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Spindle Assembly Checkpoint

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https://www.readbyqxmd.com/read/28415765/stable-aneuploid-tumors-cells-are-more-sensitive-to-ttk-inhibition-than-chromosomally-unstable-cell-lines
#1
Marion A A Libouban, Jeroen A D M de Roos, Joost C M Uitdehaag, Nicole Willemsen-Seegers, Sara Mainardi, Jelle Dylus, Jos de Man, Bastiaan Tops, Jules P P Meijerink, Zuzana Storchová, Rogier C Buijsman, René H Medema, Guido J R Zaman
Inhibition of the spindle assembly checkpoint kinase TTK causes chromosome mis-segregation and tumor cell death. However, high levels of TTK correlate with chromosomal instability (CIN), which can lead to aneuploidy. We show that treatment of tumor cells with the selective small molecule TTK inhibitor NTRC 0066-0 overrides the mitotic checkpoint, irrespective of cell line sensitivity. In stable aneuploid cells NTRC 0066-0 induced acute CIN, whereas in cells with high levels of pre-existing CIN there was only a small additional fraction of cells mis-segregating their chromosomes...
March 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415623/overexpression-of-ubiquitin-specific-proteases-44-promotes-the-malignancy-of-glioma-by-stabilizing-tumor-promoter-securin
#2
Yongxiang Zou, Guanzhong Qiu, Lei Jiang, Zheng Cai, Wei Sun, Hongkang Hu, Chengyin Lu, Weilin Jin, Guohan Hu
Ubiquitin specific peptidase 44 (USP44) has been identified as an important component of spindle assemble checkpoint (SAC) to prevent the formation of aneuploidy. However, recent study raised a controversy about the effect of USP44 in tumor. Here, we first confirmed the intranuclear localization of USP44 by testing several specific antibodies to recognize endogenous USP44. Then, data from IHC and qRT-PCR assay indicated that the high expression of USP44 existed in high-grade glioma tissues and signified a poor prognosis...
March 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28404789/the-pp2a-b56-phosphatase-promotes-the-association-of-cdc20-with-apc-c-in-mitosis
#3
Sun Joo Lee, Veronica Rodriguez-Bravo, Hyunjung Kim, Sutirtha Datta, Emily A Foley
PP2A(B56) is a serine/threonine phosphatase essential for mitosis. At the kinetochore, PP2A(B56) both stabilizes microtubule binding and promotes silencing of the spindle assembly checkpoint (SAC) through its association with the SAC protein BubR1. Cells depleted of the B56 regulatory subunits of PP2A are delayed in APC/C(Cdc20) activation, an essential step for mitotic exit. It has been hypothesized that this delay arises from increased production of the mitotic checkpoint complex (MCC), an APC/C(Cdc20) inhibitor formed at unattached kinetochores through SAC signaling...
April 12, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28386668/a-mathematical-framework-for-kinetochore-driven-activation-feedback-in-the-mitotic-checkpoint
#4
Bashar Ibrahim
Proliferating cells properly divide into their daughter cells through a process that is mediated by kinetochores, protein-complexes that assemble at the centromere of each sister chromatid. Each kinetochore has to establish a tight bipolar attachment to the spindle apparatus before sister chromatid separation is initiated. The spindle assembly checkpoint (SAC) links the biophysical attachment status of the kinetochores to mitotic progression and ensures that even a single misaligned kinetochore keeps the checkpoint active...
April 6, 2017: Bulletin of Mathematical Biology
https://www.readbyqxmd.com/read/28380042/genetic-and-pharmacological-inhibition-of-ttk-impairs-pancreatic-cancer-cell-line-growth-by-inducing-lethal-chromosomal-instability
#5
Jeran K Stratford, Feng Yan, Rebecca A Hill, Michael B Major, Lee M Graves, Channing J Der, Jen Jen Yeh
Pancreatic ductal adenocarcinoma, which accounts for the majority of pancreatic cancers, is a lethal disease with few therapeutic options. Genomic profiling of pancreatic ductal adenocarcinoma has identified a complex and heterogeneous landscape. Understanding the molecular characteristics of pancreatic ductal adenocarcinoma will facilitate the identification of potential therapeutic strategies. We analyzed the gene expression profiles of primary tumors from patients compared to normal pancreas and identified high co-overexpression of core components of the spindle assembly checkpoint, including the protein kinase TTK (also known as MPS-1)...
