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Spindle checkpoint

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https://www.readbyqxmd.com/read/28726638/understanding-inhibitor-resistance-in-mps1-kinase-through-novel-biophysical-assays-and-structures
#1
Yoshitaka Hiruma, Andre Koch, Nazila Hazraty, Foteini Tsakou, Rene H Medema, Robbie P Joosten, Anastassis Perrakis
Monopolar spindle 1 (Mps1/TTK) is a protein kinase essential in mitotic checkpoint signalling, preventing anaphase until all chromosomes are properly attached to spindle microtubules. Mps1 has emerged as a potential target for cancer therapy, and a variety of compounds have been developed to inhibit its kinase activity. Mutations in the catalytic domain of Mps1 that give rise to inhibitor resistance, but retain catalytic activity and do not display cross-resistance to other Mps1 inhibitors, have been described...
July 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28718377/downregulation-of-tyrosine-threonine-kinase-inhibits-tumor-growth-via-g2-m-arrest-in-human-endometrioid-endometrial-adenocarcinoma
#2
Jiamiao Zhang, Yan Jiang, Yu Zhao, Wanxue Wang, Yiran Xie, Huating Wang, Yihua Yang
Endometrial cancer is the most common gynecologic malignancy, about 80% of which is endometrial endometrioid carcinoma. Dysregulation of spindle assembly checkpoint plays a vital role in endometrial endometrioid carcinoma tumorigenesis and progression. The purpose of this study was to explore how tyrosine threonine kinase, a spindle assembly checkpoint-related protein, promotes the endometrial endometrioid carcinoma progression. We found that both messenger RNA and protein levels of tyrosine threonine kinase in endometrial endometrioid carcinoma tissues are higher than those in normal endometrial tissues, and its expression is associated with tumor stages...
July 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28714568/exposure-to-reversine-affects-the-chondrocyte-morphology-and-phenotype-in-vitro
#3
S Gasparini, F Villa, L Molfetta, E Repaci, P Castagnola, R Quarto, P Giannoni
Articular chondrocytes derived from osteoarthritic tissues (OA-HAC) show a severely reduced chondrogenic commitment. This impairment undermines their use for tissue-engineered cartilage repair, which relies on cell proliferation and growth to meet the therapeutic needs but also on efficient cell plasticity to recover the chondrogenic phenotype. Reversine (Rev), a 2,6-disubstituted purine inhibitor of spindle-assembly checkpoints, was described to convert differentiated mesenchymal cells to their undifferentiated precursors...
July 17, 2017: Journal of Tissue Engineering and Regenerative Medicine
https://www.readbyqxmd.com/read/28711872/cell-scientist-to-watch-kevin-corbett
#4
(no author information available yet)
Kevin Corbett graduated in biology and biochemistry from the University of Virginia. He then went to the University of California, Berkeley, to work on the structure and function of DNA topoisomerases in bacteria and archaea for his PhD with James Berger. In 2005, he moved to the laboratory of Stephen Harrison at Harvard Medical School for his postdoctoral work on kinetochore structure and function, particularly the yeast monopolin complex, which promotes proper chromosome segregation in the first meiotic division...
July 15, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28695965/role-of-mad2-expression-during-the-early-development-of-the-sea-urchin
#5
Odile Bronchain, Wael Jdey, Laetitia Caraty, Brigitte Ciapa
Mitotic arrest deficient 2 (Mad2) belongs to the spindle assembly checkpoint (SAC), a mechanism that blocks progression of the cell cycle until microtubule attachment to kinetochores is complete. It has been found to be involved in the resistance of cancer cells to "anti-mitotic" drugs such as paclitaxel. Mad2 controls meiotic progression, but its role during sea urchin development had never been investigated. Furthermore, the existence of a SAC in this species had never been proved. The present data show that a Mad2 protein, highly homologous to that of humans, is expressed in this species...
2017: International Journal of Developmental Biology
https://www.readbyqxmd.com/read/28684541/consequences-of-mitotic-slippage-for-antimicrotubule-drug-therapy
#6
Bing Cheng, Karen Carmelina Crasta
Antimicrotubule agents are commonly utilized as front-line therapies against several malignancies, either by themselves or as combination therapies. Cell-based studies have pinpointed the anti-proliferative basis of action to be a consequence of perturbation of microtubule dynamics leading to sustained activation of the spindle assembly checkpoint, prolonged mitotic arrest and mitotic cell death. However, depending on the biological context and cell type, cells may take an alternative route besides mitotic cell death via a process known as mitotic slippage...
July 6, 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28671988/checkpoints-of-apicomplexan-cell-division-identified-in-toxoplasma-gondii
#7
Carmelo A Alvarez, Elena S Suvorova
The unusual cell cycles of Apicomplexa parasites are remarkably flexible with the ability to complete cytokinesis and karyokinesis coordinately or postpone cytokinesis for several rounds of chromosome replication, and are well recognized. Despite this surprising biology, the molecular machinery required to achieve this flexibility is largely unknown. In this study, we provide comprehensive experimental evidence that apicomplexan parasites utilize multiple Cdk-related kinases (Crks) to coordinate cell division...
