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Spindle assembly checkpoint targets

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https://www.readbyqxmd.com/read/28202332/cdc20-at-the-crossroads-between-chromosome-segregation-and-mitotic-exit
#1
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...
February 12, 2017: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/28174095/anti-mitotic-agents-are-they-emerging-molecules-for-cancer-treatment
#2
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...
February 4, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28105232/trip13-is-expressed-in-colorectal-cancer-and-promotes-cancer-cell-invasion
#3
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
#4
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
#5
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
https://www.readbyqxmd.com/read/28069132/molecular-regulation-of-the-spindle-assembly-checkpoint-by-kinases-and-phosphatases
#6
G Manic, F Corradi, A Sistigu, S Siteni, I Vitale
The spindle assembly checkpoint (SAC) is a surveillance mechanism contributing to the preservation of genomic stability by monitoring the microtubule attachment to, and/or the tension status of, each kinetochore during mitosis. The SAC halts metaphase to anaphase transition in the presence of unattached and/or untensed kinetochore(s) by releasing the mitotic checkpoint complex (MCC) from these improperly-oriented kinetochores to inhibit the anaphase-promoting complex/cyclosome (APC/C). The reversible phosphorylation of a variety of substrates at the kinetochore by antagonistic kinases and phosphatases is one major signaling mechanism for promptly turning on or turning off the SAC...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/27819146/mps1-ttk-a-novel-target-and-biomarker-for-cancer
#7
Yuan Xie, Anqiang Wang, Jianzhen Lin, Liangcai Wu, Haohai Zhang, Xiaobo Yang, Xueshuai Wan, Ruoyu Miao, Xinting Sang, Haitao Zhao
Monopolar spindle1 (Mps1, also known as TTK) is the core component of the spindle assembly checkpoint, which functions to ensure proper distribution of chromosomes to daughter cells. Mps1 is hardly detectable in normal organs except the testis and placenta. However, high levels of Mps1 are found in many types of human malignancies, including glioblastoma, thyroid carcinoma, breast cancer, and other cancers. Several Mps1 inhibitors can inhibit the proliferation of cancer cells and exhibit demonstrable survival benefits...
December 1, 2016: Journal of Drug Targeting
https://www.readbyqxmd.com/read/27810909/the-ubiquitin-ligase-crl2zyg11-targets-cyclin-b1-for-degradation-in-a-conserved-pathway-that-facilitates-mitotic-slippage
#8
Riju S Balachandran, Cassandra S Heighington, Natalia G Starostina, James W Anderson, David L Owen, Srividya Vasudevan, Edward T Kipreos
The anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase is known to target the degradation of cyclin B1, which is crucial for mitotic progression in animal cells. In this study, we show that the ubiquitin ligase CRL2(ZYG-11) redundantly targets the degradation of cyclin B1 in Caenorhabditis elegans and human cells. In C. elegans, both CRL2(ZYG-11) and APC/C are required for proper progression through meiotic divisions. In human cells, inactivation of CRL2(ZYG11A/B) has minimal effects on mitotic progression when APC/C is active...
October 24, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27713168/the-aurora-kinase-a-inhibitor-tc-a2317-disrupts-mitotic-progression-and-inhibits-cancer-cell-proliferation
#9
Yoo Hong Min, Wootae Kim, Ja-Eun Kim
Mitotic progression is crucial for the maintenance of chromosomal stability. A proper progression is ensured by the activities of multiple kinases. One of these enzymes, the serine/threonine kinase Aurora A, is required for proper mitosis through the regulation of centrosome and spindle assembly. In this study, we functionally characterized a newly developed Aurora kinase A inhibitor, TC-A2317. In human lung cancer cells, TC-A2317 slowed proliferation by causing aberrant formation of centrosome and microtubule spindles and prolonging the duration of mitosis...
October 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27633003/mps1-kinase-as-a-potential-therapeutic-target-in-medulloblastoma
#10
Irina Alimova, June Ng, Peter Harris, Diane Birks, Andrew Donson, Michael D Taylor, Nicholas K Foreman, Sujatha Venkataraman, Rajeev Vibhakar
Medulloblastoma is the most common type of malignant brain tumor that affects children. Although recent advances in chemotherapy and radiation have improved outcomes, high-risk patients perform poorly with significant morbidity. Gene expression profiling has revealed that monopolar spindle 1 (MPS1) (TTK1) is highly expressed in medulloblastoma patient samples compared to that noted in normal cerebellum. MPS1 is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation...
