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Spindle checkpoint

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https://www.readbyqxmd.com/read/28938551/overexpression-of-ubiquitin-specific-proteases-44-promotes-the-malignancy-of-glioma-by-stabilizing-tumor-promoter-securin
#1
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...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28935703/hdac3-promotes-meiotic-apparatus-assembly-in-mouse-oocytes-via-modulating-tubulin-acetylation
#2
Xiaoyan Li, Xiaohui Liu, Min Gao, Longsen Han, Danhong Qiu, Haichao Wang, Bo Xiong, Shao-Chen Sun, Honglin Liu, Ling Gu
Histone deacetylases (HDACs) have been shown to deacetylate numerous cellular substrates that govern a wide array of biological processes. HDAC3, a member of the Class I HDACs, is a highly conserved and ubiquitously expressed protein. However, its roles in meiotic oocytes are currently unknown. In the present study, we find that mouse oocytes depleted of HDAC3 are unable to completely progress through meiosis, blocking at metaphase I. These HDAC3-knockdown (HDAC3-KD) oocytes show spindle/chromosome organization failure, with severely impaired kinetochore-microtubule attachments...
September 21, 2017: Development
https://www.readbyqxmd.com/read/28933982/function-and-regulation-mechanism-of-chk1-during-meiotic-maturation-in-porcine-oocytes
#3
Zheng-Wen Nie, Li Chen, Qiu-Shi Jin, Ying-Ying Gao, Tao Wang, Xia Zhang, Yi-Liang Miao
Checkpoint 1 (Chk1), as an important member of DNA replication checkpoint and DNA damage response, has an important role during the G2/M stage of mitosis. In this study, we used porcine oocyte as a model to investigate the function of Chk1 during porcine oocyte maturation. Chk1 was expressed from germinal vesicle (GV) to metaphase II (MII) stages, mainly localized in the cytoplasm at GV stage and moved to the spindle after germinal vesicle breakdown (GVBD). Chk1 depletion not only induced oocytes to be arrested at MI stage with abnormal chromosomes arrangement, but also inhibited the degradation of Cyclin B1 and decreased the expression of Mitotic Arrest Deficient 2-Like 1 (Mad2L1), one of spindle assembly checkpoint (SAC) proteins, and cadherin 1 (Cdh1), one of coactivation for anaphase-promoting complex/cyclosome (APC/C)...
September 21, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28931595/cell-cycle-transitions-a-common-role-for-stoichiometric-inhibitors
#4
Michael Hopkins, John J Tyson, Béla Novák
The cell division cycle is the process by which eukaryotic cells replicate their chromosomes and partition them to two daughter cells. To maintain the integrity of the genome, proliferating cells must be able to block progression through the division cycle at key transition points (called 'checkpoints'), if there have been problems in the replication of the chromosomes or their biorientation on the mitotic spindle. These checkpoints are governed by protein-interaction networks, composed of phase-specific cell-cycle activators and inhibitors...
September 20, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28928489/the-phosphorylation-of-a-kinetochore-protein-dam1-by-aurora-b-ipl1-kinase-promotes-chromosome-bipolar-attachment-in-yeast
#5
Fengzhi Jin, Michael Bokros, Yanchang Wang
The interaction between chromosomes and spindle microtubules is essential for chromosome segregation. The kinetochore complex mediates this interaction. Previous studies indicate that the stability of kinetochore attachment is regulated by Aurora B/Ipl1 kinase and this regulation is conserved from yeast to mammalian cells. In budding yeast Saccharomyces cerevisiae, the ten-subunit Dam1/DASH complex bridges the interaction between kinetochores and microtubules, and some in vitro evidence indicates that the phosphorylation of Dam1 protein by Ipl1 kinase destabilizes this interaction...
