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Spindle assembly checkpoint targets

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https://www.readbyqxmd.com/read/28638452/targeting-tpx2-suppresses-the-tumorigenesis-of-hepatocellular-carcinoma-cells-resulting-in-arrested-mitotic-phase-progression-and-increased-genomic-instability
#1
Chao-Wen Hsu, Yu-Chia Chen, Hsing-Hao Su, Guan-Jin Huang, Chih-Wen Shu, Tony Tong-Lin Wu, Hung-Wei Pan
Hepatocellular carcinoma (HCC) remains one of the most difficult cancers to treat, with chemotherapies being relatively ineffective. Therefore, a better knowledge of molecular hepatocarcinogenesis will provide opportunities for designing targeted therapies. TPX2 (targeting protein for Xklp2) is overexpressed as a consequence of oncogenic alterations and is likely to alter the proper regulation of chromosome segregation in cancer cells. Disrupting the machinery which is responsible for mitosis and chromosome instability in cancer cells can be one of the most successful strategies for cancer therapy...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28604727/bub1-positions-mad1-close-to-knl1-melt-repeats-to-promote-checkpoint-signalling
#2
Gang Zhang, Thomas Kruse, Blanca López-Méndez, Kathrine Beck Sylvestersen, Dimitriya H Garvanska, Simone Schopper, Michael Lund Nielsen, Jakob Nilsson
Proper segregation of chromosomes depends on a functional spindle assembly checkpoint (SAC) and requires kinetochore localization of the Bub1 and Mad1/Mad2 checkpoint proteins. Several aspects of Mad1/Mad2 kinetochore recruitment in human cells are unclear and in particular the underlying direct interactions. Here we show that conserved domain 1 (CD1) in human Bub1 binds directly to Mad1 and a phosphorylation site exists in CD1 that stimulates Mad1 binding and SAC signalling. Importantly, fusion of minimal kinetochore-targeting Bub1 fragments to Mad1 bypasses the need for CD1, revealing that the main function of Bub1 is to position Mad1 close to KNL1 MELT repeats...
June 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/28539250/target-residence-time-guided-optimization-on-ttk-kinase-results-in-inhibitors-with-potent-anti-proliferative-activity
#3
Joost C M Uitdehaag, Jos de Man, Nicole Willemsen-Seegers, Martine B W Prinsen, Marion A A Libouban, Jan Gerard Sterrenburg, Joeri J P de Wit, Judith R F de Vetter, Jeroen A D M de Roos, Rogier C Buijsman, Guido J R Zaman
The protein kinase threonine tyrosine kinase (TTK; also known as Mps1) is a critical component of the spindle assembly checkpoint and a promising drug target for the treatment of aggressive cancers, such as triple negative breast cancer. While the first TTK inhibitors have entered clinical trials, little is known about how the inhibition of TTK with small-molecule compounds affects cellular activity. We studied the selective TTK inhibitor NTRC 0066-0, which was developed in our own laboratory, together with 11 TTK inhibitors developed by other companies, including Mps-BAY2b, BAY 1161909, BAY 1217389 (Bayer), TC-Mps1-12 (Shionogi), and MPI-0479605 (Myrexis)...
May 21, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28463114/protein-phosphatase-1-inactivates-mps1-to-ensure-efficient-spindle-assembly-checkpoint-silencing
#4
Margarida Moura, Mariana Osswald, Nelson Leça, João Barbosa, António J Pereira, Helder Maiato, Claudio E Sunkel, Carlos Conde
Faithfull genome partitioning during cell division relies on the Spindle Assembly Checkpoint (SAC), a conserved signaling pathway that delays anaphase onset until all chromosomes are attached to spindle microtubules. Mps1 kinase is an upstream SAC regulator that promotes the assembly of an anaphase inhibitor through a sequential multi-target phosphorylation cascade. Thus, the SAC is highly responsive to Mps1, whose activity peaks in early mitosis as a result of its T-loop autophosphorylation. However, the mechanism controlling Mps1 inactivation once kinetochores attach to microtubules and the SAC is satisfied remains unknown...
May 2, 2017: ELife
https://www.readbyqxmd.com/read/28458300/rna-associated-protein-lsm-family-member-14-controls-oocyte-meiotic-maturation-through-regulating-mrna-pools
#5
Teng Zhang, Yuanyuan Li, Hui Li, Xue-Shan Ma, Ying-Chun Ouyang, Yi Hou, Heide Schatten, Qing-Yuan Sun
LSM family member 14 (LSM14) belongs to the RNA-associated protein (RAP) family that is widely expressed in different species, and whose functions include associating and storing mRNAs. In the present study, we found that LSM14b was essential for oocyte meiotic maturation. Lack of LSM14b caused oocyte meiotic arrest at metaphase, and misalignment of chromosomes, as well as abnormal spindle assembly checkpoint (SAC) and maturation promoting factor (MPF) activation. Cyclin B1 and Cdc20 mRNAs, whose contents changed with LSM14b expression, were likely direct targets of LSM14b...