2017: PloS One
https://www.readbyqxmd.com/read/28379780/akap95-interacts-with-nucleoporin-tpr-in-mitosis-and-is-important-for-the-spindle-assembly-checkpoint
#6
Graciela López-Soop, Torunn Rønningen, Agnieszka Rogala, Nina Richartz, Heidi Kiil Blomhoff, Bernd Thiede, Philippe Collas, Thomas Küntziger
Faithful chromosome segregation during mitosis relies on a proofreading mechanism that monitors proper kinetochore-microtubule attachments. The spindle assembly checkpoint (SAC) is based on the concerted action of numerous components that maintain a repressive signal inhibiting transition into anaphase until all chromosomes are attached. Here we show that A-Kinase Anchoring Protein 95 (AKAP95) is necessary for proper SAC function. AKAP95-depleted HeLa cells show micronuclei formed from lagging chromosomes at mitosis...
April 5, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28364521/rna-immunoprecipitation-identifies-novel-targets-of-dazl-in-human-foetal-ovary
#7
Roseanne Rosario, Richard W P Smith, Ian R Adams, Richard A Anderson
Study question: Can novel meiotic RNA targets of DAZL (deleted in azoospermia-like) be identified in the human foetal ovary? Summary answer: SYCP1 (synaptonemal complex protein-1), TEX11 (testis expressed 11) and SMC1B (structural maintenance of chromosomes 1B) are novel DAZL targets in the human foetal ovary, thus DAZL may have previously unrecognised roles in the translational regulation of RNAs involved in chromosome cohesion and DNA recombination in the oocyte from the time of initiation of meiosis...
March 1, 2017: Molecular Human Reproduction
https://www.readbyqxmd.com/read/28356326/caenorhabditis-elegans-oocytes-detect-meiotic-errors-in-the-absence-of-canonical-end-on-kinetochore-attachments
#8
Amanda C Davis-Roca, Christina C Muscat, Sarah M Wignall
Mitotically dividing cells use a surveillance mechanism, the spindle assembly checkpoint, that monitors the attachment of spindle microtubules to kinetochores as a means of detecting errors. However, end-on kinetochore attachments have not been observed in Caenorhabditis elegans oocytes and chromosomes instead associate with lateral microtubule bundles; whether errors can be sensed in this context is not known. Here, we show that C. elegans oocytes delay key events in anaphase, including AIR-2/Aurora B relocalization to the microtubules, in response to a variety of meiotic defects, demonstrating that errors can be detected in these cells and revealing a mechanism that regulates anaphase progression...
March 29, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28351953/sphingosine-1-phosphate-signaling-through-its-receptor-s1p5-promotes-chromosome-segregation-and-mitotic-progression
#9
Guillaume Andrieu, Adeline Ledoux, Sophie Branka, Magalie Bocquet, Julia Gilhodes, Thierry Walzer, Kousuke Kasahara, Masaki Inagaki, Roger A Sabbadini, Olivier Cuvillier, Anastassia Hatzoglou
Sphingosine kinase 1 (SphK1) promotes cell proliferation and survival, and its abundance is often increased in tumors. SphK1 produces the signaling lipid sphingosine 1-phosphate (S1P), which activates signaling cascades downstream five G protein-coupled receptors (S1P1-5) to modulate vascular and immune system function and promote proliferation. We identified a new function of the SphK1-S1P pathway specifically in the control of mitosis. SphK1 depletion in HeLa cells caused prometaphase arrest, whereas its overexpression or activation accelerated mitosis...
March 28, 2017: Science Signaling
https://www.readbyqxmd.com/read/28351851/centrosome-and-spindle-assembly-checkpoint-loss-leads-to-neural-apoptosis-and-reduced-brain-size
#10
John S Poulton, John C Cuningham, Mark Peifer
Accurate mitotic spindle assembly is critical for mitotic fidelity and organismal development. Multiple processes coordinate spindle assembly and chromosome segregation. Two key components are centrosomes and the spindle assembly checkpoint (SAC), and mutations affecting either can cause human microcephaly. In vivo studies in Drosophila melanogaster found that loss of either component alone is well tolerated in the developing brain, in contrast to epithelial tissues of the imaginal discs. In this study, we reveal that one reason for that tolerance is the compensatory relationship between centrosomes and the SAC...
March 28, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28349831/cell-division-cycle-20-overexpression-predicts-poor-prognosis-for-patients-with-lung-adenocarcinoma
#11
Run Shi, Qi Sun, Jing Sun, Xin Wang, Wenjie Xia, Gaochao Dong, Anpeng Wang, Feng Jiang, Lin Xu
The cell division cycle 20, a key component of spindle assembly checkpoint, is an essential activator of the anaphase-promoting complex. Aberrant expression of cell division cycle 20 has been detected in various human cancers. However, its clinical significance has never been deeply investigated in non-small-cell lung cancer. By analyzing The Cancer Genome Atlas database and using some certain online databases, we validated overexpression of cell division cycle 20 in both messenger RNA and protein levels, explored its clinical significance, and evaluated the prognostic role of cell division cycle 20 in non-small-cell lung cancer...