September 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28915607/coal-tar-pitch-extract-could-induce-chromosomal-instability-of-human-bronchial-epithelial-cells-mediated-by-spindle-checkpoint-related-proteins
#6
Peng Zhang, Zhitao Li, Na Wang, Guangcai Duan, Wei Wang, Yanming Feng, Yong Zhao, Lixia Wang, Hansong Zhu, Qiao Zhang, Xiaozhuan Liu, Weidong Wu, Yongjun Wu, Wu Yao, Jing Wang, Yiming Wu, Feifei Feng
Coal tar pitch (CTP) is a byproduct of coal tar distillation. The workers working with coal tar or in aluminum smelters, potrooms and carbon plants have the opportunities of exposing to coal tar pitch volatiles. Coal tar pitches from which polycyclic aromatic hydrocarbons (PAHs) originate have been shown to exhibit lung carcinogenicity in humans. Chromosomal instability (CIN) is a mechanism in carcinogenesis, however, whether CIN is involved in coal tar pitch-induced lung cancer remains elusive. In this present study, human bronchial epithelial cells (BEAS-2B) were first exposed to coal tar pitch extracts (CTPE) to induce a malignant transformation model...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28900014/regulation-of-the-cell-cycle-and-centrosome-biology-by-deubiquitylases
#7
REVIEW
Sarah Darling, Andrew B Fielding, Dorota Sabat-Pośpiech, Ian A Prior, Judy M Coulson
Post-translational modification of proteins by ubiquitylation is increasingly recognised as a highly complex code that contributes to the regulation of diverse cellular processes. In humans, a family of almost 100 deubiquitylase enzymes (DUBs) are assigned to six subfamilies and many of these DUBs can remove ubiquitin from proteins to reverse signals. Roles for individual DUBs have been delineated within specific cellular processes, including many that are dysregulated in diseases, particularly cancer. As potentially druggable enzymes, disease-associated DUBs are of increasing interest as pharmaceutical targets...
September 12, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28855212/sensitivity-to-bub1b-inhibition-defines-an-alternative-classification-of-glioblastoma
#8
Eunjee Lee, Margaret Pain, Huaien Wang, Jacob A Herman, Chad M Toledo, Jennifer G DeLuca, Raymund L Yong, Patrick Paddison, Jun Zhu
Glioblastoma multiforme (GBM) remains a mainly incurable disease in desperate need of more effective treatments. In this study, we develop evidence that the mitotic spindle checkpoint molecule BUB1B may offer a predictive marker for aggressiveness and effective drug response. A subset of GBM tumor isolates require BUB1B to suppress lethal kinetochore-microtubule attachment defects. Using gene expression data from GBM stem-like cells, astrocytes and neural progenitor cells that are sensitive or resistant to BUB1B inhibition, we created a computational framework to predict sensitivity to BUB1B inhibition...
August 30, 2017: Cancer Research
https://www.readbyqxmd.com/read/28851945/delayed-apc-c-activation-extends-the-first-mitosis-of-mouse-embryos
#9
Anna Ajduk, Bernhard Strauss, Jonathon Pines, Magdalena Zernicka-Goetz
The correct temporal regulation of mitosis underpins genomic stability because it ensures the alignment of chromosomes on the mitotic spindle that is required for their proper segregation to the two daughter cells. Crucially, sister chromatid separation must be delayed until all the chromosomes have attached to the spindle; this is achieved by the Spindle Assembly Checkpoint (SAC) that inhibits the Anaphase Promoting Complex/Cyclosome (APC/C) ubiquitin ligase. In many species the first embryonic M-phase is significantly prolonged compared to the subsequent divisions, but the reason behind this has remained unclear...
August 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28851706/dna-damage-induces-a-kinetochore-based-atm-atr-independent-sac-arrest-unique-to-the-first-meiotic-division-in-mouse-oocytes
#10
Simon I R Lane, Stephanie L Morgan, Tianyu Wu, Josie K Collins, Julie A Merriman, Elias ElInati, James M Turner, Keith T Jones
Mouse oocytes carrying DNA damage arrest in meiosis I, thereby preventing creation of embryos with deleterious mutations. The arrest is dependent on the spindle assembly checkpoint, which results in anaphase-promoting complex (APC) inhibition. However, little is understood about how this checkpoint is engaged following DNA damage. Here, we find that within minutes DNA damage assembles checkpoint proteins at the kinetochore, not at damage sites along chromosome arms, such that the APC is fully inhibited within 30 min...
