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.

scholarly journals The Borealin dimerization domain interacts with Sgo1 to drive Aurora B–mediated spindle assembly

2020 ◽  
Vol 31 (20) ◽  
pp. 2207-2218 ◽  
Author(s):  
Mary Kate Bonner ◽  
Julian Haase ◽  
Hayden Saunders ◽  
Hindol Gupta ◽  
Biyun Iris Li ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Spindle Assembly ◽  
Specific Role ◽  
Aurora B ◽  
Dimerization Domain ◽  
Chromosomal Passenger Complex ◽  
Chromosomal Passenger ◽  
Segregation Of Chromosomes

This study provides the molecular mechanism for the interaction of Sgo1 with the chromosomal passenger complex and explores the specific role of Sgo1 in regulating Aurora B functions that ensure the equal segregation of chromosomes.

scholarly journals Uncoupling the Central Spindle-associated Function of the Chromosomal Passenger Complex from Its Role at Centromeres

2006 ◽  
Vol 17 (4) ◽  
pp. 1897-1909 ◽  
Author(s):  
Susanne M.A. Lens ◽  
Jose A. Rodriguez ◽  
Gerben Vader ◽  
Simone W. Span ◽  
Giuseppe Giaccone ◽  
...  
Keyword(s):  
Spindle Checkpoint ◽  
Aurora B ◽  
Deletion Mutants ◽  
Chromosomal Passenger Complex ◽  
Central Spindle ◽  
Survivin Protein ◽  
C Terminus ◽  
Chromosomal Passenger ◽  
Associated Function ◽  
Bir Domain

Survivin is a component of the chromosomal passenger complex (CPC) that plays a role in maintenance of an active spindle checkpoint and in cytokinesis. To study whether these different functions can be attributed to distinct domains within the Survivin protein, we complemented Survivin-depleted cells with a variety of point- and deletion-mutants of Survivin. We show that an intact baculovirus IAP repeat (BIR) domain is required for proper spindle checkpoint functioning, but dispensable for cytokinesis. In line with this, mutants lacking an intact BIR domain localized normally to the central spindle, but their localization to inner centromeres was severely perturbed. Consequently, these mutants failed to recruit Aurora B, Borealin/Dasra B, and BubR1 to centromeres and kinetochores, but they had retained the ability to recruit Aurora B and Borealin/Dasra B to the midzone and midbody. Thus, the C terminus of Survivin is sufficient for central spindle localization and execution of cytokinesis, but the additional presence of a functional BIR domain is essential for centromere targeting and spindle checkpoint function. Importantly, our data show that the function of the CPC at the centromere can be separated from its function at the central spindle and that execution of cytokinesis does not require prior concentration of the CPC at centromeres.

scholarly journals Chromosome-directed oocyte spindle assembly depends HP1 and the Chromosomal Passenger Complex

2020 ◽  
Author(s):  
Lin-Ing Wang ◽  
Tyler DeFosse ◽  
Rachel A. Battaglia ◽  
Victoria F. Wagner ◽  
Kim S. McKim
Keyword(s):  
Homologous Chromosome ◽  
Spindle Assembly ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Chromosomal Passenger Complex ◽  
Central Spindle ◽  
Bipolar Spindle ◽  
Chromosomal Passenger ◽  
Spindle Microtubules

AbstractThe chromosomes in the oocytes of many animals appear to promote bipolar spindle assembly. In Drosophila oocytes, spindle assembly requires the chromosomal passenger complex (CPC), which consists of INCENP, Borealin, Survivin and Aurora B. To determine what recruits the CPC to the chromosomes and its role in spindle assembly, we developed a strategy to manipulate the function and localization of INCENP, which is critical for recruiting the Aurora B kinase. We found that an interaction between Borealin and HP1 is crucial for the initial recruitment of the CPC to the chromosomes and is sufficient to build kinetochores and recruit spindle microtubules. We also found that HP1 moves from the chromosomes to the spindle microtubules along with the CPC, and based on this, propose a mechanism for how the CPC moves from the chromosomes to the microtubules. Within the central spindle, rather than at the centromeres, the CPC and HP1 are required for homologous chromosome bi-orientation.

