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Spindle checkpoint

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https://www.readbyqxmd.com/read/29775579/a-mad2-mediated-translational-regulatory-mechanism-promoting-s-phase-cyclin-synthesis-controls-origin-firing-and-survival-to-replication-stress
#1
Sophie Gay, Daniele Piccini, Christopher Bruhn, Sara Ricciardi, Paolo Soffientini, Walter Carotenuto, Stefano Biffo, Marco Foiani
Cell survival to replication stress depends on the activation of the Mec1ATR -Rad53 checkpoint response that protects the integrity of stalled forks and controls the origin firing program. Here we found that Mad2, a member of the spindle assembly checkpoint (SAC), contributes to efficient origin firing and to cell survival in response to replication stress. We show that Rad53 and Mad2 promote S-phase cyclin expression through different mechanisms: while Rad53 influences Clb5,6 degradation, Mad2 promotes their protein synthesis...
May 17, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29771379/cdk-phosphorylation-licenses-kif4a-chromosome-localization-required-for-early-mitotic-progression
#2
Zhixiong Dong, Changjun Zhu, Qimin Zhan, Wei Jiang
The chromokinesin Kif4A controls proper chromosome condensation, congression/alignment, and cytokinesis to ensure faithful genetic inheritance. Here, we report that Cdk phosphorylation of human Kif4A at T1161 licenses Kif4A chromosomal localization, which, in turn, controls Kif4A early mitotic function. Phosphorylated Kif4A (Kif4AWT) or Cdk phospho-mimetic Kif4A mutant (Kif4ATE) associated with chromosomes and condensin I (non-SMC subunit CAP-G and core subunit SMC2) to regulate chromosome condensation, spindle morphology, and chromosome congression/alignment in early mitosis...
May 16, 2018: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/29748662/reducing-protein-regulator-of-cytokinesis-1-as-a-prospective-therapy-for-hepatocellular-carcinoma
#3
Xinran Liu, Yangkai Li, Lijing Meng, Xin-Yuan Liu, Anlin Peng, Yuchen Chen, Chengyu Liu, Hong Chen, Sheng Sun, Xiaoping Miao, Yu Zhang, Ling Zheng, Kun Huang
Proteins that bind to microtubule are important for cell cycle, and some of these proteins show oncogenic characteristics with mechanisms not fully understood. Herein we demonstrate overexpression of protein regulator of cytokinesis 1 (PRC1), a microtubule-associated regulator of mitosis, in human hepatocellular carcinoma (HCC). Moreover, upregulated PRC1 is associated with lower survival rates of HCC patients. Mechanistically, reducing PRC1 blocks mitotic exit of HCC cells at telophase in a spindle assembly checkpoint independent manner, and acts synergistically with microtubule-associated agents (MTAs) to suppress p53-wt or p53-null HCC cells in a p53- or p14ARF-dependent manner; while overexpressing PRC1 increases the resistance of HCC to taxol...
May 10, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29748388/the-kinetochore-proteins-cenp-e-and-cenp-f-directly-and-specifically-interact-with-distinct-bub-mitotic-checkpoint-ser-thr-kinases
#4
Giuseppe Ciossani, Katharina Overlack, Arsen Petrovic, Pim J Huis In 't Veld, Carolin Koerner, Sabine Wohlgemuth, Stefano Maffini, Andrea Musacchio
The segregation of chromosomes during cell division relies on the function of the kinetochores, protein complexes that physically connect chromosomes with microtubules of the spindle. The metazoan proteins, centromere protein E (CENP-E) and CENP-F, are components of a fibrous layer of mitotic kinetochores named the corona. Several of their features suggest that CENP-E and CENP-F are paralogs: they are very large (comprising approximately 2700 and 3200 residues, respectively), contain abundant predicted coiled-coil structures, are C-terminally prenylated, and are endowed with microtubule-binding sites at their termini...
May 10, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29743192/prolonged-cyclin-dependent-kinase-inhibition-results-in-septin-perturbations-during-return-to-growth-and-mitosis
#5
Gabriel M Gihana, Tiffany R Musser, Oscar Thompson, Soni Lacefield
We investigated how Saccharomyces cerevisiae coordinate polarization, budding, and anaphase during a unique developmental program called return to growth (RTG) in which cells in meiosis return to mitosis upon nutrient shift. Cells reentering mitosis from prophase I deviate from the normal cell cycle by budding in G2 instead of G1. We found that cells do not maintain the bipolar budding pattern, a characteristic of diploid cells. Furthermore, strict temporal regulation of M-phase cyclin-dependent kinase (CDK; M-CDK) is important for polarity establishment and morphogenesis...