August 29, 2017: Development
https://www.readbyqxmd.com/read/28840249/a-kinase-phosphatase-network-that-regulates-kinetochore-microtubule-attachments-and-the-sac
#11
Giulia Vallardi, Marilia Henriques Cordeiro, Adrian Thomas Saurin
The KMN network (for KNL1, MIS12 and NDC80 complexes) is a hub for signalling at the outer kinetochore. It integrates the activities of two kinases (MPS1 and Aurora B) and two phosphatases (PP1 and PP2A-B56) to regulate kinetochore-microtubule attachments and the spindle assembly checkpoint (SAC). We will first discuss each of these enzymes separately, to describe how they are regulated at kinetochores and why this is important for their primary function in controlling either microtubule attachments or the SAC...
2017: Progress in Molecular and Subcellular Biology
https://www.readbyqxmd.com/read/28840248/molecular-mechanisms-of-spindle-assembly-checkpoint-activation-and-silencing
#12
Kevin D Corbett
In eukaryotic cell division, the Spindle Assembly Checkpoint (SAC) plays a key regulatory role by monitoring the status of chromosome-microtubule attachments and allowing chromosome segregation only after all chromosomes are properly attached to spindle microtubules. While the identities of SAC components have been known, in some cases, for over two decades, the molecular mechanisms of the SAC have remained mostly mysterious until very recently. In the past few years, advances in biochemical reconstitution, structural biology, and bioinformatics have fueled an explosion in the molecular understanding of the SAC...
2017: Progress in Molecular and Subcellular Biology
https://www.readbyqxmd.com/read/28829971/how-kinetochore-architecture-shapes-the%C3%A2-mechanisms-of-its-function
#13
REVIEW
Ajit P Joglekar, Alexander A Kukreja
The eukaryotic kinetochore is a sophisticated multi-protein machine that segregates chromosomes during cell division. To ensure accurate chromosome segregation, it performs three major functions using disparate molecular mechanisms. It operates a mechanosensitive signaling cascade known as the spindle assembly checkpoint (SAC) to detect and signal the lack of attachment to spindle microtubules, and delay anaphase onset in response. In addition, after attaching to spindle microtubules, the kinetochore generates the force necessary to move chromosomes...
August 21, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28821799/plk1-bound-to-bub1-contributes-to-spindle-assembly-checkpoint-activity-during-mitosis
#14
Masanori Ikeda, Kozo Tanaka
For faithful chromosome segregation, the formation of stable kinetochore-microtubule attachment and its monitoring by the spindle assembly checkpoint (SAC) are coordinately regulated by mechanisms that are currently ill-defined. Here, we show that polo-like kinase 1 (Plk1), which is instrumental in forming stable kinetochore-microtubule attachments, is also involved in the maintenance of SAC activity by binding to Bub1, but not by binding to CLASP2 or CLIP-170. The effect of Plk1 on the SAC was found to be mediated through phosphorylation of Mps1, an essential kinase for the SAC, as well as through phosphorylation of the MELT repeats in Knl1...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28807937/hnf1b-loss-exacerbates-the-development-of-chromophobe-renal-cell-carcinomas
#15
Mianen Sun, Pan Tong, Wen Kong, Baijun Dong, Yiran Huang, In Young Park, Lijun Zhou, Xian-De Liu, Zhiyong Ding, Xuesong Zhang, Shanshan Bai, Peter German, Reid Powell, Quan Wang, Xuefei Tong, Nizar M Tannir, Surena F Matin, W Kimryn Rathmell, Gregory N Fuller, Ian E McCutcheon, Cheryl Lyn Walker, Jing Wang, Eric Jonasch
Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression. Here we report that the transcription factor HNF1B is downregulated in the majority of ChRCC and that the magnitude of HNF1B loss is unique to ChRCC. We also observed a strong correlation between reduced HNF1B expression and aneuploidy in ChRCC patients. In murine embryonic fibroblasts or ACHN cells, HNF1B deficiency reduced expression of the spindle checkpoint proteins MAD2L1 and BUB1B, and the cell cycle checkpoint proteins RB1 and p27...