April 30, 2017: Journal of Reproduction and Development
https://www.readbyqxmd.com/read/28441529/mps1-regulates-kinetochore-microtubule-attachment-stability-via-the-ska-complex-to-ensure-error-free-chromosome-segregation
#6
John Maciejowski, Hauke Drechsler, Kathrin Grundner-Culemann, Edward R Ballister, Jose-Antonio Rodriguez-Rodriguez, Veronica Rodriguez-Bravo, Mathew J K Jones, Emily Foley, Michael A Lampson, Henrik Daub, Andrew D McAinsh, Prasad V Jallepalli
The spindle assembly checkpoint kinase Mps1 not only inhibits anaphase but also corrects erroneous attachments that could lead to missegregation and aneuploidy. However, Mps1's error correction-relevant substrates are unknown. Using a chemically tuned kinetochore-targeting assay, we show that Mps1 destabilizes microtubule attachments (K fibers) epistatically to Aurora B, the other major error-correcting kinase. Through quantitative proteomics, we identify multiple sites of Mps1-regulated phosphorylation at the outer kinetochore...
April 24, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28415765/stable-aneuploid-tumors-cells-are-more-sensitive-to-ttk-inhibition-than-chromosomally-unstable-cell-lines
#7
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...
June 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28364521/rna-immunoprecipitation-identifies-novel-targets-of-dazl-in-human-foetal-ovary
#8
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/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/28334731/characterisation-of-cct271850-a-selective-oral-and-potent-mps1-inhibitor-used-to-directly-measure-in-vivo-mps1-inhibition-vs-therapeutic-efficacy
#10
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...
April 25, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28320825/structure-of-the-rzz-complex-and-molecular-basis-of-its-interaction-with-spindly
#11
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/28299790/tc-mps1-12-a-novel-mps1-inhibitor-suppresses-the-growth-of-hepatocellular-carcinoma-cells-via-the-accumulation-of-chromosomal-instability
#12
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, also known as TTK), 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...
June 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28271486/protein-complexes-in-the-nucleus-the-control-of-chromosome-segregation
#13
Victor M Bolanos-Garcia
Mistakes in the process of cell division can lead to the loss, gain or rearrangement of chromosomes. Significant chromosomal abnormalities are usually lethal to the cells and cause spontaneous miscarriages. However, in some cases, defects in the spindle assembly checkpoint lead to severe diseases, such as cancer and birth and development defects, including Down's syndrome. The timely and accurate control of chromosome segregation in mitosis relies on the spindle assembly checkpoint (SAC), an evolutionary conserved, self-regulated signalling system present in higher organisms...
2017: Sub-cellular Biochemistry
https://www.readbyqxmd.com/read/28270606/functional-characterization-of-cfi-402257-a-potent-and-selective-mps1-ttk-kinase-inhibitor-for-the-treatment-of-cancer
#14
Jacqueline M Mason, Xin Wei, Graham C Fletcher, Reza Kiarash, Richard Brokx, Richard Hodgson, Irina Beletskaya, Mark R Bray, Tak W Mak
Loss of cell-cycle control is a hallmark of human cancer. Cell-cycle checkpoints are essential for maintaining genome integrity and balanced growth and division. They are specifically deregulated in cancer cells and contain regulators that represent potential therapeutic targets. Monopolar spindle 1 (Mps1; also known as TTK protein kinase) is a core component of the spindle assembly checkpoint (SAC), a genome-surveillance mechanism that is important for cell survival, and has emerged as a candidate target for anticancer therapy...
March 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28249757/suppression-of-spindly-delays-mitotic-exit-and-exacerbates-cell-death-response-of-cancer-cells-treated-with-low-doses-of-paclitaxel
#15
Patrícia M A Silva, Nilza Ribeiro, Raquel T Lima, Cláudia Andrade, Vânia Diogo, Joana Teixeira, Cláudia Florindo, Álvaro Tavares, M Helena Vasconcelos, Hassan Bousbaa
Microtubule-targeting agents (MTAs) are used extensively for the treatment of diverse types of cancer. They block cancer cells in mitosis through the activation of the spindle assembly checkpoint (SAC), the surveillance mechanism that ensures accurate chromosome segregation at the onset of anaphase. However, the cytotoxic activity of MTAs is limited by premature mitotic exit (mitotic slippage) due to SAC silencing. Here we have explored the dual role of the protein Spindly in chromosome attachments and SAC silencing to analyze the consequences of its depletion on the viability of tumor cells treated with clinically relevant doses of paclitaxel...
