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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/28622684/the-association-between-mad2-and-prognosis-in-cancer-a%C3%A2-systematic-review-and-meta-analyses
#2
Tara Byrne, Helen G Coleman, Janine A Cooper, W Glenn McCluggage, Amanda McCann, Fiona Furlong
This systematic review and meta-analyses investigates the expression of the cell checkpoint regulator, mitotic arrest deficiency protein 2 (MAD2) in cancerous tissue and examines whether an association exists between MAD2 levels and cancer survival and recurrence. Studies investigating MAD2 expression in cancer tissue utilising immunohistochemistry (IHC) were identified by systematic literature searches of Medline, Embase and Web of Science databases by October 2015. Random effects meta-analyses were performed to generate pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of overall and progression-free survival according to MAD2 expression...
June 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28604727/bub1-positions-mad1-close-to-knl1-melt-repeats-to-promote-checkpoint-signalling
#3
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/28567704/fission-yeast-ctf1-a-cleavage-and-polyadenylation-factor-subunit-is-required-for-the-maintenance-of-genomic-integrity
#4
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
https://www.readbyqxmd.com/read/28564602/mad2-overexpression-uncovers-a-critical-role-for-trip13-in-mitotic-exit
#5
Daniel Henry Marks, Rozario Thomas, Yvette Chin, Riddhi Shah, Christine Khoo, Robert Benezra
The mitotic checkpoint ensures proper segregation of chromosomes by delaying anaphase until all kinetochores are bound to microtubules. This inhibitory signal is composed of a complex containing Mad2, which inhibits anaphase progression. The complex can be disassembled by p31(comet) and TRIP13; however, TRIP13 knockdown has been shown to cause only a mild mitotic delay. Overexpression of checkpoint genes, as well as TRIP13, is correlated with chromosomal instability (CIN) in cancer, but the initial effects of Mad2 overexpression are prolonged mitosis and decreased proliferation...
May 30, 2017: Cell Reports
https://www.readbyqxmd.com/read/28539402/spindle-assembly-checkpoint-signaling-and-sister-chromatid-cohesion-are-disrupted-by-hpv-e6-mediated-transformation
#6
Hazheen K Shirnekhi, Erin P Kelley, Jennifer G DeLuca, Jacob A Herman
Aneuploidy, a condition that results from unequal partitioning of chromosomes during mitosis, is a hallmark of many cancers, including those caused by human papillomaviruses (HPVs). E6 and E7 are the primary transforming proteins in HPV that drive tumor progression. In this study, we stably expressed E6 and E7 in non-cancerous RPE1 cells and analyzed the specific mitotic defects that contribute to aneuploidy in each cell line. We find that E6-expression results in multiple chromosomes associated with one or both spindle poles, causing a significant mitotic delay...
May 24, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28512144/tog-tubulin-binding-specificity-promotes-microtubule-dynamics-and-mitotic-spindle-formation
#7
Amy E Byrnes, Kevin C Slep
XMAP215, CLASP, and Crescerin use arrayed tubulin-binding tumor overexpressed gene (TOG) domains to modulate microtubule dynamics. We hypothesized that TOGs have distinct architectures and tubulin-binding properties that underlie each family's ability to promote microtubule polymerization or pause. As a model, we investigated the pentameric TOG array of a Drosophila melanogaster XMAP215 member, Msps. We found that Msps TOGs have distinct architectures that bind either free or polymerized tubulin, and that a polarized array drives microtubule polymerization...
June 5, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28506992/reduced-mad2-levels-dampen-the-apoptotic-response-to-non-exchange-sex-chromosomes-and-lead-to-sperm-aneuploidy
#8
Imrul Faisal, Liisa Kauppi
In meiosis, non-exchange homologous chromosomes are at risk for mis-segregation and should be monitored by the spindle assembly checkpoint (SAC) to avoid formation of aneuploid gametes. Sex chromosome mis-segregation is particularly common and can lead to sterility or to aneuploid offspring (e.g. individuals with Turner or Klinefelter syndrome). Despite major implications for health and reproduction, modifiers of meiotic SAC robustness and the subsequent apoptotic response in male mammals remain obscure. Levels of SAC proteins, e...
