Cell division control by the Chromosomal Passenger Complex

Waal, Maike S. van der; Hengeveld, Rutger C C; Horst, Armando van der; Lens, Susanne M.A.

doi:10.1016/j.yexcr.2012.03.015

Cited by 137 publications

(110 citation statements)

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“…For example, XIAP and cIAP activate NF‐κB and c‐Jun N‐terminal kinases (JNK), resulting in cell survival and proliferation 21. Some studies have shown atypical roles for IAPs in chromosome segregation during cell mitosis 39, 41. Expression of cIAP1 is exclusively present in the cell nuclei of hematopoietic stem cells and some cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

et al. 2018

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Medulloblastoma (MB) is the most common type of malignant childhood brain tumor. We previously showed that inhibitors of apoptosis proteins (IAP) small‐molecule inhibitors (LCL161 or LBW242) combined with chemotherapy have synergistic antiproliferative effects on MB cells. The synergistic antitumor effects of combination treatments happen through induction of autophagy and caspase‐3/7‐activated apoptosis. Here, we investigated the effects of IAP inhibitors or silencing IAP on cell cycle regulation. We discovered that treatment with IAP inhibitors or their combination with conventional chemotherapy (vincristine or cisplatin), as well as RNAi knockdown of cIAP1/2 or XIAP arrested MB cells in the G2/M phase through downregulation of cyclin B1‐CDK1 and cyclin A‐CDK1/2. Among these three IAPs, only silencing cIAP1 expression enhanced p21 dependent‐G2/M phase accumulation. IAP inhibitors reduced cIAP1 expression and increased p21 expression in time course experiments. Furthermore, cIAP1 can govern p21 proteasomal degradation via neddylation in lieu of ubiquitination. Inhibition of IAPs significantly abrogated cIAP1‐mediated p21 degradation. We also observed an inverse correlation between nuclear cIAP1 and nuclear p21 expressions in MB tumor tissues. These findings provide new mechanistic evidence of the influence of IAP inhibitors on MB cell proliferation through disruption of the cell cycle.

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Section: Discussionmentioning

confidence: 99%

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

et al. 2018

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“…Thus, the presence of chromatin trapped in the cytokinesis plane may cause the regression of the cleavage furrow. As this delays or even prevents abscission and promotes polyploidy, [49][50][51][52] misaligned chromosomes resulting from an accelerated mitosis and SAC abrogation may account for the abortion of cytokinesis induced by MPS1 inhibitors. Consistently, videomicroscopic studies revealed that the progenies of Mps-BAY1-or Mps-BAY2a-treated cells often remain interconnected through a thin chromatin bridge and then fuse to form one single cell with a double chromosomal content.…”

Section: Discussionmentioning

confidence: 99%

Characterization of novel MPS1 inhibitors with preclinical anticancer activity

et al. 2013

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,5,6,11,12,13 Monopolar spindle 1 (MPS1), a mitotic kinase that is overexpressed in several human cancers, contributes to the alignment of chromosomes to the metaphase plate as well as to the execution of the spindle assembly checkpoint (SAC). Here, we report the identification and functional characterization of three novel inhibitors of MPS1 of two independent structural classes, N-(4-{2- [(2-cyanophenyl) and N-cyclopropyl-4-{8-(isobutylamino)imidazo[1,2-a]pyrazin-3-yl}benzamide (Mps-BAY2b) (two imidazopyrazines). By selectively inactivating MPS1, these small inhibitors can arrest the proliferation of cancer cells, causing their polyploidization and/or their demise. Cancer cells treated with Mps-BAY1 or Mps-BAY2a manifested multiple signs of mitotic perturbation including inefficient chromosomal congression during metaphase, unscheduled SAC inactivation and severe anaphase defects. Videomicroscopic cell fate profiling of histone 2B-green fluorescent protein-expressing cells revealed the capacity of MPS1 inhibitors to subvert the correct timing of mitosis as they induce a premature anaphase entry in the context of misaligned metaphase plates. Hence, in the presence of MPS1 inhibitors, cells either divided in a bipolar (but often asymmetric) manner or entered one or more rounds of abortive mitoses, generating gross aneuploidy and polyploidy, respectively. In both cases, cells ultimately succumbed to the mitotic catastrophe-induced activation of the mitochondrial pathway of apoptosis. Of note, low doses of MPS1 inhibitors and paclitaxel (a microtubular poison) synergized at increasing the frequency of chromosome misalignments and missegregations in the context of SAC inactivation. This resulted in massive polyploidization followed by the activation of mitotic catastrophe. A synergistic interaction between paclitaxel and MPS1 inhibitors could also be demonstrated in vivo, as the combination of these agents efficiently reduced the growth of tumor xenografts and exerted superior antineoplastic effects compared with either compound employed alone. Altogether, these results suggest that MPS1 inhibitors may exert robust anticancer activity, either as standalone therapeutic interventions or combined with microtubule-targeting chemicals. Mitosis is a sophisticated process that ensures the faithful inheritance of the genetic material by the cellular progeny while preventing aneuploidy and chromosomal instability (CIN), two established hallmarks of cancer. 1-3 A set of protein kinases that are collectively known as mitotic kinases, including Aurora kinases (AURKs), mitotic cyclin-dependent kinases (CDKs), Polo-like kinases and monopolar spindle 1 (MPS1), regulates and coordinates multiple aspects of chromosome segregation during mitosis. 4 MPS1 (also known as TTK) is a dual-specificity kinase (meaning that it phosphorylates both serine/threonine and tyrosine residues) with an established role in the proper alignment and orientation of chromosomes on the metaphase plate. 5 MPS1 is a core component of the spindle assembl...

