scholarly journals Delayed Chromosome Alignment to the Spindle Equator Increases the Rate of Chromosome Missegregation in Cancer Cell Lines

Biomolecules ◽  
2018 ◽  
Vol 9 (1) ◽  
pp. 10 ◽  
Author(s):  
Kinue Kuniyasu ◽  
Kenji Iemura ◽  
Kozo Tanaka
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Chromosome Missegregation ◽  
Spindle Poles ◽  
Anaphase Onset ◽  
Sister Chromatids ◽  
Chromosome Congression ◽  
Chromosome Alignment ◽  
In Cells

For appropriate chromosome segregation, kinetochores on sister chromatids have to attach to microtubules from opposite spindle poles (bi-orientation). Chromosome alignment at the spindle equator, referred to as congression, can occur through the attachment of kinetochores to the lateral surface of spindle microtubules, facilitating bi-orientation establishment. However, the contribution of this phenomenon to mitotic fidelity has not been clarified yet. Here, we addressed whether delayed chromosome alignment to the spindle equator increases the rate of chromosome missegregation. Cancer cell lines depleted of Kid, a chromokinesin involved in chromosome congression, showed chromosome alignment with a slight delay, and increased frequency of lagging chromosomes. Delayed chromosome alignment concomitant with an increased rate of lagging chromosomes was also seen in cells depleted of kinesin family member 4A (KIF4A), another chromokinesin. Cells that underwent chromosome missegregation took relatively longer time to align chromosomes in both control and Kid/KIF4A-depleted cells. Tracking of late-aligning chromosomes showed that they exhibit a higher rate of lagging chromosomes. Intriguingly, the metaphase of cells that underwent chromosome missegregation was shortened, and delaying anaphase onset ameliorated the increased chromosome missegregation. These data suggest that late-aligning chromosomes do not have sufficient time to establish bi-orientation, leading to chromosome missegregation. Our data imply that delayed chromosome alignment is not only a consequence, but also a cause of defective bi-orientation establishment, which can lead to chromosomal instability in cells without severe mitotic defects.

scholarly journals GTSE1 tunes microtubule stability for chromosome alignment and segregation through MCAK inhibition

2016 ◽  
Author(s):  
Shweta Bendre ◽  
Arnaud Rondelet ◽  
Conrad Hall ◽  
Nadine Schmidt ◽  
Yu-Chih Lin ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Chromosome Segregation ◽  
Genome Stability ◽  
Cancer Cell Lines ◽  
Dynamic Regulation ◽  
Spindle Positioning ◽  
Chromosome Missegregation ◽  
Microtubule Stability ◽  
Chromosome Alignment

AbstractThe dynamic regulation of microtubules during mitosis is critical for accurate chromosome segregation and genome stability. Cancer cell lines with hyperstabilized kinetochore microtubules have increased segregation errors and elevated chromosomal instability (CIN), but the genetic defects responsible remain largely unknown. The microtubule depolymerase MCAK can influence CIN through its impact on microtubule stability, but how its potent activity is controlled in cells remains unclear. Here we show that GTSE1, a protein found overexpressed in aneuploid cancer cell lines and tumours, regulates microtubule stability during mitosis by inhibiting MCAK microtubule depolymerase activity. Cells lacking GTSE1 have defects in chromosome alignment and spindle positioning due to microtubule instability caused by excess MCAK activity. Reducing GTSE1 levels in CIN cancer cell lines reduces chromosome missegregation defects, while artificially inducing GTSE1 levels in chromosomally stable cells elevates chromosome missegregation and CIN. Thus GTSE1 inhibition of MCAK activity regulates the balance of microtubule stability that determines the fidelity of chromosome alignment, segregation, and chromosomal stability.

scholarly journals GTSE1 tunes microtubule stability for chromosome alignment and segregation by inhibiting the microtubule depolymerase MCAK

2016 ◽  
Vol 215 (5) ◽  
pp. 631-647 ◽  
Author(s):  
Shweta Bendre ◽  
Arnaud Rondelet ◽  
Conrad Hall ◽  
Nadine Schmidt ◽  
Yu-Chih Lin ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Chromosome Segregation ◽  
Genome Stability ◽  
Cancer Cell Lines ◽  
Dynamic Regulation ◽  
Spindle Positioning ◽  
Chromosome Missegregation ◽  
Microtubule Stability ◽  
Chromosome Alignment