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 Centromere-localized Aurora B kinase is required for the fidelity of chromosome segregation

2019 ◽  
Vol 219 (2) ◽  
Author(s):  
Cai Liang ◽  
Zhenlei Zhang ◽  
Qinfu Chen ◽  
Haiyan Yan ◽  
Miao Zhang ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Essential Role ◽  
Spindle Assembly Checkpoint ◽  
Histone H3 ◽  
Spindle Assembly ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Chromosome Missegregation ◽  
Proper Timing ◽  
Segregation Of Chromosomes

Aurora B kinase plays an essential role in chromosome bi-orientation, which is a prerequisite for equal segregation of chromosomes during mitosis. However, it remains largely unclear whether centromere-localized Aurora B is required for faithful chromosome segregation. Here we show that histone H3 Thr-3 phosphorylation (H3pT3) and H2A Thr-120 phosphorylation (H2ApT120) can independently recruit Aurora B. Disrupting H3pT3-mediated localization of Aurora B at the inner centromere impedes the decline in H2ApT120 during metaphase and causes H2ApT120-dependent accumulation of Aurora B at the kinetochore-proximal centromere. Consequently, silencing of the spindle assembly checkpoint (SAC) is delayed, whereas the fidelity of chromosome segregation is negligibly affected. Further eliminating an H2ApT120-dependent pool of Aurora B restores proper timing for SAC silencing but increases chromosome missegregation. Our data indicate that H2ApT120-mediated localization of Aurora B compensates for the loss of an H3pT3-dependent pool of Aurora B to correct improper kinetochore–microtubule attachments. This study provides important insights into how centromeric Aurora B regulates SAC and kinetochore attachment to microtubules to ensure error-free chromosome segregation.

Interplay between mitotic kinesins and the Aurora kinase–PP1 (protein phosphatase 1) axis

2013 ◽  
Vol 41 (6) ◽  
pp. 1761-1765 ◽  
Author(s):  
John C. Meadows
Keyword(s):  
Protein Phosphatase ◽  
Spindle Assembly Checkpoint ◽  
Spindle Checkpoint ◽  
Aurora Kinase ◽  
Protein Phosphatase 1 ◽  
Aurora B ◽  
Spatial Gradient ◽  
Cell Cycle Regulators ◽  
Aurora B Kinase ◽  
Surveillance Mechanism

Correct transmission of genetic information from mother to daughter cells is necessary for development and survival. Accurate segregation is achieved by bipolar attachment of sister kinetochores in each chromatid pair to spindle microtubules emanating from opposite spindle poles, a process known as chromosome bi-orientation. Achieving this requires dynamic interplay between kinetochore proteins, kinesin motor proteins and cell cycle regulators. Chromosome bi-orientation is monitored by a surveillance mechanism known as the SAC (spindle assembly checkpoint). The Aurora B kinase, which is bound to the inner centromere during early mitosis, plays a central role in both chromosome bi-orientation and the spindle checkpoint. The application of tension across centromeres establishes a spatial gradient of high phosphorylation activity at the inner centromere and low phosphorylation activity at the outer kinetochore. This gradient is further refined by the association of PP1 (protein phosphatase 1) to the outer kinetochore, which stabilizes kinetochore–microtubule interactions and silences the spindle checkpoint by dephosphorylating Aurora B kinase targets when chromosome bi-orientation is achieved. In the present review, I discuss emerging evidence that bidirectional cross-talk between mitotic kinesins and the Aurora kinase–PP1 axis is crucial for co-ordinating chromosome bi-orientation and spindle checkpoint signalling in eukaryotes.

scholarly journals Bub1, Sgo1, and Mps1 mediate a distinct pathway for chromosome biorientation in budding yeast

2011 ◽  
Vol 22 (9) ◽  
pp. 1473-1485 ◽  
Author(s):  
Zuzana Storchová ◽  
Justin S. Becker ◽  
Nicolas Talarek ◽  
Sandra Kögelsberger ◽  
David Pellman
Keyword(s):  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Budding Yeast ◽  
Spindle Pole ◽  
Growth Defect ◽  
Aurora B ◽  
Mitotic Kinase ◽  
Sister Chromatids ◽  
Chromosome Alignment ◽  
Chromosomal Passenger