March 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28334731/characterisation-of-cct271850-a-selective-oral-and-potent-mps1-inhibitor-used-to-directly-measure-in-vivo-mps1-inhibition-vs-therapeutic-efficacy
#12
Amir Faisal, Grace W Y Mak, Mark D Gurden, Cristina P R Xavier, Simon J Anderhub, Paolo Innocenti, Isaac M Westwood, Sébastien Naud, Angela Hayes, Gary Box, Melanie R Valenti, Alexis K De Haven Brandon, Lisa O'Fee, Jessica Schmitt, Hannah L Woodward, Rosemary Burke, Rob L M vanMontfort, Julian Blagg, Florence I Raynaud, Suzanne A Eccles, Swen Hoelder, Spiros Linardopoulos
BACKGROUND: The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis. One of the best characterised checkpoint pathways is the spindle assembly checkpoint, which prevents anaphase onset until the appropriate attachment and tension across kinetochores is achieved. MPS1 kinase activity is essential for the activation of the spindle assembly checkpoint and has been shown to be deregulated in human tumours with chromosomal instability and aneuploidy...
March 23, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28320825/structure-of-the-rzz-complex-and-molecular-basis-of-its-interaction-with-spindly
#13
Shyamal Mosalaganti, Jenny Keller, Anika Altenfeld, Michael Winzker, Pascaline Rombaut, Michael Saur, Arsen Petrovic, Annemarie Wehenkel, Sabine Wohlgemuth, Franziska Müller, Stefano Maffini, Tanja Bange, Franz Herzog, Herbert Waldmann, Stefan Raunser, Andrea Musacchio
Kinetochores are macromolecular assemblies that connect chromosomes to spindle microtubules (MTs) during mitosis. The metazoan-specific ≈800-kD ROD-Zwilch-ZW10 (RZZ) complex builds a fibrous corona that assembles on mitotic kinetochores before MT attachment to promote chromosome alignment and robust spindle assembly checkpoint signaling. In this study, we combine biochemical reconstitutions, single-particle electron cryomicroscopy, cross-linking mass spectrometry, and structural modeling to build a complete model of human RZZ...
April 3, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28320824/molecular-mechanism-of-dynein-recruitment-to-kinetochores-by-the-rod-zw10-zwilch-complex-and-spindly
#14
José B Gama, Cláudia Pereira, Patrícia A Simões, Ricardo Celestino, Rita M Reis, Daniel J Barbosa, Helena R Pires, Cátia Carvalho, João Amorim, Ana X Carvalho, Dhanya K Cheerambathur, Reto Gassmann
The molecular motor dynein concentrates at the kinetochore region of mitotic chromosomes in animals to accelerate spindle microtubule capture and to control spindle checkpoint signaling. In this study, we describe the molecular mechanism used by the Rod-Zw10-Zwilch complex and the adaptor Spindly to recruit dynein to kinetochores in Caenorhabditis elegans embryos and human cells. We show that Rod's N-terminal β-propeller and the associated Zwilch subunit bind Spindly's C-terminal domain, and we identify a specific Zwilch mutant that abrogates Spindly and dynein recruitment in vivo and Spindly binding to a Rod β-propeller-Zwilch complex in vitro...
April 3, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28318489/deletion-of-the-mad2l1-spindle-assembly-checkpoint-gene-is-tolerated-in-mouse-models-of-acute-t-cell-lymphoma-and-hepatocellular-carcinoma
#15
Floris Foijer, Lee A Albacker, Bjorn Bakker, Diana C Spierings, Ying Yue, Stephanie Z Xie, Stephanie H Davis, Annegret Lutum-Jehle, Darin Takemoto, Brian Hare, Brinley Furey, Roderick T Bronson, Peter M Lansdorp, Allan Bradley, Peter K Sorger
Chromosome instability (CIN) is deleterious to normal cells because of the burden of aneuploidy. However, most human solid tumors have an abnormal karyotype implying that gain and loss of chromosomes by cancer cells confers a selective advantage. CIN can be induced in the mouse by inactivating the spindle assembly checkpoint. This is lethal in the germline but we show here that adult T cells and hepatocytes can survive conditional inactivation of the Mad2l1 SAC gene and resulting CIN. This causes rapid onset of acute lymphoblastic leukemia (T-ALL) and progressive development of hepatocellular carcinoma (HCC), both lethal diseases...