May 9, 2018: Journal of Cell Biology
https://www.readbyqxmd.com/read/29742018/the-kinase-domain-of-ck1-enzymes-contains-the-localization-cue-essential-for-compartmentalized-signaling-at-the-spindle-pole
#6
Zachary C Elmore, Rodrigo X Guillen, Kathleen L Gould
CK1 protein kinases contribute to multiple biological processes, but how they are tailored to function in compartmentalized signaling events is largely unknown. Hhp1 and Hhp2 (Hhp1/2) are the soluble CK1 family members in Schizosaccharomyces pombe. One of their functions is to inhibit the septation initiation network (SIN) during a mitotic checkpoint arrest. The SIN is assembled by Sid4 at spindle pole bodies (SPBs), and though Hhp1/2 co-localize there, it is not known how they are targeted there nor if their SPB localization is required for SIN inhibition...
May 9, 2018: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29739877/role-of-kip2-during-early-mitosis-impact-on-spindle-pole-body-separation-and-chromosome-capture
#7
Beryl Augustine, Cheen Fei Chin, Foong May Yeong
Mitotic spindle dynamics are regulated during the cell cycle by microtubule motor proteins. One such protein is Kip2p, a plus-ended motor that regulates the polymerization and stability of cytoplasmic microtubules (cMTs). Kip2p levels are regulated during the cell cycle and its overexpression leads to the formation of hyper-elongated cMTs. To investigate the significance of varying Kip2p levels during the cell cycle and the hyper-elongated cMTs, we overexpressed KIP2 in G1 phase and examined the effects on the separation of spindle pole bodies (SPBs) and chromosome segregation...
May 8, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29731963/aurora-b-prevents-premature-removal-of-spindle-assembly-checkpoint-proteins-from-the-kinetochore-a-key-role-for-aurora-b-in-mitosis
#8
Mark D Gurden, Simon J Anderhub, Amir Faisal, Spiros Linardopoulos
Accurate chromosome segregation is dependent on the spindle assembly checkpoint (SAC). In current models, the key direct role of Aurora B in the SAC has been suggested to be to promote rapid kinetochore localisation of MPS1, allowing MPS1 to generate the checkpoint signal. However, Aurora B is also thought to play an indirect role in the SAC through the destabilisation of kinetochore-microtubule (KT-MT) attachments. Here, we demonstrate that Aurora B activity is not required for the kinetochore recruitment of the majority of SAC proteins...
April 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29727616/the-bub3-bub1-complex-promotes-telomere-dna-replication
#9
Feng Li, Hyeung Kim, Zhejian Ji, Tianpeng Zhang, Bohong Chen, Yuanlong Ge, Yang Hu, Xuyang Feng, Xin Han, Huimin Xu, Youwei Zhang, Hongtao Yu, Dan Liu, Wenbin Ma, Zhou Songyang
Telomeres and telomere-binding proteins form complex secondary nucleoprotein structures that are critical for genome integrity but can present serious challenges during telomere DNA replication. It remains unclear how telomere replication stress is resolved during S phase. Here, we show that the BUB3-BUB1 complex, a component in spindle assembly checkpoint, binds to telomeres during S phase and promotes telomere DNA replication. Loss of the BUB3-BUB1 complex results in telomere replication defects, including fragile and shortened telomeres...
May 3, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29724911/arf6-protects-sister-chromatid-cohesion-to-ensure-the-formation-of-stable-kinetochore-microtubule-attachments
#10
Mohamed Bourmoum, Ricardo Charles, Audrey Claing
Sister chromatid cohesion, ensured by the protein complex, cohesin, is crucial for the establishment of stable bipolar attachments of chromosomes to the spindle microtubules and their faithful segregation. Here, we demonstrate that the GTPase ARF6 prevents the premature loss of sister chromatid cohesion. During mitosis, ARF6 depleted cells normally completed chromosome congression. However, at the metaphase plate, chromosomes failed to establish stable kinetochore-microtubule attachments because of the impaired cohesion at centromeres...