May 28, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28202332/cdc20-at-the-crossroads-between-chromosome-segregation-and-mitotic-exit
#16
REVIEW
Maria Kapanidou, Natalie L Curtis, Victor M Bolanos-Garcia
Cell-division cycle protein 20 homologue (Cdc20) has important functions in chromosome segregation and mitotic exit. Cdc20 is the target of the spindle assembly checkpoint (SAC) and a key cofactor of the anaphase-promoting complex or cyclosome (APC/C) E3 ubiquitin ligase, thus regulating APC/C ubiquitin activity on specific substrates for their subsequent degradation by the proteasome. Here we discuss the roles of Cdc20 in SAC signalling and mitotic exit, describe how the integration of traditional approaches with emerging technologies has revealed new details of Cdc20 functions, comment about the potential of Cdc20 as a therapeutic target for the treatment of human malignancies, and discuss recent advances and controversies in the mechanistic understanding of the control of chromosome segregation during cell division...
March 2017: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/28174095/anti-mitotic-agents-are-they-emerging-molecules-for-cancer-treatment
#17
REVIEW
Larissa Siqueira Penna, João Antonio Pêgas Henriques, Diego Bonatto
Mutations in cancer cells frequently result in cell cycle alterations that lead to unrestricted growth compared to normal cells. Considering this phenomenon, many drugs have been developed to inhibit different cell-cycle phases. Mitotic phase targeting disturbs mitosis in tumor cells, triggers the spindle assembly checkpoint and frequently results in cell death. The first anti-mitotics to enter clinical trials aimed to target tubulin. Although these drugs improved the treatment of certain cancers, and many anti-microtubule compounds are already approved for clinical use, severe adverse events such as neuropathies were observed...
May 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28105232/trip13-is-expressed-in-colorectal-cancer-and-promotes-cancer-cell-invasion
#18
Kenji Kurita, Masao Maeda, Mohammed A Mansour, Toshio Kokuryo, Keisuke Uehara, Yukihiro Yokoyama, Masato Nagino, Michinari Hamaguchi, Takeshi Senga
Thyroid hormone receptor interactor 13 (TRIP13) is a member of the ATPases associated with various cellular activities family of proteins and is highly conserved in a wide range of species. Recent studies have demonstrated that TRIP13 is critical for the inactivation of the spindle assembly checkpoint and is associated with the progression of certain cancers. In the present study, the role of TRIP13 in colorectal cancer (CRC) was examined. Reverse transcription-quantitative polymerase chain reaction analysis revealed that TRIP13 messenger RNA was highly expressed in multiple CRC tissues...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28072388/a-sequential-multi-target-mps1-phosphorylation-cascade-promotes-spindle-checkpoint-signaling
#19
Zhejian Ji, Haishan Gao, Luying Jia, Bing Li, Hongtao Yu
The master spindle checkpoint kinase Mps1 senses kinetochore-microtubule attachment and promotes checkpoint signaling to ensure accurate chromosome segregation. The kinetochore scaffold Knl1, when phosphorylated by Mps1, recruits checkpoint complexes Bub1-Bub3 and BubR1-Bub3 to unattached kinetochores. Active checkpoint signaling ultimately enhances the assembly of the mitotic checkpoint complex (MCC) consisting of BubR1-Bub3, Mad2, and Cdc20, which inhibits the anaphase-promoting complex or cyclosome bound to Cdc20 (APC/C(Cdc20)) to delay anaphase onset...
January 10, 2017: ELife
https://www.readbyqxmd.com/read/28069571/apc-c-dysfunction-limits-excessive-cancer-chromosomal-instability
#20
Laurent Sansregret, James O Patterson, Sally Dewhurst, Carlos López-García, André Koch, Nicholas McGranahan, William Chong Hang Chao, David J Barry, Andrew Rowan, Rachael Instrell, Stuart Horswell, Michael Way, Michael Howell, Martin R Singleton, René H Medema, Paul Nurse, Mark Petronczki, Charles Swanton
Intercellular heterogeneity, exacerbated by chromosomal instability (CIN), fosters tumor heterogeneity and drug resistance. However, extreme CIN correlates with improved cancer outcome, suggesting that karyotypic diversity required to adapt to selection pressures might be balanced in tumors against the risk of excessive instability. Here, we used a functional genomics screen, genome editing, and pharmacologic approaches to identify CIN-survival factors in diploid cells. We find partial anaphase-promoting complex/cyclosome (APC/C) dysfunction lengthens mitosis, suppresses pharmacologically induced chromosome segregation errors, and reduces naturally occurring lagging chromosomes in cancer cell lines or following tetraploidization...
February 2017: Cancer Discovery
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