June 1, 2017: Development
https://www.readbyqxmd.com/read/28455985/coal-tar-pitch-extract-could-induce-chromosomal-instability-of-human-bronchial-epithelial-cells-mediated-by-spindle-checkpoint-related-proteins
#9
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...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28366743/different-functionality-of-cdc20-binding-sites-within-the-mitotic-checkpoint-complex
#10
Katharina Sewart, Silke Hauf
The mitotic checkpoint is a cellular safeguard that prevents chromosome missegregation in eukaryotic cells [1, 2]. Suboptimal functioning may foster chromosome missegregation in cancer cells [3]. Checkpoint signaling produces the "mitotic checkpoint complex" (MCC), which prevents anaphase by targeting Cdc20, the activator of the anaphase-promoting complex/cyclosome (APC/C). Recent biochemical and structural studies revealed that the human MCC binds two Cdc20 molecules, one (Cdc20(M)) through well-characterized, cooperative binding to Mad2 and Mad3/BubR1 (forming the "core MCC") and the other one (Cdc20(A)) through additional binding sequences in Mad3/BubR1 [4-6]...
April 24, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28178520/identification-of-a-sgo2-dependent-but-mad2-independent-pathway-controlling-anaphase-onset-in-fission-yeast
#11
John C Meadows, Theresa C Lancaster, Graham J Buttrick, Alicja M Sochaj, Liam J Messin, Maria Del Mar Mora-Santos, Kevin G Hardwick, Jonathan B A Millar
The onset of anaphase is triggered by activation of the anaphase-promoting complex/cyclosome (APC/C) following silencing of the spindle assembly checkpoint (SAC). APC/C triggers ubiquitination of Securin and Cyclin B, which leads to loss of sister chromatid cohesion and inactivation of Cyclin B/Cdk1, respectively. This promotes relocalization of Aurora B kinase and other components of the chromosome passenger complex (CPC) from centromeres to the spindle midzone. In fission yeast, this is mediated by Clp1 phosphatase-dependent interaction of CPC with Klp9/MKLP2 (kinesin-6)...
February 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/28177905/trap1-protein-signature-predicts-outcome-in-human-metastatic-colorectal-carcinoma
#12
Francesca Maddalena, Vittorio Simeon, Giulia Vita, Annamaria Bochicchio, Luciana Possidente, Lorenza Sisinni, Giacomo Lettini, Valentina Condelli, Danilo Swann Matassa, Valeria Li Bergolis, Alberto Fersini, Sante Romito, Michele Aieta, Antonio Ambrosi, Franca Esposito, Matteo Landriscina
TRAP1 is a HSP90 molecular chaperone upregulated in colorectal carcinomas and involved in control of intracellular signaling, cell cycle, apoptosis and drug resistance, stemness and bioenergetics through co-traslational regulation of a network of client proteins. Thus, the clinical significance of TRAP1 protein network was analyzed in human colorectal cancers. TRAP1 and/or its client proteins were quantified, by immunoblot analysis, in 60 surgical specimens of colorectal carcinomas at different stages and, by immunohistochemistry, in 9 colorectal adenomatous polyps, 11 in situ carcinomas and 55 metastatic colorectal tumors...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28176922/inhibition-of-skp2-sensitizes-lung-cancer-cells-to-paclitaxel
#13
Tonghai Huang, Lin Yang, Guangsuo Wang, Guanggui Ding, Bin Peng, Yuxin Wen, Zheng Wang
S-phase kinase-associated protein 2 (Skp2) is an E3 ubiquitin ligase and plays an important role in the control of cell cycle progression. Skp2 is upregulated in several cancers, including lung cancers, but the role of Skp2 in the tumorigenesis and anticancer drug resistance in human lung cancer remains to be determined. We report here that Skp2 positively regulated mitotic arrest deficient 2 (MAD2) expression and that inhibition of Skp2 sensitizes human lung cancer cells to paclitaxel. Knockdown of Skp2 by small interfering RNA (siRNA) decreased Mad2 messenger RNA (mRNA) and protein levels in A549 and NCI-H1975 cells, accompanied with upregulation of p27 but decrease of the phosphorylation of retinoblastoma (Rb)...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28157697/trip13-impairs-mitotic-checkpoint-surveillance-and-is-associated-with-poor-prognosis-in-multiple-myeloma
#14
Yi Tao, Guang Yang, Hongxing Yang, Dongliang Song, Liangning Hu, Bingqian Xie, Houcai Wang, Lu Gao, Minjie Gao, Hongwei Xu, Zhijian Xu, Xiaosong Wu, Yiwen Zhang, Weiliang Zhu, Fenghuang Zhan, Jumei Shi
AAA-ATPase TRIP13 is one of the chromosome instability gene recently established in multiple myeloma (MM), the second most common and incurable hematological malignancy. However, the specific function of TRIP13 in MM is largely unknown. Using sequential gene expression profiling, we demonstrated that high TRIP13 expression levels were positively correlated with progression, disease relapse, and poor prognosis in MM patients. Overexpressing human TRIP13 in myeloma cells prompted cell growth and drug resistance, and overexpressing murine TRIP13, which shares 93% sequence identity with human TRIP13, led to colony formation of NIH/3T3 fibroblasts in vitro and tumor formation in vivo...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28112196/the-kinetochore-dependent-and-independent-formation-of-the-cdc20-mad2-complex-and-its-functions-in-hela-cells
#15
Jianquan Li, Nanmao Dang, Daniel James Wood, Jun-Yong Huang
The mitotic checkpoint complex (MCC) is formed from two sub-complexes of CDC20-MAD2 and BUBR1-BUB3, and current models suggest that it is generated exclusively by the kinetochores after nuclear envelope breakdown (NEBD). However, neither sub-complex has been visualised in vivo, and when and where they are formed during the cell cycle and their response to different SAC conditions remains elusive. Using single cell analysis in HeLa cells, we show that the CDC20-MAD2 complex is cell cycle regulated with a "Bell" shaped profile and peaks at prometaphase...
