scholarly journals Heat shock‐induced mitotic arrest requires heat shock protein 105 for the activation of spindle assembly checkpoint

2018 ◽  
Vol 33 (3) ◽  
pp. 3936-3953 ◽  
Author(s):  
Ayana Kakihana ◽  
Yui Oto ◽  
Youhei Saito ◽  
Yuji Nakayama
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Mitotic Arrest

scholarly journals Depletion of Survivin suppresses docetaxel-induced apoptosis in HeLa cells by facilitating mitotic slippage

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Teng-Long Han ◽  
Hang Sha ◽  
Jun Ji ◽  
Yun-Tian Li ◽  
Deng-Shan Wu ◽  
...  
Keyword(s):  
Hela Cells ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Clonogenic Survival ◽  
Mitotic Arrest ◽  
Apoptosis Pathway ◽  
Mitotic Slippage ◽  
Intrinsic Apoptosis Pathway ◽  
Apoptosis Protein ◽  
Induced Apoptosis

AbstractThe anticancer effects of taxanes are attributed to the induction of mitotic arrest through activation of the spindle assembly checkpoint. Cell death following extended mitotic arrest is mediated by the intrinsic apoptosis pathway. Accordingly, factors that influence the robustness of mitotic arrest or disrupt the apoptotic machinery confer drug resistance. Survivin is an inhibitor of apoptosis protein. Its overexpression is associated with chemoresistance, and its targeting leads to drug sensitization. However, Survivin also acts specifically in the spindle assembly checkpoint response to taxanes. Hence, the failure of Survivin-depleted cells to arrest in mitosis may lead to taxane resistance. Here we show that Survivin depletion protects HeLa cells against docetaxel-induced apoptosis by facilitating mitotic slippage. However, Survivin depletion does not promote clonogenic survival of tumor cells but increases the level of cellular senescence induced by docetaxel. Moreover, lentiviral overexpression of Survivin does not provide protection against docetaxel or cisplatin treatment, in contrast to the anti-apoptotic Bcl-xL or Bcl-2. Our findings suggest that targeting Survivin may influence the cell response to docetaxel by driving the cells through aberrant mitotic progression, rather than directly sensitizing cells to apoptosis.

scholarly journals Melatonin protects mouse oocyte from heat stress damage

2020 ◽  
Vol 6 (3) ◽  
pp. 13
Author(s):  
Haiyan Du ◽  
Shouhong Wang ◽  
Weiwei Huang
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 70 ◽  
Spindle Assembly ◽  
Shock Group ◽  
Mouse Oocyte ◽  
Control Group ◽  
Mouse Oocytes ◽  
Early Apoptosis ◽  
Maturation Rate

Objective: To explore the potential effect of melatonin on the in-vitro maturation of mouse oocytes under heat shock condition.Methods: This study used a heat shock model of mouse oocyte maturation. The oocytes were randomly divided into three groups: control group, heat shock group and heat shock + melatonin group, in order to evaluate the effect of 1×10−9 mol/L melatonin on the quality of oocytes after heat shock.Results: In comparison with the control group, the maturation rate of mouse oocytes in heat shock group was significantly decreased [(33.00 ± 0.07)% vs. (85.00 ± 0.03)%, p < .01], with abnormal spindle assembly, and the early apoptosis rate was significantly increased [(59.7 ± 4.5)% vs. (22.0 ± 3.5)%, p < .01]. Compared with heat shock group, the maturation rate ofoocytes was significantly increased in heat shock + melatonin group [(70.00 ± 0.05)% vs. (33.00 ± 0.07)%, p < .01], meanwhile, the spindle abnormality rate and the early apoptosis rate were significantly decreased accordingly [(37.3 ± 6.1)% vs. (59.7 ± 4.5)%, p < .01]. The expression level of heat shock protein 70 was significantly up-regulated in heat shock + melatonin group in comparison with other two groups (p < .01).Conclusions: By regulating the over-expression of heat shock protein 70, melatonin can improve the declined maturation rate of oocytes and the increased rates of spindle assembly abnormality and early apoptosis caused by heat shock.

