Microtubule assembly during mitosis – from distinct origins to distinct functions?

Meunier, Sylvain; Vernos, Isabelle

doi:10.1242/jcs.092429

Cited by 97 publications

(126 citation statements)

References 160 publications

(191 reference statements)

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“…As long as kinetochore-spindle attachments remain unchanged, the total number of microtubules in this group is conserved regardless of the spindle size. Nonkinetochore microtubules (non-kMT) are the highly dynamical microtubules that seed throughout the spindle (41)(42)(43)(44). Non-kMTs likely assume largely an even density profile, similar to that observed in bipolar spindle self-assembled in Xenopus egg extract without centrosomes (17).…”

Section: Model Setupmentioning

confidence: 92%

Spindle Size Scaling Contributes to Robust Silencing of Mitotic Spindle Assembly Checkpoint

Chen

Liu

2016

Biophysical Journal

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Chromosome segregation during mitosis hinges on proper assembly of the microtubule spindle that establishes bipolar attachment to each chromosome. Experiments demonstrate allometry of mitotic spindles and a universal scaling relationship between spindle size and cell size across metazoans, which indicates a conserved principle of spindle assembly at play during evolution. However, the nature of this principle is currently unknown. Researchers have focused on deriving the mechanistic underpinning of the size scaling from the mechanical aspects of the spindle assembly process. In this work we take a different standpoint and ask: What is the size scaling for? We address this question from the functional perspectives of spindle assembly checkpoint (SAC). SAC is the critical surveillance mechanism that prevents premature chromosome segregation in the presence of unattached or misattached chromosomes. The SAC signal gets silenced after and only after the last chromosome-spindle attachment in mitosis. We previously established a model that explains the robustness of SAC silencing based on spindle-mediated spatiotemporal regulation of SAC proteins. Here, we refine the previous model, and find that robust and timely SAC silencing entails proper size scaling of mitotic spindle. This finding provides, to our knowledge, a novel, function-oriented angle toward understanding the observed spindle allometry, and the universal scaling relationship between spindle size and cell size in metazoans. In a broad sense, the functional requirement of robust SAC silencing could have helped shape the spindle assembly mechanism in evolution.

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Section: Model Setupmentioning

confidence: 92%

Spindle Size Scaling Contributes to Robust Silencing of Mitotic Spindle Assembly Checkpoint

Chen

Liu

2016

Biophysical Journal

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“…The CDK1/cyclin B1 complex also phosphorylates and activates enzymes regulating the mitosis-specific microtubule reorganization [26-29]. It was therefore hypothesized that the activity of this complex is affected directly or indirectly by PPP.…”

Section: Introductionmentioning

confidence: 99%

Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via Insulin-like growth factor-1 receptor-independent mechanism

et al. 2014

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Picropodophyllin (PPP) is an anticancer drug undergoing clinical development in NSCLC. PPP has been shown to suppress IGF-1R signaling and to induce a G2/M cell cycle phase arrest but the exact mechanisms remain to be elucidated.The present study identified an IGF-1-independent mechanism of PPP leading to pro-metaphase arrest. The mitotic block was induced in human cancer cell lines and in an A549 xenograft mouse but did not occur in normal hepatocytes/mouse tissues.Cell cycle arrest by PPP occurred in vitro and in vivo accompanied by prominent CDK1 activation, and was IGF-1R-independent since it occurred also in IGF-1R-depleted and null cells. The tumor cells were not arrested in G2/M but in mitosis. Centrosome separation was prevented during mitotic entry, resulting in a monopolar mitotic spindle with subsequent prometaphase-arrest, independent of Plk1/Aurora A or Eg5, and leading to cell features of mitotic catastrophe. PPP also increased soluble tubulin and decreased spindle-associated tubulin within minutes, indicating that it interfered with microtubule dynamics.These results provide a novel IGF-1R-independent mechanism of antitumor effects of PPP.

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“…Spindle organization and dynamics change throughout mitosis [1]. During the initial phases of mitosis, MTs organize into a bipolar spindle consisting of two antiparallel interdigitating arrays that connect the chromosomes to the two spindle poles and align them on the metaphase plate.…”

Section: Introductionmentioning

confidence: 99%

Aurora A kinase and its substrate TACC3 are required for central spindle assembly

Lioutas

Vernos

2013

EMBO Reports

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Cell division entails a marked reorganization of the microtubule network to form the spindle, a molecular machine that ensures accurate chromosome segregation to the daughter cells. Spindle organization is highly dynamic throughout mitosis and requires the activity of several kinases and complex regulatory mechanisms. Aurora A (AurA) kinase is essential for the assembly of the metaphase bipolar spindle and, thus, it has been difficult to address its function during the last phases of mitosis. Here, we examine the consequences of inhibiting AurA in cells undergoing anaphase, and show that AurA kinase activity is necessary for the assembly of a robust central spindle during anaphase. We also identify TACC3 as an AurA substrate essential in central spindle formation.

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Microtubule assembly during mitosis – from distinct origins to distinct functions?

Cited by 97 publications

References 160 publications

Spindle Size Scaling Contributes to Robust Silencing of Mitotic Spindle Assembly Checkpoint

Spindle Size Scaling Contributes to Robust Silencing of Mitotic Spindle Assembly Checkpoint

Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via Insulin-like growth factor-1 receptor-independent mechanism

Aurora A kinase and its substrate TACC3 are required for central spindle assembly

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