July 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28661483/gene-knockout-of-zmym3-in-mice-arrests-spermatogenesis-at-meiotic-metaphase-with-defects-in-spindle-assembly-checkpoint
#8
Xiangjing Hu, Bin Shen, Shangying Liao, Yan Ning, Longfei Ma, Jian Chen, Xiwen Lin, Daoqin Zhang, Zhen Li, Chunwei Zheng, Yanmin Feng, Xingxu Huang, Chunsheng Han
ZMYM3, a member of the MYM-type zinc finger protein family and a component of a LSD1-containing transcription repressor complex, is predominantly expressed in the mouse brain and testis. Here, we show that ZMYM3 in the mouse testis is expressed in somatic cells and germ cells until pachytene spermatocytes. Knockout (KO) of Zmym3 in mice using the CRISPR-Cas9 system resulted in adult male infertility. Spermatogenesis of the KO mice was arrested at the metaphase of the first meiotic division (MI). ZMYM3 co-immunoprecipitated with LSD1 in spermatogonial stem cells, but its KO did not change the levels of LSD1 or H3K4me1/2 or H3K9me2...
June 29, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28659416/haspin-inhibition-reveals-functional-differences-of-interchromatid-axis-localized-aurkb-and-aurkc
#9
Suzanne M Quartuccio, Shweta S Dipali, Karen Schindler
Aneuploidy is the leading genetic abnormality contributing to infertility, and chromosome segregation errors are common during female mammalian meiosis I (MI). Previous results indicate that haspin kinase regulates resumption of meiosis from prophase arrest, chromosome condensation, and kinetochore-microtubule attachments during early prometaphase of MI. Here, we report that haspin inhibition in late prometaphase I causes acceleration of MI, bypass of the spindle assembly checkpoint (SAC), and loss of interchromatid axis localized Aurora kinase C...
June 28, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28659378/the-aaa-atpase-trip13-remodels-horma-domains-through-n-terminal-engagement-and-unfolding
#10
Qiaozhen Ye, Dong Hyun Kim, Ihsan Dereli, Scott C Rosenberg, Goetz Hagemann, Franz Herzog, Attila Tóth, Don W Cleveland, Kevin D Corbett
Proteins of the conserved HORMA domain family, including the spindle assembly checkpoint protein MAD2 and the meiotic HORMADs, assemble into signaling complexes by binding short peptides termed "closure motifs". The AAA+ ATPase TRIP13 regulates both MAD2 and meiotic HORMADs by disassembling these HORMA domain-closure motif complexes, but its mechanisms of substrate recognition and remodeling are unknown. Here, we combine X-ray crystallography and crosslinking mass spectrometry to outline how TRIP13 recognizes MAD2 with the help of the adapter protein p31(comet) We show that p31(comet) binding to the TRIP13 N-terminal domain positions the disordered MAD2 N-terminus for engagement by the TRIP13 "pore loops", which then unfold MAD2 in the presence of ATP N-terminal truncation of MAD2 renders it refractory to TRIP13 action in vitro, and in cells causes spindle assembly checkpoint defects consistent with loss of TRIP13 function...
June 28, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28649649/patterns-of-cell-cycle-checkpoint-deregulation-associated-with-intrinsic-molecular-subtypes-of-human-breast-cancer-cells
#11
Jacquelyn J Bower, Leah D Vance, Matthew Psioda, Stephanie L Smith-Roe, Dennis A Simpson, Joseph G Ibrahim, Katherine A Hoadley, Charles M Perou, William K Kaufmann
Genomic instability is a hallmark of breast cancer, contributes to tumor heterogeneity, and influences chemotherapy resistance. Although Gap 2 and mitotic checkpoints are thought to prevent genomic instability, the role of these checkpoints in breast cancer is poorly understood. Here, we assess the Gap 2 and mitotic checkpoint functions of 24 breast cancer and immortalized mammary epithelial cell lines representing four of the six intrinsic molecular subtypes of breast cancer. We found that patterns of cell cycle checkpoint deregulation were associated with the intrinsic molecular subtype of breast cancer cell lines...
2017: NPJ Breast Cancer
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
#12
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/28634351/a-dynamical-model-for-activating-and-silencing-the-mitotic-checkpoint
#13
Richard Henze, Peter Dittrich, Bashar Ibrahim
The spindle assembly checkpoint (SAC) is an evolutionarily conserved mechanism, exclusively sensitive to the states of kinetochores attached to microtubules. During metaphase, the anaphase-promoting complex/cyclosome (APC/C) is inhibited by the SAC but it rapidly switches to its active form following proper attachment of the final spindle. It had been thought that APC/C activity is an all-or-nothing response, but recent findings have demonstrated that it switches steadily. In this study, we develop a detailed mathematical model that considers all 92 human kinetochores and all major proteins involved in SAC activation and silencing...