scholarly journals Probing Spindle Assembly Mechanisms with Monastrol, a Small Molecule Inhibitor of the Mitotic Kinesin, Eg5

2000 ◽  
Vol 150 (5) ◽  
pp. 975-988 ◽  
Author(s):  
Tarun M. Kapoor ◽  
Thomas U. Mayer ◽  
Margaret L. Coughlin ◽  
Timothy J. Mitchison
Keyword(s):  
Small Molecule ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Small Molecule Inhibitor ◽  
Mitotic Arrest ◽  
Molecule Inhibitor ◽  
Egg Extracts ◽  
A Cell ◽  
Kinesin Eg5 ◽  
Mitotic Kinesin Eg5

Monastrol, a cell-permeable small molecule inhibitor of the mitotic kinesin, Eg5, arrests cells in mitosis with monoastral spindles. Here, we use monastrol to probe mitotic mechanisms. We find that monastrol does not inhibit progression through S and G2 phases of the cell cycle or centrosome duplication. The mitotic arrest due to monastrol is also rapidly reversible. Chromosomes in monastrol-treated cells frequently have both sister kinetochores attached to microtubules extending to the center of the monoaster (syntelic orientation). Mitotic arrest–deficient protein 2 (Mad2) localizes to a subset of kinetochores, suggesting the activation of the spindle assembly checkpoint in these cells. Mad2 localizes to some kinetochores that have attached microtubules in monastrol-treated cells, indicating that kinetochore microtubule attachment alone may not satisfy the spindle assembly checkpoint. Monastrol also inhibits bipolar spindle formation in Xenopus egg extracts. However, it does not prevent the targeting of Eg5 to the monoastral spindles that form. Imaging bipolar spindles disassembling in the presence of monastrol allowed direct observations of outward directed forces in the spindle, orthogonal to the pole-to-pole axis. Monastrol is thus a useful tool to study mitotic processes, detection and correction of chromosome malorientation, and contributions of Eg5 to spindle assembly and maintenance.

scholarly journals Discovery of Novel Agents on Spindle Assembly Checkpoint to Sensitize Vinorelbine-Induced Mitotic Cell Death against Human Non-Small Cell Lung Cancers

2020 ◽  
Vol 21 (16) ◽  
pp. 5608
Author(s):  
Ya-Ching Chang ◽  
Yu-Ling Tseng ◽  
Wohn-Jenn Leu ◽  
Chi-Min Du ◽  
Yi-Huei Jiang ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
B Cell Lymphoma ◽  
Cyclin B1 ◽  
Mitotic Arrest ◽  
Small Cell ◽  
Nsclc Cell Line ◽  
Synergistic Activity ◽  
Small Cell Lung ◽  
Lung Cancers

Non-small cell lung cancer (NSCLC) accounts about 80% of all lung cancers. More than two-thirds of NSCLC patients have inoperable, locally advanced or metastatic tumors. Non-toxic agents that synergistically potentiate cancer-killing activities of chemotherapeutic drugs are in high demand. YL-9 was a novel and non-cytotoxic compound with the structure related to sildenafil but showing much less activity against phosphodiesterase type 5 (PDE5). NCI-H460, an NSCLC cell line with low PDE5 expression, was used as the cell model. YL-9 synergistically potentiated vinorelbine-induced anti-proliferative and apoptotic effects in NCI-H460 cells. Vinorelbine induced tubulin acetylation and Bub1-related kinase (BUBR1) phosphorylation, a necessary component in spindle assembly checkpoint. These effects, as well as BUBR1 cleavage, were substantially enhanced in co-treatment with YL-9. Several mitotic arrest signals were enhanced under combinatory treatment of vinorelbine and YL-9, including an increase of mitotic spindle abnormalities, increased cyclin B1 expression, B-cell lymphoma 2 (Bcl-2) phosphorylation and increased phosphoproteins. Moreover, YL-9 also displayed synergistic activity in combining with vinorelbine to induce apoptosis in A549 cells which express PDE5. In conclusion. the data suggest that YL-9 is a novel agent that synergistically amplifies vinorelbine-induced NSCLC apoptosis through activation of spindle assembly checkpoint and increased mitotic arrest of the cell cycle. YL-9 shows the potential for further development in combinatory treatment against NSCLC.

