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https://www.readbyqxmd.com/read/29207686/molecular-targeting-of-the-aurora-a-smad5-oncogenic-axis-restores-chemosensitivity-in-human-breast-cancer-cells
#1
Mateusz Opyrchal, Malgorzata Gil, Jeffrey L Salisbury, Mathew P Goetz, Vera Suman, Amy Degnim, James McCubrey, Tufia Haddad, Ianko Iankov, Chenye B Kurokawa, Nicole Shumacher, James N Ingle, Evanthia Galanis, Antonino B D'Assoro
Although the majority of breast cancers initially respond to the cytotoxic effects of chemotherapeutic agents, most breast cancer patients experience tumor relapse and ultimately die because of drug resistance. Breast cancer cells undergoing epithelial to mesenchymal transition (EMT) acquire a CD44+/CD24-/ALDH1+ cancer stem cell-like phenotype characterized by an increased capacity for tumor self-renewal, intrinsic drug resistance and high proclivity to develop distant metastases. We uncovered in human breast tumor xenografts a novel non-mitotic role of Aurora-A kinase in promoting breast cancer metastases through activation of EMT and expansion of breast tumor initiating cells (BTICs)...
October 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/29202611/aurora-kinase-a-as-a-possible-marker-for-endocrine-resistance-in-early-estrogen-receptor-positive-breast-cancer
#2
Anne E Lykkesfeldt, Benedikte R Iversen, Maj-Britt Jensen, Bent Ejlertsen, Anita Giobbie-Hurder, Birgit E Reiter, Tove Kirkegaard, Birgitte B Rasmussen
BACKGROUND: Cell culture studies have disclosed that the mitotic Aurora kinase A is causally involved in both tamoxifen and aromatase inhibitor resistant cell growth and thus may be a potential new marker for endocrine resistance in the clinical setting. MATERIAL AND METHODS: Archival tumor tissue was available from 1323 Danish patients with estrogen receptor (ER) positive primary breast cancer, who participated in the Breast International Group (BIG) 1-98 trial, comparing treatment with tamoxifen and letrozole and both in a sequence...
December 4, 2017: Acta Oncologica
https://www.readbyqxmd.com/read/29187526/aurora-a-kinase-phosphorylates-hec1-to-regulate-metaphase-kinetochore-microtubule-dynamics
#3
Keith F DeLuca, Amanda Meppelink, Amanda J Broad, Jeanne E Mick, Olve B Peersen, Sibel Pektas, Susanne M A Lens, Jennifer G DeLuca
Precise regulation of kinetochore-microtubule attachments is essential for successful chromosome segregation. Central to this regulation is Aurora B kinase, which phosphorylates kinetochore substrates to promote microtubule turnover. A critical target of Aurora B is the N-terminal "tail" domain of Hec1, which is a component of the NDC80 complex, a force-transducing link between kinetochores and microtubules. Although Aurora B is regarded as the "master regulator" of kinetochore-microtubule attachment, other mitotic kinases likely contribute to Hec1 phosphorylation...
November 29, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29170278/a-mitosis-specific-and-r-loop-driven-atr-pathway-promotes-faithful-chromosome-segregation
#4
Lilian Kabeche, Hai Dang Nguyen, Remi Buisson, Lee Zou
The ATR kinase is crucial for DNA damage and replication stress responses. Here, we describe a surprising role of ATR in mitosis. Acute inhibition or degradation of ATR in mitosis induces whole-chromosome missegregation. The effect of ATR ablation is not due to altered CDK1 activity, DNA damage responses, or unscheduled DNA synthesis, but to loss of an ATR function at centromeres. In mitosis, ATR localizes to centromeres through Aurora A-regulated association with CENP-F, allowing ATR to engage RPA-coated centromeric R loops...
November 23, 2017: Science
https://www.readbyqxmd.com/read/29141582/a-novel-interaction-between-kinase-activities-in-regulation-of-cilia-formation
#5
Nicole DeVaul, Katerina Koloustroubis, Rong Wang, Ann O Sperry
BACKGROUND: The primary cilium is an extension of the cell membrane that encloses a microtubule-based axoneme. Primary cilia are essential for transmission of environmental cues that determine cell fate. Disruption of primary cilia function is the molecular basis of numerous developmental disorders. Despite their biological importance, the mechanisms governing their assembly and disassembly are just beginning to be understood. Cilia growth and disassembly are essential events when cells exit and reenter into the cell cycle...