May 3, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29709477/spindle-pole-body-component-25-homolog-expressed-by-ecm-stiffening-is-required-for-lung-cancer-cell-proliferation
#11
Jangho Jeong, Seula Keum, Daehwan Kim, Eunae You, Panseon Ko, Jieun Lee, Jaegu Kim, Jung-Woong Kim, Sangmyung Rhee
Accumulating evidence has shown that matrix stiffening in cancer tissue by the deposition of extracellular matrix (ECM) is closely related with severe tumor progression. However, much less is known about the genes affected by matrix stiffness and its signaling for cancer progression. In the current research, we investigated the differential gene expression of a non-small lung adenocarcinoma cell line, H1299, cultured under the conditions of soft (∼0.5 kPa) and stiff (∼40 kPa) matrices, mimicking the mechanical environments of normal and cancerous tissues, respectively...
April 27, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29706521/chromosome-segregation-is-biased-by-kinetochore-size
#12
Danica Drpic, Ana C Almeida, Paulo Aguiar, Fioranna Renda, Joana Damas, Harris A Lewin, Denis M Larkin, Alexey Khodjakov, Helder Maiato
Chromosome missegregation during mitosis or meiosis is a hallmark of cancer and the main cause of prenatal death in humans. The gain or loss of specific chromosomes is thought to be random, with cell viability being essentially determined by selection. Several established pathways including centrosome amplification, sister-chromatid cohesion defects, or a compromised spindle assembly checkpoint can lead to chromosome missegregation. However, how specific intrinsic features of the kinetochore-the critical chromosomal interface with spindle microtubules-impact chromosome segregation remains poorly understood...
April 20, 2018: Current Biology: CB
https://www.readbyqxmd.com/read/29688794/spindle-assembly-checkpoint-strength-is-linked-to-cell-fate-in-the-c-elegans-embryo
#13
Abigail R Gerhold, Vincent Poupart, Jean-Claude Labbé, Paul S Maddox
The spindle assembly checkpoint (SAC) is a conserved mitotic regulator that preserves genome stability by monitoring kinetochore-microtubule attachments and blocking anaphase onset until chromosome bi-orientation is achieved. Despite its central role in maintaining mitotic fidelity, the ability of the SAC to delay mitotic exit in the presence of kinetochore-microtubule attachment defects (SAC "strength") appears to vary widely. How different cellular aspects drive this variation remains largely unknown...
April 24, 2018: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29669289/usp9x-limits-mitotic-checkpoint-complex-turnover-to-strengthen-the-spindle-assembly-checkpoint-and-guard-against-chromosomal-instability
#14
Agnieszka Skowyra, Lindsey A Allan, Adrian T Saurin, Paul R Clarke
Faithful chromosome segregation during mitosis depends on the spindle assembly checkpoint (SAC), which delays progression through mitosis until every chromosome has stably attached to spindle microtubules via the kinetochore. We show here that the deubiquitinase USP9X strengthens the SAC by antagonizing the turnover of the mitotic checkpoint complex produced at unattached kinetochores. USP9X thereby opposes activation of anaphase-promoting complex/cyclosome (APC/C) and specifically inhibits the mitotic degradation of SAC-controlled APC/C substrates...
April 17, 2018: Cell Reports
https://www.readbyqxmd.com/read/29649038/the-effect-and-mechanism-of-millepachine-disrupted-spindle-assembly-in-tumor-cells
#15
Wenshuang Wu, Feng Liu, Anping Su, Yanping Gong, Wanjun Zhao, Yang Liu, Haoyu Ye, Jingqiang Zhu
Millepachine (MIL) is a bioactive natural product that shows great potential for cancer treatment. Previous studies showed that MIL was a novel cancer drug candidate with a special structure. To provide reference for the research and development of MIL, we further investigated the mechanism of MIL inducing G2/M arrest and found MIL disrupted spindle assembly in tumor cells. In this study, we investigated the disrupting spindle assembly effects of MIL with a focus on its potential mechanism of action. First, we indicated that MIL did not inhibit microtubule polymerization from the results of in-vivo microtubule nucleation assay and microtubule polymerization in-vitro assay but delayed this process by inhibiting the production of ATP in tumor cells...