scholarly journals Alternative Cdc20 translational isoforms bypass the spindle assembly checkpoint to control mitotic arrest duration

2021 ◽  
Author(s):  
Mary Jane Tsang ◽  
Iain M Cheeseman
Keyword(s):  
Translational Regulation ◽  
Spindle Assembly Checkpoint ◽  
Critical Role ◽  
Spindle Assembly ◽  
Mitotic Arrest ◽  
Mitotic Exit ◽  
Regulatory Control ◽  
Cycle Arrest ◽  
Anaphase Onset ◽  
Mitotic Slippage

Mitotic chromosome segregation defects activate the Spindle Assembly Checkpoint (SAC), which inhibits the APC/C co-activator Cdc20 to induce a prolonged cell cycle arrest. Once errors are corrected, the SAC is silenced thereby allowing anaphase onset and mitotic exit to proceed. However, in the presence of persistent, unresolvable errors, cells can undergo "mitotic slippage", exiting mitosis into a tetraploid G1 state and escaping the cell death that results from a prolonged arrest. The molecular logic that allows cells to balance these dueling mitotic arrest and slippage behaviors remains unclear. Here we demonstrate that human cells modulate their mitotic arrest duration through the presence of conserved, alternative Cdc20 translational isoforms. Translation initiation at downstream start sites results in truncated Cdc20 isoforms that are resistant to SAC-mediated inhibition and promote mitotic exit even in the presence of mitotic perturbations. Targeted molecular changes or naturally-occurring mutations in cancer cells that alter the relative Cdc20 isoform levels or its translational regulatory control modulate both mitotic arrest duration and anti-mitotic drug sensitivity. Our work reveals a critical role for the differential translational regulation of Cdc20 in mitotic arrest timing, with important implications for the diagnosis and treatment of human cancers.

scholarly journals The Chromosomal Passenger Complex Controls Spindle Checkpoint Function Independent from Its Role in Correcting Microtubule–Kinetochore Interactions

2007 ◽  
Vol 18 (11) ◽  
pp. 4553-4564 ◽  
Author(s):  
Gerben Vader ◽  
Carin W.A. Cruijsen ◽  
Tanja van Harn ◽  
Martijn J.M. Vromans ◽  
René H. Medema ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Checkpoint ◽  
Coiled Coil ◽  
Spindle Assembly ◽  
Mitotic Arrest ◽  
Aurora B ◽  
Checkpoint Control ◽  
Chromosomal Passenger Complex ◽  
Coiled Coil Domain ◽  
Chromosomal Passenger

The chromosomal passenger complex (CPC) is a critical regulator of chromosome segregation during mitosis by correcting nonbipolar microtubule-kinetochore interactions. By severing these interactions, the CPC is thought to create unattached kinetochores that are subsequently sensed by the spindle assembly checkpoint (SAC) to prevent premature mitotic exit. We now show that spindle checkpoint function of the CPC and its role in eliminating nonbipolar attachments can be uncoupled. Replacing the chromosomal passenger protein INCENP with a mutant allele that lacks its coiled-coil domain results in an overt defect in a SAC-mediated mitotic arrest in response to taxol treatment, indicating that this domain is critical for CPC function in spindle checkpoint control. Surprisingly, this mutant could restore alignment and cytokinesis during unperturbed cell divisions and was capable of resolving syntelic attachments. Also, Aurora-B kinase was localized and activated normally on centromeres in these cells, ruling out a role for the coiled-coil domain in general Aurora-B activation. Thus, mere microtubule destabilization of nonbipolar attachments by the CPC is insufficient to install a checkpoint-dependent mitotic arrest, and additional, microtubule destabilization–independent CPC signaling toward the spindle assembly checkpoint is required for this arrest, potentially through amplification of the unattached kinetochore-derived checkpoint signal.

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