The dynamic regulation of microtubules (MTs) during mitosis is critical for accurate chromosome segregation and genome stability. Cancer cell lines with hyperstabilized kinetochore MTs have increased segregation errors and elevated chromosomal instability (CIN), but the genetic defects responsible remain largely unknown. The MT depolymerase MCAK (mitotic centromere-associated kinesin) can influence CIN through its impact on MT stability, but how its potent activity is controlled in cells remains unclear. In this study, we show that GTSE1, a protein found overexpressed in aneuploid cancer cell lines and tumors, regulates MT stability during mitosis by inhibiting MCAK MT depolymerase activity. Cells lacking GTSE1 have defects in chromosome alignment and spindle positioning as a result of MT instability caused by excess MCAK activity. Reducing GTSE1 levels in CIN cancer cell lines reduces chromosome missegregation defects, whereas artificially inducing GTSE1 levels in chromosomally stable cells elevates chromosome missegregation and CIN. Thus, GTSE1 inhibition of MCAK activity regulates the balance of MT stability that determines the fidelity of chromosome alignment, segregation, and chromosomal stability.

scholarly journals A quantitative and semi-automated method for determining misaligned and lagging chromosomes during mitosis

2020 ◽  
pp. mbc.E20-09-0585
Author(s):  
Luciano Gama Braga ◽  
Diogjena Katerina Prifti ◽  
Chantal Garand ◽  
Pawan Kumar Saini ◽  
Sabine Elowe
Keyword(s):  
Chromosome Segregation ◽  
Hallmarks Of Cancer ◽  
Analytical Geometry ◽  
Daughter Cells ◽  
Chromosome Missegregation ◽  
Automated Method ◽  
Sister Chromatids ◽  
Chromosome Congression ◽  
Chromosome Alignment ◽  
In Cells

Accurate chromosome alignment at metaphase facilitates the equal segregation of sister chromatids to each of the nascent daughter cells. Lack of proper metaphase alignment is an indicator of defective chromosome congression and aberrant kinetochore-microtubule attachments which in turn promotes chromosome missegregation and aneuploidy, hallmarks of cancer. Tools to sensitively, accurately and quantitatively measure chromosome alignment at metaphase will facilitate understanding of the contribution of chromosome segregation errors to the development of aneuploidy. In this work, we have developed and validated a method based on analytical geometry to measure several indicators of chromosome misalignment. We generated semi-automated and flexible ImageJ2/Fiji pipelines to quantify kinetochore misalignment at metaphase plates as well as lagging chromosomes at anaphase. These tools will ultimately allow sensitive and systematic quantitation of these chromosome segregation defects in cells undergoing mitosis.

Immunocytochemical demonstration of collagen types I and IV in cells isolated from malignant mesothelioma and in lung cancer cell lines

Lung Cancer ◽  
1990 ◽  
Vol 6 (1-2) ◽  
pp. 16-27 ◽  
Author(s):  
H. Kataoka ◽  
B. Wikström ◽  
J. Klominek ◽  
R.E. Gay ◽  
S. Gay ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Malignant Mesothelioma ◽  
Cancer Cell Lines ◽  
Lung Cancer Cell ◽  
Collagen Types ◽  
In Cells

scholarly journals Chromosome oscillation promotes Aurora A–dependent Hec1 phosphorylation and mitotic fidelity

2021 ◽  
Vol 220 (7) ◽  
Author(s):  
Kenji Iemura ◽  
Toyoaki Natsume ◽  
Kayoko Maehara ◽  
Masato T. Kanemaki ◽  
Kozo Tanaka
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Chromosomal Instability ◽  
Oscillation Amplitude ◽  
Cancer Cell Lines ◽  
Aurora A ◽  
Chromosome Missegregation ◽  
Phosphorylation Level ◽  
Chromosome Motion

Most cancer cells show chromosomal instability, a condition where chromosome missegregation occurs frequently. We found that chromosome oscillation, an iterative chromosome motion during metaphase, is attenuated in cancer cell lines. We also found that metaphase phosphorylation of Hec1 at serine 55, which is mainly dependent on Aurora A on the spindle, is reduced in cancer cell lines. The Aurora A–dependent Hec1-S55 phosphorylation level was regulated by the chromosome oscillation amplitude and vice versa: Hec1-S55 and -S69 phosphorylation by Aurora A is required for efficient chromosome oscillation. Furthermore, enhancement of chromosome oscillation reduced the number of erroneous kinetochore–microtubule attachments and chromosome missegregation, whereas inhibition of Aurora A during metaphase increased such errors. We propose that Aurora A–mediated metaphase Hec1-S55 phosphorylation through chromosome oscillation, together with Hec1-S69 phosphorylation, ensures mitotic fidelity by eliminating erroneous kinetochore–microtubule attachments. Attenuated chromosome oscillation and the resulting reduced Hec1-S55 phosphorylation may be a cause of CIN in cancer cell lines.

scholarly journals Bipolar spindle attachments affect redistributions of ZW10, a Drosophila centromere/kinetochore component required for accurate chromosome segregation.