August 14, 2017: Cancer Research
https://www.readbyqxmd.com/read/28805800/optogenetic-control-of-kinetochore-function
#16
Huaiying Zhang, Chanat Aonbangkhen, Ekaterina V Tarasovetc, Edward R Ballister, David M Chenoweth, Michael A Lampson
Kinetochores act as hubs for multiple activities during cell division, including microtubule interactions and spindle checkpoint signaling. Each kinetochore can act autonomously, and activities change rapidly as proteins are recruited to, or removed from, kinetochores. Understanding this dynamic system requires tools that can manipulate kinetochores on biologically relevant temporal and spatial scales. Optogenetic approaches have the potential to provide temporal and spatial control with molecular specificity...
October 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28794013/control-mechanisms-in-germ-cells-mediated-by-p53-family-proteins
#17
REVIEW
Jakob Gebel, Marcel Tuppi, Katharina Krauskopf, Daniel Coutandin, Susanne Pitzius, Sebastian Kehrloesser, Christian Osterburg, Volker Dötsch
Germ cells are totipotent and, in principle, immortal as they are the source for new germ cells in each generation. This very special role requires tight quality control systems. The p53 protein family constitutes one of the most important quality surveillance systems in cells. Whereas p53 has become famous for its role as the guardian of the genome in its function as the most important somatic tumor suppressor, p63 has been nicknamed 'guardian of the female germ line'. p63 is strongly expressed in resting oocytes and responsible for eliminating those that carry DNA double-strand breaks...
August 9, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28763871/-the-function-of-aurora-a-and-its-role-in-the-development-of-liver-cancer
#18
M Li, Z G Ren
Aurora A plays a key role in cellular mitosis. It is located in the centrosome and spindle, and is mainly involved in the processes of centrosome maturation and separation, bipolar spindle assembly, and the regulation of mitotic progression. Recent studies have suggested that Aurora A is involved in tumorigenesis and tumor development through multiple mechanisms. Overexpression of Aurora A could cause abnormal centrosome amplification, aneuploidy formation, and G2/M checkpoint defects, which result in chromosome instability and imbalance between cell division and apoptosis, and eventually leads to abnormal cell proliferation...
June 20, 2017: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
https://www.readbyqxmd.com/read/28759042/inhibition-of-the-spindle-assembly-checkpoint-kinase-mps-1-as-a-novel-therapeutic-strategy-in-malignant-mesothelioma
#19
A Szymiczek, M Carbone, S Pastorino, A Napolitano, M Tanji, M Minaai, I Pagano, J M Mason, H I Pass, M R Bray, T W Mak, H Yang
Malignant mesothelioma (MM) is an aggressive malignancy, highly resistant to current medical and surgical therapies, whose tumor cells characteristically show a high level of aneuploidy and genomic instability. We tested our hypothesis that targeting chromosomal instability in MM would improve response to therapy. Thr/Tyr kinase (TTK)/monopolar spindle 1 kinase (Mps-1) is a kinase of the spindle assembly checkpoint that controls cell division and cell fate. CFI-402257 is a novel, selective inhibitor of Mps-1 with antineoplastic activity...
July 31, 2017: Oncogene
https://www.readbyqxmd.com/read/28757527/rad51-maintains-chromosome-integrity-and-mitochondrial-distribution-during-porcine-oocyte-maturation-in-vitro
#20
Zhe-Long Jin, Nam-Hyung Kim
DNA repair protein RAD51 homolog 1 (RAD51) plays a central role in homologous recombination (HR) repair of DNA breaks. HR depends on the formation of a RAD51 recombinase filament that facilitates strand invasion. However, the role of RAD51 during porcine oocyte maturation is unknown. The objective of this study was to investigate the expression and function of RAD51 during porcine oocyte maturation in vitro. RAD51 was mainly localized to the nucleus at the germinal vesicle (GV) stage, and was widely distributed in the cytoplasm between the GV breakdown (GVBD) and metaphase II stage...
July 30, 2017: Journal of Reproduction and Development
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