June 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28607478/precocious-centriole-disengagement-and-centrosome-fragmentation-induced-by-mitotic-delay
#14
Menuka Karki, Neda Keyhaninejad, Charles B Shuster
The spindle assembly checkpoint (SAC) delays mitotic progression until all sister chromatid pairs achieve bi-orientation, and while the SAC can maintain mitotic arrest for extended periods, moderate delays in mitotic progression have significant effects on the resulting daughter cells. Here we show that when retinal-pigmented epithelial (RPE1) cells experience mitotic delay, there is a time-dependent increase in centrosome fragmentation and centriole disengagement. While most cells with disengaged centrioles maintain spindle bipolarity, clustering of disengaged centrioles requires the kinesin-14, HSET...
June 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28604727/bub1-positions-mad1-close-to-knl1-melt-repeats-to-promote-checkpoint-signalling
#15
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/28603453/centromeric-non-coding-transcription-opening-the-black-box-of-chromosomal-instability
#16
REVIEW
Rodrigo Cáceres-Gutiérrez, Luis A Herrera
In eukaryotes, mitosis is tightly regulated to avoid the generation of numerical chromosome aberrations, or aneuploidies. The aneuploid phenotype is a consequence of chromosomal instability (CIN), i.e., an enhanced rate of chromosome segregation errors, which is frequently found in cancer cells and is associated with tumor aggressiveness and increased tumor cell survival potential. To avoid the generation of aneuploidies, cells rely on the spindle assembly checkpoint (SAC), a widely conserved mechanism that protects the genome against this type of error...
June 2017: Current Genomics
https://www.readbyqxmd.com/read/28600783/kinetochore-malfunction-in-human-pathologies
#17
Bas de Wolf, Geert J P L Kops
The cell cycle culminates in mitosis with the purpose of dividing the cell's DNA content equally over two daughter cells. Error-free segregation relies on correct connections between chromosomes and spindle microtubules. Kinetochores are complex multi-protein assemblies that mediate these connections and are the platforms for attachment-error-correction and spindle assembly checkpoint signaling. Proper kinetochore function is therefore key in preventing aneuploidization. Mutations in genes encoding kinetochore proteins are associated with several severe developmental disorders associated with microcephaly, and kinetochore defects contribute to chromosomal instability in certain cancers...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28590163/merotelic-kinetochore-attachment-in-oocyte-meiosis-ii-causes-sister-chromatids-segregation-errors-in-aged-mice
#18
Jin-Mei Cheng, Jian Li, Ji-Xin Tang, Xiao-Xia Hao, Zhi-Peng Wang, Tie-Cheng Sun, Xiu-Xia Wang, Yan Zhang, Su-Ren Chen, Yi-Xun Liu
Mammalian oocyte chromosomes undergo 2 meiotic divisions to generate haploid gametes. The frequency of chromosome segregation errors during meiosis I increase with age. However, little attention has been paid to the question of how aging affects sister chromatid segregation during oocyte meiosis II. More importantly, how aneuploid metaphase II (MII) oocytes from aged mice evade the spindle assembly checkpoint (SAC) mechanism to complete later meiosis II to form aneuploid embryos remains unknown. Here, we report that MII oocytes from naturally aged mice exhibited substantial errors in chromosome arrangement and configuration compared with young MII oocytes...
June 7, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28582586/tension-sensors-reveal-how-the-kinetochore-shares-its-load
#19
REVIEW
Edward D Salmon, Kerry Bloom
At metaphase in mitotic cells, pulling forces at the kinetochore-microtubule interface create tension by stretching the centromeric chromatin between oppositely oriented sister kinetochores. This tension is important for stabilizing the end-on kinetochore microtubule attachment required for proper bi-orientation of sister chromosomes as well as for satisfaction of the Spindle Assembly Checkpoint and entry into anaphase. How force is coupled by proteins to kinetochore microtubules and resisted by centromere stretch is becoming better understood as many of the proteins involved have been identified...
July 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28567704/fission-yeast-ctf1-a-cleavage-and-polyadenylation-factor-subunit-is-required-for-the-maintenance-of-genomic-integrity
#20
Amit Sonkar, Sachin Gaurav, Shakil Ahmed
Accurate segregation of chromosome during mitosis requires the coordinated action of several cell cycle checkpoints that monitor replication of the genome and the attachment of sister chromatids to the mitotic spindle apparatus. Here we have characterized the fission yeast Ctf1, an ortholog of S. cerevisiae Rna15 in the maintenance of genomic integrity. The ctf1 is nonessential for the cell survival and its deletion strain exhibit cold sensitivity. The ctf1 deleted cells exhibit genetic interaction with spindle checkpoint protein Mad2 and Bub1...
May 31, 2017: Molecular Genetics and Genomics: MGG
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