regulated midzone formation during anaphase by recruiting Aurora B. 17 However Aurora B is also involved in many other processes in mitosis, such as chromatin modification and microtubule-kinetochore attachment, but not in cytokinesis. 23 Therefore, we examined the location of Aurora B, which appeared to be dynamically localized throughout the mitosis (Fig.…”

Section: Knockdown Of Ewsr1 Leads To Mitotic Spindle Abnormalitiesmentioning

confidence: 99%

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EWSR1 regulates mitosis by dynamically influencing microtubule acetylation

et al. 2016

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EWSR1, participating in transcription and splicing, has been identified as a translocation partner for various transcription factors, resulting in translocation, which in turn plays crucial roles in tumorigenesis. Recent studies have investigated the role of EWSR1 in mitosis. However, the effect of EWSR1 on mitosis is poorly understood. Here, we observed that depletion of EWSR1 resulted in cell cycle arrest in the mitotic phase, mainly due to an increase in the time from nuclear envelope breakdown to metaphase, resulting in a high percentage of unaligned chromosomes and multipolar spindles. We also demonstrated that EWSR1 is a spindle-associated protein that interacts with a-tubulin during mitosis. EWSR1 depletion increased the cold-sensitivity of spindle microtubules, and decreased the rate of spindle assembly. EWSR1 regulated the level of microtubule acetylation in the mitotic spindle; microtubule acetylation was rescued in EWSR1-depleted mitotic cells following suppression of HDAC6 activity by its specific inhibitor or siRNA treatment. In summary, these results suggest that EWSR1 regulates the acetylation of microtubules in a cell cycledependent manner through its dynamic location on spindle MTs, and may be a novel regulator for mitosis progress independent of its translocation.

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Section: Introductionmentioning

confidence: 99%

Section: Knockdown Of Ewsr1 Leads To Mitotic Spindle Abnormalitiesmentioning

confidence: 99%

EWSR1 regulates mitosis by dynamically influencing microtubule acetylation

et al. 2016

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“…28 Since previous report suggested that EWS is involved in organizing the spindle, we then measured O-GlcNAcylation and the localization of EWS to metaphase-anaphase spindles. 29 EWS O-GlcNAcylation was significantly increased on EWS in the OGA K D cells (Fig.…”

Section: Oga Knockdown Increases Mitotic O-glcnacylation Of Numa and mentioning

confidence: 99%

Reduced O-GlcNAcase expression promotes mitotic errors and spindle defects

et al. 2016

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Alterations in O-GlcNAc cycling, the addition and removal of O-GlcNAc, lead to mitotic defects and increased aneuploidy. Herein, we generated stable O-GlcNAcase (OGA, the enzyme that removes OGlcNAc) knockdown HeLa cell lines and characterized the effect of the reduction in OGA activity on cell cycle progression. After release from G 1 /S, the OGA knockdown cells progressed normally through S phase but demonstrated mitotic exit defects. Cyclin A was increased in the knockdown cells while Cyclin B and D expression was reduced. Retinoblastoma protein (RB) phosphorylation was also increased in the knockdown compared to control. At M phase, the knockdown cells showed more compact spindle chromatids than control cells and had a greater percentage of cells with multipolar spindles. Furthermore, the timing of the inhibitory tyrosine phosphorylation of Cyclin Dependent Kinase 1 (CDK1) was altered in the OGA knockdown cells. Although expression and localization of the chromosomal passenger protein complex (CPC) was unchanged, histone H3 threonine 3 phosphorylation was decreased in one of the OGA knockdown cell lines. The Ewing Sarcoma Breakpoint Region 1 Protein (EWS) participates in organizing the CPC at the spindle and is a known substrate for O-GlcNAc transferase (OGT, the enzyme that adds OGlcNAc). EWS O-GlcNAcylation was significantly increased in the OGA knockdown cells promoting uneven localization of the mitotic midzone. Our data suggests that O-GlcNAc cycling is an essential mechanism for proper mitotic signaling and spindle formation, and alterations in the rate of O-GlcNAc cycling produces aberrant spindles and promotes aneuploidy.

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“…This interaction may further deplete the normal function of the remaining wildtype EWS allele. We previously demonstrated that EWS relocates the mitotic regulator Aurora B kinase to the midzone15. The midzone is required for the maintenance of spindle architecture, spindle elongation, and cleavage furrow formation2335.…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that EWS maintains mitotic integrity14. We subsequently demonstrated that EWS interaction regulates the relocation of Aurora B kinase to the midzone during late mitosis15. Compromised relocation of Aurora B kinase results in chromosomal instability (CIN) and aneuploidy, both hallmarks of cancer16.…”

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Loss of Ewing sarcoma EWS allele promotes tumorigenesis by inducing chromosomal instability in zebrafish

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Galbraith

Turner

et al. 2016

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The Ewing sarcoma family of tumors expresses aberrant EWSR1- (EWS) fusion genes that are derived from chromosomal translocation. Although these fusion genes are well characterized as transcription factors, their formation leaves a single EWS allele in the sarcoma cells, and the contribution that the loss of EWS makes towards disease pathogenesis is unknown. To address this question, we utilized zebrafish mutants for ewsa and tp53. The zebrafish tp53(M214K)w/m line and the ewsaw/m, zygotic ewsam/m, and Maternal-Zygotic (MZ) ewsam/m lines all displayed zero to low incidence of tumorigenesis. However, when the ewsa and tp53 mutant lines were crossed with each other, the incidence of tumorigenesis drastically increased. Furthermore, 27 hour post fertilization (hpf) MZ ewsam/m mutant embryos displayed a higher incidence of aberrant chromosome numbers and mitotic dysfunction compared to wildtype zebrafish embryos. Consistent with this finding, tumor samples obtained from ewsam/m;tp53w/m zebrafish displayed loss of heterozygosity (LOH) for the wildtype tp53 locus. These results suggest that wildtype Ewsa inhibits LOH induction, possibly by maintaining chromosomal stability. We propose that the loss of ewsa promotes tumorigenesis, and EWS deficiency may contribute to the pathogenesis of EWS-fusion-expressing sarcomas.

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Ewing sarcoma EWS protein regulates midzone formation by recruiting Aurora B kinase to the midzone

Cited by 16 publications

References 44 publications

EWSR1 regulates mitosis by dynamically influencing microtubule acetylation

EWSR1 regulates mitosis by dynamically influencing microtubule acetylation

Reduced O-GlcNAcase expression promotes mitotic errors and spindle defects

Loss of Ewing sarcoma EWS allele promotes tumorigenesis by inducing chromosomal instability in zebrafish

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