November 2016: Oncology Reports
https://www.readbyqxmd.com/read/27623074/infrank-a-ranking-based-identification-of-influential-genes-in-biological-networks
#11
Xiuliang Cui, Xiaofeng Li, Jin Li, Xue Wang, Wen Sun, Zhuo Cheng, Jin Ding, Hongyang Wang
Capturing the predominant driver genes is critical in the analysis of high-throughput experimental data; however, existing methods scarcely include the unique characters of biological networks. Herein we introduced a ranking-based computational framework (inFRank) to rank the proteins by their influence. Using inFRank, we identified the top 20 influential genes in hepatocellular carcinoma (HCC). Network analysis revealed a prominent community composed of 7 influential genes. Intriguingly, five genes among the community were critical for mitotic spindle assembly checkpoint (SAC), suggesting that dysregulation of SAC could be a distinct feature of HCC and targeting SAC-associated genes might be a promising therapeutic strategy...
September 7, 2016: Oncotarget
https://www.readbyqxmd.com/read/27540016/the-novel-tubulin-binding-checkpoint-activator-bal101553-inhibits-eb1-dependent-migration-and-invasion-and-promotes-differentiation-of-glioblastoma-stem-like-cells
#12
Raphael Berges, Aurélie Tchoghandjian, Stephane Honore, Marie-Anne Esteve, Dominique Figarella-Branger, Felix Bachmann, Heidi A Lane, Diane Braguer
Glioblastoma (GBM) patients have limited treatment options. Cancer stem-like cells (CSLCs) contribute to GBM invasiveness and repopulation; hence, they represent promising targets for novel therapies. BAL101553 is a prodrug of BAL27862, a novel microtubule-destabilizing agent inhibiting tumor cell proliferation through activation of the Spindle Assembly Checkpoint, which is currently in Phase 1/2 clinical development. Broad anti-cancer activity has been demonstrated against human cancer models, including tumors refractory to conventional treatments...
August 18, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27524485/ccan-assembly-configures-composite-binding-interfaces-to-promote-cross-linking-of-ndc80-complexes-at-the-kinetochore
#13
Gülsah Pekgöz Altunkaya, Francesca Malvezzi, Zuzana Demianova, Tomasz Zimniak, Gabriele Litos, Florian Weissmann, Karl Mechtler, Franz Herzog, Stefan Westermann
Partitioning of the genome requires kinetochores, large protein complexes that mediate dynamic attachment of chromosomes to the spindle. Kinetochores contain two supramolecular protein assemblies. The ten-protein KMN network harbors key microtubule-binding sites in the Ndc80 complex and mediates assembly of checkpoint complexes via the KNL-1/Spc105 protein [1, 2]. As KMN does not contact DNA directly, it relies on different centromere-binding proteins for recruitment and cell-cycle-dependent assembly. These proteins are collectively referred to as the CCAN (constitutive centromere-associated network) [2-4]...
September 12, 2016: Current Biology: CB
https://www.readbyqxmd.com/read/27512141/inhibition-of-bcl-xl-sensitizes-cells-to-mitotic-blockers-but-not-mitotic-drivers
#14
Ailsa Bennett, Olivia Sloss, Caroline Topham, Louisa Nelson, Anthony Tighe, Stephen S Taylor
Cell fate in response to an aberrant mitosis is governed by two competing networks: the spindle assembly checkpoint (SAC) and the intrinsic apoptosis pathway. The mechanistic interplay between these two networks is obscured by functional redundancy and the ability of cells to die either in mitosis or in the subsequent interphase. By coupling time-lapse microscopy with selective pharmacological agents, we systematically probe pro-survival Bcl-xL in response to various mitotic perturbations. Concentration matrices show that BH3-mimetic-mediated inhibition of Bcl-xL synergises with perturbations that induce an SAC-mediated mitotic block, including drugs that dampen microtubule dynamics, and inhibitors targeting kinesins and kinases required for spindle assembly...
August 2016: Open Biology
https://www.readbyqxmd.com/read/27435760/spindle-assembly-checkpoint-as-a-potential-target-in-colorectal-cancer-current-status-and-future-perspectives
#15
Vânia Diogo, Joana Teixeira, Patrícia M A Silva, Hassan Bousbaa
Colorectal cancer (CRC), one of the most common malignancies worldwide, is often diagnosed at an advanced stage, and resistance to chemotherapeutic and existing targeted therapy is a major obstacle to its successful treatment. New targets that offer alternative clinical options are therefore urgently needed. Recently, perturbation of the spindle assembly checkpoint (SAC), the surveillance mechanism that maintains anaphase inhibition until all chromosomes reach the metaphase plate, has been regarded as a promising target to fight cancer cells, either alone or in combination regimens...