November 15, 2017: BMC Cell Biology
https://www.readbyqxmd.com/read/29126912/agbl2-promotes-cancer-cell-growth-through-irgm-regulated-autophagy-and-enhanced-aurora-a-activity-in-hepatocellular-carcinoma
#6
Li-Li Wang, Xiao-Han Jin, Mu-Yan Cai, Hai-Gang Li, Jie-Wei Chen, Feng-Wei Wang, Chen-Yuan Wang, Wei-Wei Hu, Fang Liu, Dan Xie
AGBL2 has been reported to catalyze α-tubulin detyrosination, by which it promotes tumorigenesis and cancer progression. However, its potential role in the pathogenesis of hepatocellular carcinoma (HCC) has not been revealed yet. In the present study, AGBL2 was frequently found being overexpressed in HCC tissues and cell lines. In a large cohort of clinical HCC tissues, high expression of AGBL2 was positively associated with tumor size, tumor multiplicity and advanced clinical stage (p < 0.05), and it was an independent prognostic factor for HCC patients...
November 8, 2017: Cancer Letters
https://www.readbyqxmd.com/read/29122619/aurora-a-functional-single-nucleotide-polymorphism-snp-correlates-with-clinical-outcome-in-patients-with-advanced-solid-tumors-treated-with-alisertib-an-investigational-aurora-a-kinase-inhibitor
#7
Huifeng Niu, Hyunjin Shin, Feng Gao, Jacob Zhang, Brittany Bahamon, Hadi Danaee, Bohuslav Melichar, Russell J Schilder, Robert L Coleman, Gerald Falchook, Antoine Adenis, Kian Behbakht, Angela DeMichele, Elizabeth Claire Dees, Kimberly Perez, Ursula Matulonis, Piotr Sawrycki, Dirk Huebner, Jeffrey Ecsedy
BACKGROUND: Alisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. Aurora A contains two functional single nucleotide polymorphisms (SNPs; codon 31 [F/I] and codon 57 [V/I]) that lead to functional changes. This study investigated the prognostic and predictive significance of these SNPs. METHODS: This study evaluated associations between Aurora A SNPs and overall survival (OS) in The Cancer Genome Atlas (TCGA) database. The Aurora A SNPs were also evaluated as predictive biomarkers for clinical outcomes to alisertib in two phase 2 studies (NCT01045421 and NCT01091428)...
November 2017: EBioMedicine
https://www.readbyqxmd.com/read/29074977/the-translation-of-cyclin-b1-and-b2-is-differentially-regulated-during-mouse-oocyte-reentry-into-the-meiotic-cell-cycle
#8
Seung Jin Han, João Pedro Sousa Martins, Ye Yang, Min Kook Kang, Enrico Maria Daldello, Marco Conti
Control of protein turnover is critical for meiotic progression. Using RiboTag immunoprecipitation, RNA binding protein immunoprecipitation, and luciferase reporter assay, we investigated how rates of mRNA translation, protein synthesis and degradation contribute to the steady state level of Cyclin B1 and B2 in mouse oocytes. Ribosome loading onto Ccnb1 and Mos mRNAs increases during cell cycle reentry, well after germinal vesicle breakdown (GVBD). This is followed by the translation of reporters containing 3' untranslated region of Mos or Ccnb1 and the accumulation of Mos and Cyclin B1 proteins...
October 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29074706/aurora-a-activation-in-mitosis-promoted-by-bugz
#9
Yuejia Huang, Teng Li, Stephanie C Ems-McClung, Claire E Walczak, Claude Prigent, Xueliang Zhu, Xuemin Zhang, Yixian Zheng
Protein phase separation or coacervation has emerged as a potential mechanism to regulate biological functions. We have shown that coacervation of a mostly unstructured protein, BuGZ, promotes assembly of spindle and its matrix. BuGZ in the spindle matrix binds and concentrates tubulin to promote microtubule (MT) assembly. It remains unclear, however, whether BuGZ could regulate additional proteins to promote spindle assembly. In this study, we report that BuGZ promotes Aurora A (AurA) activation in vitro. Depletion of BuGZ in cells reduces the amount of phosphorylated AurA on spindle MTs...