January 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28105216/identification-of-potential-therapeutic-targets-for-colorectal-cancer-by-bioinformatics-analysis
#16
Ming Yan, Maomin Song, Rixing Bai, Shi Cheng, Wenmao Yan
The aim of the present study was to identify potential therapeutic targets for colorectal cancer (CRC). The gene expression profile GSE32323, containing 34 samples, including 17 specimens of CRC tissues and 17 of paired normal tissues from CRC patients, was downloaded from the Gene Expression Omnibus database. Following data preprocessing using the Affy and preprocessCore packages, the differentially-expressed genes (DEGs) between the two types of samples were identified with the Linear Models for Microarray Analysis package...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28102834/basis-of-catalytic-assembly-of-the-mitotic-checkpoint-complex
#17
Alex C Faesen, Maria Thanasoula, Stefano Maffini, Claudia Breit, Franziska Müller, Suzan van Gerwen, Tanja Bange, Andrea Musacchio
In mitosis, for each daughter cell to inherit an accurate copy of the genome from the mother cell, sister chromatids in the mother cell must attach to microtubules emanating from opposite poles of the mitotic spindle, a process known as bi-orientation. A surveillance mechanism, termed the spindle assembly checkpoint (SAC), monitors the microtubule attachment process and can temporarily halt the separation of sister chromatids and the completion of mitosis until bi-orientation is complete. SAC failure results in abnormal chromosome numbers, termed aneuploidy, in the daughter cells, a hallmark of many tumours...
February 23, 2017: Nature
https://www.readbyqxmd.com/read/28096334/role-of-cct-chaperonin-in-the-disassembly-of-mitotic-checkpoint-complexes
#18
Sharon Kaisari, Danielle Sitry-Shevah, Shirly Miniowitz-Shemtov, Adar Teichner, Avram Hershko
The mitotic checkpoint system prevents premature separation of sister chromatids in mitosis and thus ensures the fidelity of chromosome segregation. When this checkpoint is active, a mitotic checkpoint complex (MCC), composed of the checkpoint proteins Mad2, BubR1, Bub3, and Cdc20, is assembled. MCC inhibits the ubiquitin ligase anaphase promoting complex/cyclosome (APC/C), whose action is necessary for anaphase initiation. When the checkpoint signal is turned off, MCC is disassembled, a process required for exit from checkpoint-arrested state...
January 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
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/28017606/generation-of-a-spindle-checkpoint-arrest-from-synthetic-signaling-assemblies
#20
Ivan Yuan, Ioanna Leontiou, Priya Amin, Karen M May, Sadhbh Soper Ní Chafraidh, Eliška Zlámalová, Kevin G Hardwick
The spindle checkpoint acts as a mitotic surveillance system, monitoring interactions between kinetochores and spindle microtubules and ensuring high-fidelity chromosome segregation [1-3]. The checkpoint is activated by unattached kinetochores, and Mps1 kinase phosphorylates KNL1 on conserved MELT motifs to generate a binding site for the Bub3-Bub1 complex [4-7]. This leads to dynamic kinetochore recruitment of Mad proteins [8, 9], a conformational change in Mad2 [10-12], and formation of the mitotic checkpoint complex (MCC: Cdc20-Mad3-Mad2 [13-15])...
January 9, 2017: Current Biology: CB
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