1996 ◽  
Vol 134 (5) ◽  
pp. 1127-1140 ◽  
Author(s):  
B C Williams ◽  
M Gatti ◽  
M L Goldberg
Keyword(s):  
Chromosome Segregation ◽  
Male Meiosis ◽  
Chromosome Behavior ◽  
Bipolar Spindle ◽  
Chromosome Missegregation ◽  
Spindle Poles ◽  
Anaphase Onset ◽  
Sister Chromatids ◽  
Chromosome Separation ◽  
Meiosis I

Previous efforts have shown that mutations in the Drosophila ZW10 gene cause massive chromosome missegregation during mitotic divisions in several tissues. Here we demonstrate that mutations in ZW10 also disrupt chromosome behavior in male meiosis I and meiosis II, indicating that ZW10 function is common to both equational and reductional divisions. Divisions are apparently normal before anaphase onset, but ZW10 mutants exhibit lagging chromosomes and irregular chromosome segregation at anaphase. Chromosome missegregation during meiosis I of these mutants is not caused by precocious separation of sister chromatids, but rather the nondisjunction of homologs. ZW10 is first visible during prometaphase, where it localizes to the kinetochores of the bivalent chromosomes (during meiosis I) or to the sister kinetochores of dyads (during meiosis II). During metaphase of both divisions, ZW10 appears to move from the kinetochores and to spread toward the poles along what appear to be kinetochore microtubules. Redistributions of ZW10 at metaphase require bipolar attachments of individual chromosomes or paired bivalents to the spindle. At the onset of anaphase I or anaphase II, ZW10 rapidly relocalizes to the kinetochore regions of the separating chromosomes. In other mutant backgrounds in which chromosomes lag during anaphase, the presence or absence of ZW10 at a particular kinetochore predicts whether or not the chromosome moves appropriately to the spindle poles. We propose that ZW10 acts as part of, or immediately downstream of, a tension-sensing mechanism that regulates chromosome separation or movement at anaphase onset.

scholarly journals Fluorescent transmembrane anion transporters: shedding light on anionophoric activity in cells

2016 ◽  
Vol 7 (8) ◽  
pp. 5069-5077 ◽  
Author(s):  
Stuart N. Berry ◽  
Vanessa Soto-Cerrato ◽  
Ethan N. W. Howe ◽  
Harriet J. Clarke ◽  
Ishna Mistry ◽  
...  
Keyword(s):  
Transport Properties ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Anion Transport ◽  
Anion Transporters ◽  
In Cells

A series of fluorescent anion transporters have been synthesised and their anion transport properties and interactions with cancer cell lines studied.

scholarly journals Sorafenib decreases proliferation and induces apoptosis of prostate cancer cells by inhibition of the androgen receptor and Akt signaling pathways

2012 ◽  
Vol 19 (3) ◽  
pp. 305-319 ◽  
Author(s):  
Su Jung Oh ◽  
Holger H H Erb ◽  
Alfred Hobisch ◽  
Frédéric R Santer ◽  
Zoran Culig
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cell Lines ◽  
Cancer Cell ◽  
Prostate Cancer Cell ◽  
Cancer Cell Lines ◽  
Prostate Cancer Cell Lines ◽  
Inhibition Of Proliferation ◽  
Prostate Cancers ◽  
In Cells

Antihormonal and chemotherapy are standard treatments for nonorgan-confined prostate cancer. The effectivity of these therapies is limited and the development of alternative approaches is necessary. In the present study, we report on the use of the multikinase inhibitor sorafenib in a panel of prostate cancer cell lines and their derivatives which mimic endocrine and chemotherapy resistance. 3H-thymidine incorporation assays revealed that sorafenib causes a dose-dependent inhibition of proliferation of all cell lines associated with downregulation of cyclin-dependent kinase 2 and cyclin D1 expression. Apoptosis was induced at 2 μM of sorafenib in androgen-sensitive cells, whereas a higher dose of the drug was needed in castration-resistant cell lines. Sorafenib stimulated apoptosis in prostate cancer cell lines through downregulation of myeloid cell leukemia-1 (MCL-1) expression and Akt phosphorylation. Although concentrations of sorafenib required for the antitumor effect in therapy-resistant sublines were higher than those needed in parental cells, the drug showed efficacy in cells which became resistant to bicalutamide and docetaxel respectively. Most interestingly, we show that sorafenib has an inhibitory effect on androgen receptor (AR) and prostate-specific antigen expression. In cells in which AR expression was downregulated by short interfering RNA, the treatment with sorafenib increased apoptosis in an additive manner. In summary, the results of the present study indicate that there is a potential to use sorafenib in prostate cancers as an adjuvant therapy option to current androgen ablation treatments, but also in progressed prostate cancers that become unresponsive to standard therapies.

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