March 20, 2017: ELife
https://www.readbyqxmd.com/read/28315713/maternal-senp7-programs-meiosis-architecture-and-embryo-survival-in-mouse
#16
ChunJie Huang, Di Wu, XiaoFei Jiao, Faheem Ahmed Khan, ChengLiang Xiong, XiaoMing Liu, Jing Yang, TaiLang Yin, LiJun Huo
Understanding the mechanisms underlying abnormal egg production and pregnancy loss is significant for human fertility. SENP7, a SUMO poly-chain editing enzyme, has been regarded as a mitotic regulator of heterochromatin integrity and DNA repair. Herein, we report the roles of SENP7 in mammalian reproductive scenario. Mouse oocytes deficient in SENP7 experienced meiotic arrest at prophase I and metaphase I stages, causing substantial decrease of mature eggs. Hyperaceylation and hypomethylation of histone H3 and up-regulation of Cdc14B/C accompanied by down-regulation of CyclinB1 and CyclinB2 were further recognized as contributors to defective M-phase entry and spindle assembly in oocytes...
March 15, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28315405/location-and-functional-analysis-of-the-aspergillus-nidulans-aurora-kinase-confirm-mitotic-functions-and-suggest-non-mitotic-roles
#17
Colin P De Souza, Shahr B Hashmi, Natalie Hage, Rebecca M Fitch, Aysha H Osmani, Stephen A Osmani
Filamentous fungi have devastating negative impacts as pathogens and agents of food spoilage but also have critical ecological importance and are utilized for industrial applications. The characteristic multinucleate nature of filamentous fungi is facilitated by limiting if, when and where septation, the fungal equivalent of cytokinesis, occurs. In the model filamentous fungus Aspergillus nidulans septation does not occur immediately after mitosis and is an incomplete process resulting in the formation of a septal pore whose permeability is cell cycle regulated...
March 14, 2017: Fungal Genetics and Biology: FG & B
https://www.readbyqxmd.com/read/28299790/tc-mps1-12-a-novel-mps1-inhibitor-suppresses-a-growth-of-hepatocellular-carcinoma-cells-via-accumulated-chromosomal-instability
#18
Minji Choi, Yoo Hong Min, Jaehyuk Pyo, Chang-Woo Lee, Chang-Young Jang, Ja-Eun Kim
BACKGROUND AND PURPOSE: Chromosomal instability is not only a hallmark of cancer, but also an attractive therapeutic target. A diverse set of mitotic kinases maintains chromosomal stability. One of these is monopolar spindle 1 (Mps1), which is essential for chromosome alignment and for the spindle assembly checkpoint (SAC). Pharmacological inhibition of Mps1 has been suggested as a cancer therapeutic; however, despite the existence of a novel Mps1 inhibitor, TC Mps1 12, no such studies have been performed...
March 15, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28298492/-wait-anaphase-signals-are-not-confined-to-the-mitotic-spindle
#19
Lydia Reńe Heasley, Steven M Markus, Jennifer G DeLuca
The Spindle Assembly Checkpoint ensures the faithful inheritance of chromosomes by arresting mitotic progression in the presence of kinetochores that are not attached to spindle microtubules. This is achieved through inhibition of the Anaphase Promoting Complex/Cyclosome by a kinetochore-derived 'wait anaphase' signal known as the Mitotic Checkpoint Complex. It remains unclear whether the localization and activity of these inhibitory complexes are restricted to the mitotic spindle compartment or are diffusible throughout the cytoplasm...
March 15, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28287092/loss-of-centromere-cohesion-in-aneuploid-human-oocytes-correlates-with-decreased-kinetochore-localization-of-the-sac-proteins-bub1-and-bubr1
#20
Julie Lagirand-Cantaloube, Cendrine Ciabrini, Sophie Charrasse, Alice Ferrieres, Anna Castro, Tal Anahory, Thierry Lorca
In human eggs, aneuploidy increases with age and can result in infertility and genetic diseases. Studies in mouse oocytes suggest that reduced centromere cohesion and spindle assembly checkpoint (SAC) activity could be at the origin of chromosome missegregation. Little is known about these two features in humans. Here, we show that in human eggs, inter-kinetochore distances of bivalent chromosomes strongly increase with age. This results in the formation of univalent chromosomes during metaphase I (MI) and of single chromatids in metaphase II (MII)...
March 13, 2017: Scientific Reports
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