Dissecting the role of Aurora A during spindle assembly

Sardón, Teresa; Peset, Isabel; Petrova, Boryana; Vernos, Isabelle

doi:10.1038/emboj.2008.173

Cited by 80 publications

(52 citation statements)

References 25 publications

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“…Cells that migrated to the bottom side of the membrane were stained and counted. The histogram showed that the results have statistical significance (p<0.05) spindle assembly, in large part by promoting microtubules assembly and organization [18]. Consistent with previous study, we also found that chromosome alignment and spindle bipolarity were disrupted in alisertib-treated cells.…”

Section: Discussionsupporting

confidence: 90%

Alisertib (MLN8237), a selective Aurora-A kinase inhibitor, induces apoptosis in human tongue squamous cell carcinoma cell both in vitro and in vivo

Lin

Zhang

2014

Tumor Biol.

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Aurora-A kinases are overexpressed in many cancer tissues and cells. Alisertib is an investigational, orally administered, selective, small-molecule Aurora-A kinase inhibitor with preclinical activity against a broad range of tumors. Our study was aimed to detect the effects of alisertib on human tongue squamous cell carcinoma (HTSCC). Treatment of a human tongue squamous cell carcinoma cell line, HSC-3, with alisertib to inhibition of Aurora-A kinases reduced proliferation and induced apoptosis, which was accompanied by activation of the ATM/Chk2/p53 pathway. In vivo, inhibition of Aurora-A kinases in established xenografted tumors decreased tumor size and weight. Kaplan-Meyer survival analysis demonstrated that the cumulative survival time of mice without Aurora-A kinases was significantly longer than those with Aurora-A kinases. Our data provide the basis for developing alisertib to treat human tongue squamous cell carcinoma.

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Section: Discussionsupporting

confidence: 90%

Alisertib (MLN8237), a selective Aurora-A kinase inhibitor, induces apoptosis in human tongue squamous cell carcinoma cell both in vitro and in vivo

Lin

Zhang

2014

Tumor Biol.

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“…Upon release from importin α, TPX2 activates Aurora-A kinase in a microtubule-dependent manner, which itself is also an essential regulator for spindle assembly (Tsai et al, 2003; Sardon et al, 2008). TPX2 locks Aurora-A in the active state by inducing its conformational change that renders the key residue T288 inaccessible to the phosphatase (Bayliss et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

GM130 Regulates Golgi-Derived Spindle Assembly by Activating TPX2 and Capturing Microtubules

Wei

Zhang

Wynn

et al. 2015

Cell

117

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Summary Spindle assembly requires the coordinated action of multiple cellular structures to nucleate and organize microtubules in a precise spatiotemporal manner. Among them the contributions of centrosomes, chromosomes and microtubules have been well studied, yet the involvement of membrane-bound organelles remains largely elusive. Here we provide mechanistic evidence for a membrane-based, Golgi-derived microtubule assembly pathway in mitosis. Upon mitotic entry, the Golgi matrix protein GM130 interacts with importin α via a classical nuclear localization signal that recruits importin α to the Golgi membranes. Sequestration of importin α by GM130 liberates the spindle assembly factor TPX2, which activates Aurora-A kinase and stimulates local microtubule nucleation. Upon filament assembly, nascent microtubules are further captured by GM130, thus linking Golgi membranes to the spindle. Our results reveal an active role for the Golgi in regulating spindle formation to ensure faithful organelle inheritance.

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“…3E). A recent report also showed that the kinase activity of Aurora A is important for its localization to the mitotic spindles in Xenopus egg extracts (33). histone H3 phosphorylation by Aurora B kinase (Fig.…”

Section: Inactivation Of Aurora Kinases Uncouples the Nuclearmentioning

confidence: 99%

Cdk1 Activity Is Required for Mitotic Activation of Aurora A during G2/M Transition of Human Cells

Horn

Chu

Fan

et al. 2010

Journal of Biological Chemistry

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In mammalian cells entry into and progression through mitosis are regulated by multiple mitotic kinases. How mitotic kinases interact with each other and coordinately regulate mitosis remains to be fully understood. Here we employed a chemical biology approach using selective small molecule kinase inhibitors to dissect the relationship between Cdk1 and Aurora A kinases during G 2 /M transition. We find that activation of Aurora A first occurs at centrosomes at late G 2 and is required for centrosome separation independently of Cdk1 activity. Upon entry into mitosis, Aurora A then becomes fully activated downstream of Cdk1 activation. Inactivation of Aurora A or Plk1 individually during a synchronized cell cycle shows no significant effect on Cdk1 activation and entry into mitosis. However, simultaneous inactivation of both Aurora A and Plk1 markedly delays Cdk1 activation and entry into mitosis, suggesting that Aurora A and Plk1 have redundant functions in the feedback activation of Cdk1. Together, our data suggest that Cdk1, Aurora A, and Plk1 mitotic kinases participate in a feedback activation loop and that activation of Cdk1 initiates the feedback loop activity, leading to rapid and timely entry into mitosis in human cells. In addition, live cell imaging reveals that the nuclear cycle of cells becomes uncoupled from cytokinesis upon inactivation of both Aurora A and Aurora B kinases and continues to oscillate in a Cdk1-dependent manner in the absence of cytokinesis, resulting in multinucleated, polyploidy cells.

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Dissecting the role of Aurora A during spindle assembly

Cited by 80 publications

References 25 publications

Alisertib (MLN8237), a selective Aurora-A kinase inhibitor, induces apoptosis in human tongue squamous cell carcinoma cell both in vitro and in vivo

Alisertib (MLN8237), a selective Aurora-A kinase inhibitor, induces apoptosis in human tongue squamous cell carcinoma cell both in vitro and in vivo

GM130 Regulates Golgi-Derived Spindle Assembly by Activating TPX2 and Capturing Microtubules

Cdk1 Activity Is Required for Mitotic Activation of Aurora A during G2/M Transition of Human Cells

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