Hice1, a Novel Microtubule-Associated Protein Required for Maintenance of Spindle Integrity and Chromosomal Stability in Human Cells

Wu, Guikai; Lin, Yi-Tzu; Wei, Randy; Chen, Yumay; Shan, Zhiyin; Lee, Wen‐Hwa

doi:10.1128/mcb.01923-07

Cited by 67 publications

(118 citation statements)

References 39 publications

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“…33 Defective structure and altered dynamics of MTs result in abnormal spindle function, and in turn lead to chromosome alignment errors and cell cycle arrest. 34 Depletion of EWSR1 reduced the regrowth ability of spindle MTs, indicating a role for EWSR1 in spindle assembly. Consistent with this, depletion of EWSR1 led to a significant delay in M phase progression, and the expression of either GFP-EWSR1 or GFP-EWSR1DNLS rescued the prolonged time from NEB to metaphase resulting from EWSR1 knockdown, suggesting that the cell cycle function of EWSR1 mainly depends on its role outside the nucleus.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

EWSR1 regulates mitosis by dynamically influencing microtubule acetylation

et al. 2016

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“…Hice1, one of the subunits of the Augmin complex, has been shown to bind to MT directly through its Nterminal domain (16). Thus, investigation on the mechanism underlying the Hice1-MT interaction is likely a key step in understanding the biological processes of how Augmin recruits the Nedd1-γ-TuRC complex to the spindles and mediates MT-based MT nucleation at these sites.…”

mentioning

confidence: 99%

Regulation of microtubule-based microtubule nucleation by mammalian polo-like kinase 1

Johmura

Soung²,

Park³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Bipolar spindle formation is pivotal for accurate segregation of mitotic chromosomes during cell division. A growing body of evidence suggests that, in addition to centrosome-and chromatinbased microtubule (MT) nucleation, MT-based MT nucleation plays an important role for proper bipolar spindle formation in various eukaryotic organisms. Although a recently discovered Augmin complex appears to play a central role in this event, how Augmin is regulated remains unknown. Here we provide evidence that a mammalian polo-like kinase 1 (Plk1) localizes to mitotic spindles and promotes MT-based MT nucleation by directly regulating Augmin. Mechanistically, we demonstrated that Cdc2-dependent phosphorylation on a γ-tubulin ring complex (γ-TuRC) recruitment protein, Nedd1/GCP-WD, at the previously uncharacterized S460 residue induces the Nedd1-Plk1 interaction. This step appeared to be critical to allow Plk1 to phosphorylate the Hice1 subunit of the Augmin complex to promote the Augmin-MT interaction and MT-based MT nucleation from within the spindle. Loss of either the Nedd1 S460 function or the Plk1-dependent Hice1 phosphorylation impaired both the Augmin-MT interaction and γ-tubulin recruitment to the spindles, thus resulting in improper bipolar spindle formation that ultimately leads to mitotic arrest and apoptotic cell death. Thus, via the formation of the Nedd1-Plk1 complex and subsequent Augmin phosphorylation, Plk1 regulates spindle MT-based MT nucleation to accomplish normal bipolar spindle formation and mitotic progression. mitosis | spindle assembly | polo-box domain | distributive phosphorylation | Ser/Thr protein kinase

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“…Seventy‐six genes showed a genetic aberration incidence of 10% or more in CIMP‐positive RCCs ( n = 19), whereas only four genes did so in CIMP‐negative RCCs ( n = 87) (Tables 2 and 3). Genes encoding microtubule‐associated proteins, such as DNAH2, DNAH5, DNAH10 ,31 RP1 32 and HAUS8 ,33, 34 those involved in histone modification, such as NCOA1 ,35 those involved in cell adhesion, such as CELSR1, CELSR2 ,36 CTNND1 ,37 LAMC2 38 and TJP1 ,39 and tumor‐related genes such as BAP1 40 and ATM ,41 were frequently mutated in CIMP‐positive RCCs (Table 3). As shown in Tables 2 and 3, 235 genetic aberrations (173 non‐synonymous single‐nucleotide mutations and 62 indels) revealed by whole‐exome analysis in the initial cohort were all successfully verified by Sanger sequencing.…”