June 23, 2016: Clinical Colorectal Cancer
https://www.readbyqxmd.com/read/27383047/mps1-kinase-regulates-tumor-cell-viability-via-its-novel-role-in-mitochondria
#16
X Zhang, Y Ling, Y Guo, Y Bai, X Shi, F Gong, P Tan, Y Zhang, C Wei, X He, A Ramirez, X Liu, C Cao, H Zhong, Q Xu, R Z Ma
Targeting mitotic kinase monopolar spindle 1 (Mps1) for tumor therapy has been investigated for many years. Although it was suggested that Mps1 regulates cell viability through its role in spindle assembly checkpoint (SAC), the underlying mechanism remains less defined. In an endeavor to reveal the role of high levels of mitotic kinase Mps1 in the development of colon cancer, we unexpectedly found the amount of Mps1 required for cell survival far exceeds that of maintaining SAC in aneuploid cell lines. This suggests that other functions of Mps1 besides SAC are also employed to maintain cell viability...
July 7, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27378817/fatostatin-inhibits-cancer-cell-proliferation-by-affecting-mitotic-microtubule-spindle-assembly-and-cell-division
#17
Ankur A Gholkar, Keith Cheung, Kevin J Williams, Yu-Chen Lo, Shadia A Hamideh, Chelsea Nnebe, Cindy Khuu, Steven J Bensinger, Jorge Z Torres
The sterol regulatory element-binding protein (SREBP) transcription factors have become attractive targets for pharmacological inhibition in the treatment of metabolic diseases and cancer. SREBPs are critical for the production and metabolism of lipids and cholesterol, which are essential for cellular homeostasis and cell proliferation. Fatostatin was recently discovered as a specific inhibitor of SREBP cleavage-activating protein (SCAP), which is required for SREBP activation. Fatostatin possesses antitumor properties including the inhibition of cancer cell proliferation, invasion, and migration, and it arrests cancer cells in G2/M phase...
August 12, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27339139/modular-elements-of-the-tpr-domain-in-the-mps1-n-terminus-differentially-target-mps1-to-the-centrosome-and-kinetochore
#18
Joseph R Marquardt, Jennifer L Perkins, Kyle J Beuoy, Harold A Fisk
Faithful segregation of chromosomes to two daughter cells is regulated by the formation of a bipolar mitotic spindle and the spindle assembly checkpoint, ensuring proper spindle function. Here we show that the proper localization of the kinase Mps1 (monopolar spindle 1) is critical to both these processes. Separate elements in the Mps1 N-terminal extension (NTE) and tetratricopeptide repeat (TPR) domains govern localization to either the kinetochore or the centrosome. The third TPR (TPR3) and the TPR-capping helix (C-helix) are each sufficient to target Mps1 to the centrosome...
July 12, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27325694/phosphorylation-of-astrin-regulates-its-kinetochore-function
#19
Hee Jin Chung, Ji Eun Park, Nam Soo Lee, Hongtae Kim, Chang-Young Jang
The error-free segregation of chromosomes, which requires the precisely timed search and capture of chromosomes by spindles during early mitotic and meiotic cell division, is responsible for genomic stability and is achieved by the spindle assembly checkpoint in the metaphase-anaphase transition. Mitotic kinases orchestrate M phase events, such as the reorganization of cell architecture and kinetochore (KT) composition with the exquisite phosphorylation of mitotic regulators, to ensure timely and temporal progression...
August 19, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27317434/usp9x-stabilizes-xiap-to-regulate-mitotic-cell-death-and-chemoresistance-in-aggressive-b-cell-lymphoma
#20
Katharina Engel, Martina Rudelius, Jolanta Slawska, Laura Jacobs, Behnaz Ahangarian Abhari, Bettina Altmann, Julia Kurutz, Abirami Rathakrishnan, Vanesa Fernández-Sáiz, Andrä Brunner, Bianca-Sabrina Targosz, Felicia Loewecke, Christian Johannes Gloeckner, Marius Ueffing, Simone Fulda, Michael Pfreundschuh, Lorenz Trümper, Wolfram Klapper, Ulrich Keller, Philipp J Jost, Andreas Rosenwald, Christian Peschel, Florian Bassermann
The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies. However, it has remained unclear how cells execute cell fate decisions under conditions of SAC-induced mitotic arrest. Here, we identify USP9X as the mitotic deubiquitinase of the X-linked inhibitor of apoptosis protein (XIAP) and demonstrate that deubiquitylation and stabilization of XIAP by USP9X lead to increased resistance toward mitotic spindle poisons. We find that primary human aggressive B-cell lymphoma samples exhibit high USP9X expression that correlate with XIAP overexpression...
2016: EMBO Molecular Medicine
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