October 26, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29070411/chemical-space-big-data-challenge-for-molecular-diversity
#10
Mahendra Awale, Ricardo Visini, Daniel Probst, Josep Arús-Pous, Jean-Louis Reymond
Chemical space describes all possible molecules as well as multi-dimensional conceptual spaces representing the structural diversity of these molecules. Part of this chemical space is available in public databases ranging from thousands to billions of compounds. Exploiting these databases for drug discovery represents a typical big data problem limited by computational power, data storage and data access capacity. Here we review recent developments of our laboratory, including progress in the chemical universe databases (GDB) and the fragment subset FDB-17, tools for ligand-based virtual screening by nearest neighbor searches, such as our multi-fingerprint browser for the ZINC database to select purchasable screening compounds, and their application to discover potent and selective inhibitors for calcium channel TRPV6 and Aurora A kinase, the polypharmacology browser (PPB) for predicting off-target effects, and finally interactive 3D-chemical space visualization using our online tools WebDrugCS and WebMolCS...
October 25, 2017: Chimia
https://www.readbyqxmd.com/read/29065986/critical-risk-benefit-assessment-of-the-novel-anti-cancer-aurora-a-kinase-inhibitor-alisertib-mln8237-a-comprehensive-review-of-the-clinical-data
#11
REVIEW
Yaman Tayyar, Luqman Jubair, Sora Fallaha, Nigel A J McMillan
BACKGROUND: Many current anticancer chemotherapeutics suffer from significant side effects, which have led to the exploration of more targeted therapies. This resulted in the exploration of inhibitors of Aurora A kinase as a potential anti-cancer treatment. Alisertib (MLN8237) has proven to be a potent Aurora A kinase inhibitor that had the highest safety profile among its therapeutic family. Phase I/II/III clinical trials with Alisertib have been carried out and reported promising efficacy, yet serious side effects...
November 2017: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29050234/a-small-molecule-inhibitor-targeting-the-aurkc-i%C3%AE%C2%BAb%C3%AE-interaction-decreases-transformed-growth-of-mda-mb-231-breast-cancer-cells
#12
Eun Hee Han, Jin-Young Min, Shin-Ae Yoo, Sung-Joon Park, Yun-Jeong Choe, Hee Sub Yun, Zee-Won Lee, Sun Woo Jin, Hyung Gyun Kim, Hye Gwang Jeong, Hyun Kyoung Kim, Nam Doo Kim, Young-Ho Chung
The Aurora kinases, Aurora A (AURKA), Aurora B (AURKB), and Aurora C (AURKC), are serine/threonine kinases required for the control of mitosis (AURKA and AURKB) or meiosis (AURKC). Several Aurora kinase inhibitors are being investigated as novel anticancer therapeutics. Recent studies demonstrated that AURKC activation contributes to breast cancer cell transformation. Therefore, AURKC is both a promising marker and therapeutic target for breast cancer; however, its signaling network has not been fully characterized...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29050230/a-potential-panel-of-two-long-non-coding-rna-signature-to-predict-recurrence-of-patients-with-laryngeal-cancer
#13
Zhigang Bai, Enhong Shi, Qiwei Wang, Zhouwei Dong, Ping Xu
Accumulating evidence has shown that aberrant lncRNA expression plays an oncogenic or tumor-suppressive role in the tumorigenesis of laryngeal cancer. However, the prognostic roles of lncRNAs in laryngeal cancer recurrence are still poorly understood. In this study, we obtained lncRNA expression profiles of 109 patients with laryngeal cancer by mining previously published gene expression microarray data from the Gene Expression Omnibus (GEO) and identified two lncRNAs associated with laryngeal cancer recurrence in the training dataset by using Cox regression analysis...