June 2018: Anti-cancer Drugs
https://www.readbyqxmd.com/read/29629151/a-three-in-one-bullet-for-oesophageal-cancer-replication-fork-collapse-spindle-attachment-failure-and-enhanced-radiosensitivity-generated-by-a-ruthenium-ii-metallo-intercalator
#16
Martin R Gill, Paul J Jarman, Swagata Halder, Michael G Walker, Hiwa K Saeed, Jim A Thomas, Carl Smythe, Kristijan Ramadan, Katherine A Vallis
Substitutionally inert ruthenium(ii) polypyridyl complexes have been developed as DNA intercalating agents yet cellular DNA damage responses to this binding modality are largely unexplored. Here, we show the nuclear-targeting complex [Ru(phen)2 (tpphz)]2+ (phen = 1,10-phenanthroline, tpphz = tetrapyridophenazine) generates rapid and pronounced stalling of replication fork progression in p53-deficient human oesophageal cancer cells. In response, replication stress and double-strand break (DSB) DNA damage response (DDR) pathways are activated and cell proliferation is inhibited by growth arrest...
January 28, 2018: Chemical Science
https://www.readbyqxmd.com/read/29618387/deregulation-of-the-spindle-assembly-checkpoint-is-associated-with-paclitaxel-resistance-in-ovarian-cancer
#17
Taryne Chong, Amila Sarac, Cindy Q Yao, Linda Liao, Nicola Lyttle, Paul C Boutros, John M S Bartlett, Melanie Spears
BACKGROUND: Ovarian cancer is the leading gynecologic cancer diagnosed in North America and because related symptoms are not disease specific, this often leads to late detection, an advanced disease state, and the need for chemotherapy. Ovarian cancer is frequently sensitive to chemotherapy at diagnosis but rapid development of drug resistance leads to disease progression and ultimately death in the majority of patients. RESULTS: We have generated paclitaxel resistant ovarian cell lines from their corresponding native cell lines to determine driver mechanisms of drug resistance using gene expression arrays...
April 4, 2018: Journal of Ovarian Research
https://www.readbyqxmd.com/read/29608172/live-cell-imaging-of-chromosome-segregation-during-mitosis
#18
Prajakta Varadkar, Kazuyo Takeda, Brenton McCright
Chromosomes must be reliably and uniformly segregated into daughter cells during mitotic cell division. Fidelity of chromosomal segregation is controlled by multiple mechanisms that include the Spindle Assembly Checkpoint (SAC). The SAC is part of a complex feedback system that is responsible for prevention of a cell progress through mitosis unless all chromosomal kinetochores have attached to spindle microtubules. Chromosomal lagging and abnormal chromosome segregation is an indicator of dysfunctional cell cycle control checkpoints and can be used to measure the genomic stability of dividing cells...
March 14, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29560129/-hsa-mir-155-5p-drives-aneuploidy-at-early-stages-of-cellular-transformation
#19
Sara Pagotto, Angelo Veronese, Alessandra Soranno, Paola Lanuti, Mirco Di Marco, Marco Vincenzo Russo, Alice Ramassone, Marco Marchisio, Pasquale Simeone, Paolo E Guanciali Franchi, Giandomenico Palka, Renato Mariani Costantini, Carlo M Croce, Rosa Visone
Hsa-miR-155-5p (miR-155) is overexpressed in most solid and hematological malignancies. It promotes loss of genomic integrity in cancer cells by targeting genes involved in microsatellite instability and DNA repair; however, the link between miR-155 and aneuploidy has been scarcely investigated. Here we describe a novel mechanism by which miR-155 causes chromosomal instability. Using osteosarcoma cells (U2OS) and normal human dermal fibroblast (HDF), two well-established models for the study of chromosome congression, we demonstrate that miR-155 targets the spindle checkpoint proteins BUB1, CENP-F, and ZW10, thus compromising chromosome alignment at the metaphase plate...
February 27, 2018: Oncotarget
https://www.readbyqxmd.com/read/29556295/downregulation-of-ubiquitin-specific-peptidase-39-suppresses-the-proliferation-and-induces-the-apoptosis-of-human-colorectal-cancer-cells
#20
Zhiyuan Xing, Fengbo Sun, Wang He, Zhiwei Wang, Xiuqi Song, Fengjuan Zhang
Ubiquitin-specific peptidase 39 (USP39) has been reported to participate in the mitotic spindle checkpoint and the process of cytokinesis. and has been identified as a therapeutic target for various types of cancer. However, the effect of USP39 in colorectal cancer (CRC) has not been investigated. To explore the functional role of USP39 in CRC cell growth, lentivirus-mediated RNA interference was applied to inhibit USP39 expression in SW1116 and HCT116 cells. The relative USP39 mRNA and protein expression levels were significantly reduced in the USP39 knockdown cells, as verified by reverse transcription-quantitative polymerase chain reaction and western blot analysis...
April 2018: Oncology Letters
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