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https://www.readbyqxmd.com/read/28430635/unsuccessful-mitosis-in-multicellular-tumour-spheroids
#1
Annie Molla, Morgane Couvet, Jean-Luc Coll
Multicellular spheroids are very attractive models in oncology because they mimic the 3D organization of the tumour cells with their microenvironment. We show here using 3 different cell types (mammary TSA/pc, embryonic kidney Hek293 and cervical cancer HeLa), that when the cells are growing as spheroids the frequency of binucleated cells is augmented as occurs in some human tumours.We therefore describe mitosis in multicellular spheroids by following mitotic markers and by time-lapse experiments. Chromosomes alignment appears to be correct on the metaphasic plate and the passenger complex is well localized on centromere...
February 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415805/regulatory-functional-territory-of-plk-1-and-their-substrates-beyond-mitosis
#2
REVIEW
Shiv Kumar, Garima Sharma, Chiranjib Chakraborty, Ashish Ranjan Sharma, Jaebong Kim
Polo-like kinase 1 (PLK-1) is a well-known (Ser/Thr) mitotic protein kinase and is considered as a proto-oncogene. As hyper-activation of PLK-1 is broadly associated with poor prognosis and cancer progression, it is one of the most extensively studied mitotic kinases. During mitosis, PLK-1 regulates various cell cycle events, such as spindle pole maturation, chromosome segregation and cytokinesis. However, studies have demonstrated that the role of PLK-1 is not only restricted to mitosis, but PLK-1 can also regulate other vital events beyond mitosis, including transcription, translation, ciliogenesis, checkpoint adaptation and recovery, apoptosis, chromosomes dynamics etc...
March 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415765/stable-aneuploid-tumors-cells-are-more-sensitive-to-ttk-inhibition-than-chromosomally-unstable-cell-lines
#3
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
#4
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/28410373/parallel-reorganization-of-protein-function-in-the-spindle-checkpoint-pathway-through-evolutionary-paths-in-the-fitness-landscape-that-appear-neutral-in-laboratory-experiments
#5
Alex N Nguyen Ba, Bob Strome, Selma Osman, Elizabeth-Ann Legere, Taraneh Zarin, Alan M Moses
Regulatory networks often increase in complexity during evolution through gene duplication and divergence of component proteins. Two models that explain this increase in complexity are: 1) adaptive changes after gene duplication, such as resolution of adaptive conflicts, and 2) non-adaptive processes such as duplication, degeneration and complementation. Both of these models predict complementary changes in the retained duplicates, but they can be distinguished by direct fitness measurements in organisms with short generation times...
April 14, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28410192/pellino-1-inactivates-mitotic-spindle-checkpoint-by-targeting-bubr1-for-ubiquitinational-degradation
#6
Jihyun Park, Hye-Young Park, Suhyeon Kim, Hyun-Soo Kim, Ji Y Park, Heounjeong Go, Chang-Woo Lee
Aberrant constitutive activation of receptor-mediated downstream signalling plays an active role in the deregulation of cell cycle control. The mitotic spindle checkpoint is important in preventing abnormal mitotic cell cycle with chromosome missegregation from achieving neoplastic aneuploidy. However, mechanisms coupling receptor-mediated signalling to mitotic spindle checkpoint regulation remain unclear. Pellino 1 is a receptor signal-responsive E3 ubiquitin ligase, and the application of certain receptor-mediated signalling regulates the expression and activity of Pellino 1...
March 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28404789/the-pp2a-b56-phosphatase-promotes-the-association-of-cdc20-with-apc-c-in-mitosis
#7
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
#8
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
#9
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
#10
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/28366744/fission-yeast-apc15-stabilizes-mcc-cdc20-apc-c-complexes-ensuring-efficient-cdc20-ubiquitination-and-checkpoint-arrest
#11
Karen M May, Flora Paldi, Kevin G Hardwick
During mitosis, cells must segregate the replicated copies of their genome to their daughter cells with extremely high fidelity. Segregation errors lead to an abnormal chromosome number (aneuploidy), which typically results in disease or cell death [1]. Chromosome segregation and anaphase onset are initiated through the action of the multi-subunit E3 ubiquitin ligase known as the anaphase-promoting complex or cyclosome (APC/C [2]). The APC/C is inhibited by the spindle checkpoint in the presence of kinetochore attachment defects [3, 4]...
March 28, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28364521/rna-immunoprecipitation-identifies-novel-targets-of-dazl-in-human-foetal-ovary
#12
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/28360097/chk2-overexpression-and-mislocalisation-within-mitotic-structures-enhances-chromosomal-instability-and-hepatocellular-carcinoma-progression
#13
Vinicio Carloni, Matteo Lulli, Stefania Madiai, Tommaso Mello, Andrew Hall, Tu Vinh Luong, Massimo Pinzani, Krista Rombouts, Andrea Galli
OBJECTIVE: Chromosomal instability (CIN) is the most common form of genomic instability, which promotes hepatocellular carcinoma (HCC) progression by enhancing tumour heterogeneity, drug resistance and immunity escape. CIN per se is an important factor of DNA damage, sustaining structural chromosome abnormalities but the underlying mechanisms are unknown. DESIGN: DNA damage response protein checkpoint kinase 2 (Chk2) expression was evaluated in an animal model of diethylnitrosamine-induced HCC characterised by DNA damage and elevated mitotic errors...
March 30, 2017: Gut
https://www.readbyqxmd.com/read/28356326/caenorhabditis-elegans-oocytes-detect-meiotic-errors-in-the-absence-of-canonical-end-on-kinetochore-attachments
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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