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“…Aurora-B, together with the proteins INCENP, Survivin and Borealin, is a component of the chromosomal passenger complex (CPC), which localizes along the chromosome arms in prophase, concentrates in the inner centromere region from prometaphase to metaphase, moves to the central spindle and cortex in anaphase, and remains in the midbody in telophase (Lens et al 2010). The CPC ensures accurate chromosome segregation by regulating chromosome structure, cohesin removal from the chromosomal arms, spindle formation, kinetochore assembly, correction of non-bipolar chromosome-microtubule connections, spindle assembly checkpoint (SAC), and cytokinesis (van der Waal et al 2012). Aurora-C is highly similar to Aurora-B and joins the CPC, but it has been found expressed substantially only in germ cells during spermatogenesis and oogenesis, included meiosis, and in some cancer cell lines (Gabillard et al 2011, Baldini et al 2012a.…”

Section: Introductionmentioning

confidence: 99%

Effects of selective inhibitors of Aurora kinases on anaplastic thyroid carcinoma cell lines

Baldini¹,

Tuccilli²,

Prinzi³

et al. 2014

Endocrine Related Cancer

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Aurora kinases are serine/threonine kinases that play an essential role in cell division. Their aberrant expression and/or function induce severe mitotic abnormalities, resulting in either cell death or aneuploidy. Overexpression of Aurora kinases is often found in several malignancies, among which is anaplastic thyroid carcinoma (ATC). We have previously demonstrated the in vitro efficacy of Aurora kinase inhibitors in restraining cell growth and survival of different ATC cell lines. In this study, we sought to establish which Aurora might represent the preferential drug target for ATC. To this end, the effects of two selective inhibitors of Aurora-A (MLN8237) and Aurora-B (AZD1152) on four human ATC cell lines (CAL-62, BHT-101, 8305C, and 8505C) were analysed. Both inhibitors reduced cell proliferation in a time-and dose-dependent manner, with IC 50 ranges of 44.3-134.2 nM for MLN8237 and of 9.2-461.3 nM for AZD1152. Immunofluorescence experiments and time-lapse videomicroscopy yielded evidence that each inhibitor induced distinct mitotic phenotypes, but both of them prevented the completion of cytokinesis. As a result, poliploidy increased in all AZD1152-treated cells, and in two out of four cell lines treated with MLN8237. Apoptosis was induced in all the cells by MLN8237, and in BHT-101, 8305C, and 8505C by AZD1152, while CAL-62 exposed to AZD1152 died through necrosis after multiple rounds of endoreplication. Both inhibitors were capable of blocking anchorage-independent cell growth. In conclusion, we demonstrated that either Aurora-A or Aurora-B might represent therapeutic targets for the ATC treatment, but inhibition of Aurora-A appears more effective for suppressing ATC cell proliferation and for inducing the apoptotic pathway.

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Cell division control by the Chromosomal Passenger Complex

Cited by 137 publications

References 177 publications

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

Characterization of novel MPS1 inhibitors with preclinical anticancer activity

Effects of selective inhibitors of Aurora kinases on anaplastic thyroid carcinoma cell lines

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