The conserved mitotic kinase Bub1 performs multiple functions that are only partially characterized. Besides its role in the spindle assembly checkpoint and chromosome alignment, Bub1 is crucial for the kinetochore recruitment of multiple proteins, among them Sgo1. Both Bub1 and Sgo1 are dispensable for growth of haploid and diploid budding yeast, but they become essential in cells with higher ploidy. We find that overexpression of SGO1 partially corrects the chromosome segregation defect of bub1Δ haploid cells and restores viability to bub1Δ tetraploid cells. Using an unbiased high-copy suppressor screen, we identified two members of the chromosomal passenger complex (CPC), BIR1 (survivin) and SLI15 (INCENP, inner centromere protein), as suppressors of the growth defect of both bub1Δ and sgo1Δ tetraploids, suggesting that these mutants die due to defects in chromosome biorientation. Overexpression of BIR1 or SLI15 also complements the benomyl sensitivity of haploid bub1Δ and sgo1Δ cells. Mutants lacking SGO1 fail to biorient sister chromatids attached to the same spindle pole (syntelic attachment) after nocodazole treatment. Moreover, the sgo1Δ cells accumulate syntelic attachments in unperturbed mitoses, a defect that is partially corrected by BIR1 or SLI15 overexpression. We show that in budding yeast neither Bub1 nor Sgo1 is required for CPC localization or affects Aurora B activity. Instead we identify Sgo1 as a possible partner of Mps1, a mitotic kinase suggested to have an Aurora B–independent function in establishment of biorientation. We found that Sgo1 overexpression rescues defects caused by metaphase inactivation of Mps1 and that Mps1 is required for Sgo1 localization to the kinetochore. We propose that Bub1, Sgo1, and Mps1 facilitate chromosome biorientation independently of the Aurora B–mediated pathway at the budding yeast kinetochore and that both pathways are required for the efficient turnover of syntelic attachments.

scholarly journals Uncoupling Anaphase-Promoting Complex/Cyclosome Activity from Spindle Assembly Checkpoint Control by Deregulating Polo-Like Kinase 1

2005 ◽  
Vol 25 (5) ◽  
pp. 2031-2044 ◽  
Author(s):  
Barbara C. M. van de Weerdt ◽  
Marcel A. T. M. van Vugt ◽  
Catherine Lindon ◽  
Jos J. W. Kauw ◽  
Marieke J. Rozendaal ◽  
...  
Keyword(s):  
Double Mutant ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Mitotic Catastrophe ◽  
Anaphase Promoting Complex ◽  
Checkpoint Control ◽  
Mitotic Progression ◽  
Specific Antibodies ◽  
Mitotic Entry

ABSTRACT Polo-like kinase 1 (Plk1) plays a role in numerous events in mitosis, but how the multiple functions of Plk1 are separated is poorly understood. We studied regulation of Plk1 through two putative phosphorylation residues, Ser-137 and Thr-210. Using phospho-specific antibodies, we found that Thr-210 phosphorylation precedes Ser-137 phosphorylation in vivo, the latter occurring specifically in late mitosis. We show that expression of two activating mutants of these residues, S137D and T210D, results in distinct mitotic phenotypes. Whereas expression of both phospho-mimicking mutants as well as of the double mutant leads to accelerated mitotic entry, further progression through mitosis is dramatically different: the T210D mutant causes a spindle assembly checkpoint-dependent delay, whereas the expression of the S137D mutant or the double mutant results in untimely activation of the anaphase-promoting complex/cyclosome (APC/C) and frequent mitotic catastrophe. Using nonphosphorylatable Plk1-S137A and Plk1-T210A mutants, we show that both sites contribute to proper mitotic progression. Based on these observations, we propose that Plk1 function is altered at different stages of mitosis through consecutive posttranslational events, e.g., at Ser-137 and Thr-210. Furthermore, our data show that uncontrolled Plk1 activation can uncouple APC/C activity from spindle assembly checkpoint control.

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