Section: Resultsmentioning

confidence: 99%

“…Aberrations of genes involved in cell adhesion, such as CELSR1, CELSR2 ,36 CTNND1 ,37 LAMC2 38 and TJP1 ,39 may affect the invasiveness and metastatic potential of CIMP‐positive RCCs (CIMP‐positive RCCs show invasive growth and distant metastasis more frequently than CIMP‐negative RCCs13). Moreover, genetic aberrations of microtubule‐associated proteins, such as DNAH2, DNAH5, DNAH10 ,31 RP1 32 and HAUS8 ,33, 34 may be correlated with dysregulation of the spindle checkpoint in CIMP‐positive RCCs. DNAH2, DNAH5 and DNAH10 encode the heavy chains of axonal dynein 31.…”

Section: Discussionmentioning

confidence: 99%

“…RP1 belongs to the EB1 family, which has been shown to play an important role in the regulation of microtubule dynamics and chromosome segregation 3233, 34. SIFT21, 23 and PolyPhen‐222 scores have suggested that many of the amino acid substitutions due to genetic aberrations listed in Table 3 could potentially affect protein functions in CIMP‐positive RCCs.…”

Section: Discussionmentioning

confidence: 99%

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Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas

Arai¹,

Gotoh²,

Tian³

et al. 2015

Intl Journal of Cancer

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CpG‐island methylator phenotype (CIMP)‐positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poor patient outcome. The aim of this study was to clarify the molecular pathways participating in CIMP‐positive renal carcinogenesis. Genome (whole‐exome and copy number), transcriptome and proteome (two‐dimensional image converted analysis of liquid chromatography‐mass spectrometry) analyses were performed using tissue specimens of 87 CIMP‐negative and 14 CIMP‐positive clear cell RCCs and corresponding specimens of non‐cancerous renal cortex. Genes encoding microtubule‐associated proteins, such as DNAH2, DNAH5, DNAH10, RP1 and HAUS8, showed a 10% or higher incidence of genetic aberrations (non‐synonymous single‐nucleotide mutations and insertions/deletions) in CIMP‐positive RCCs, whereas CIMP‐negative RCCs lacked distinct genetic characteristics. MetaCore pathway analysis of CIMP‐positive RCCs revealed that alterations of mRNA or protein expression were significantly accumulated in six pathways, all participating in the spindle checkpoint, including the “The metaphase checkpoint (p = 1.427 × 10−6),” “Role of Anaphase Promoting Complex in cell cycle regulation (p = 7.444 × 10−6)” and “Spindle assembly and chromosome separation (p = 9.260 × 10−6)” pathways. Quantitative RT‐PCR analysis revealed that mRNA expression levels for genes included in such pathways, i.e., AURKA, AURKB, BIRC5, BUB1, CDC20, NEK2 and SPC25, were significantly higher in CIMP‐positive than in CIMP‐negative RCCs. All CIMP‐positive RCCs showed overexpression of Aurora kinases, AURKA and AURKB, and this overexpression was mainly attributable to increased copy number. These data suggest that abnormalities of the spindle checkpoint pathway participate in CIMP‐positive renal carcinogenesis, and that AURKA and AURKB may be potential therapeutic targets in more aggressive CIMP‐positive RCCs.

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Hice1, a Novel Microtubule-Associated Protein Required for Maintenance of Spindle Integrity and Chromosomal Stability in Human Cells

Cited by 67 publications

References 39 publications

EWSR1 regulates mitosis by dynamically influencing microtubule acetylation

EWSR1 regulates mitosis by dynamically influencing microtubule acetylation

Regulation of microtubule-based microtubule nucleation by mammalian polo-like kinase 1

Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas

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