September 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29045126/characterization-of-three-druggable-hot-spots-in-the-aurora-a-tpx2-interaction-using-biochemical-biophysical-and-fragment-based-approaches
#14
Patrick J McIntyre, Patrick M Collins, Lukáš Vrzal, Kristian Birchall, Laurence H Arnold, Chido Mpamhanga, Peter J Coombs, Selena G Burgess, Mark W Richards, Anja Winter, Václav Veverka, Frank von Delft, Andy Merritt, Richard Bayliss
The mitotic kinase Aurora-A and its partner protein TPX2 (Targeting Protein for Xenopus kinesin-like protein 2) are overexpressed in cancers, and it has been proposed that they work together as an oncogenic holoenzyme. TPX2 is responsible for activating Aurora-A during mitosis, ensuring proper cell division. Disruption of the interface with TPX2 is therefore a potential target for novel anticancer drugs that exploit the increased sensitivity of cancer cells to mitotic stress. Here, we investigate the interface using coprecipitation assays and isothermal titration calorimetry to quantify the energetic contribution of individual residues of TPX2...
November 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28993511/cell-cycle-dependent-tumor-engraftment-and-migration-are-enabled-by-aurora-a
#15
Tony L H Chu, Marisa Connell, Lixin Zhou, Zhengcheng He, Jennifer R Won, Seyed M Rahavi, Helen Chen, Pooja Mohan, Oksana Nemirovsky, Abbas Fotovati, Miguel Angel Pujana, Gregor Sd Reid, Torsten O Nielsen, Nelly Pante, Christopher A Maxwell
Cell cycle progression and the acquisition of a migratory phenotype are hallmarks of human carcinoma cells that are perceived as independent processes but may be interconnected by molecular pathways that control microtubule nucleation at centrosomes. Here, cell cycle progression dramatically impacts the engraftment kinetics of 4T1-luciferase2 breast cancer cells in immunocompetent BALB/c or immunocompromised NOD-SCID gamma (NSG) mice. Multi-parameter imaging of wound closure assays was used to track cell cycle progression, cell migration, and associated phenotypes in epithelial cells or carcinoma cells expressing a fluorescence ubiquitin cell cycle indicator...
October 9, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28972102/plk4-and-aurora-a-cooperate-in-the-initiation-of-acentriolar-spindle-assembly-in-mammalian-oocytes
#16
Leah Bury, Paula A Coelho, Angela Simeone, Samantha Ferries, Claire E Eyers, Patrick A Eyers, Magdalena Zernicka-Goetz, David M Glover
Establishing the bipolar spindle in mammalian oocytes after their prolonged arrest is crucial for meiotic fidelity and subsequent development. In contrast to somatic cells, the first meiotic spindle assembles in the absence of centriole-containing centrosomes. Ran-GTP can promote microtubule nucleation near chromatin, but additional unidentified factors are postulated for the activity of multiple acentriolar microtubule organizing centers in the oocyte. We now demonstrate that partially overlapping, nonredundant functions of Aurora A and Plk4 kinases contribute to initiate acentriolar meiosis I spindle formation...
November 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28967900/aurora-a-mediated-phosphorylation-of-lkb1-compromises-lkb1-ampk-signaling-axis-to-facilitate-nsclc-growth-and-migration
#17
X Zheng, J Chi, J Zhi, H Zhang, D Yue, J Zhao, D Li, Y Li, M Gao, J Guo
Deletion or loss-of-function mutation of LKB1, frequently occurring in non-small cell lung cancers (NSCLCs), is a predominant caution of NSCLC initiation and progression. However, the upstream signaling pathways governing LKB1 activation are largely unknown. Here, we report that LKB1 undergoes Aurora kinase A (AURKA)-mediated phosphorylation, which largely compromises the LKB1/AMPK signaling axis, in turn leading to the elevation of NSCLC cell proliferation, invasion and migration. Mechanically, AURKA-mediated phosphorylation of LKB1 impairs LKB1 interaction with and phosphorylation of its downstream target AMPKα, which has critical roles in governing cancer cell energy metabolic homeostasis and tumorigenesis...
October 2, 2017: Oncogene
https://www.readbyqxmd.com/read/28935709/cip2a-acts-as-a-scaffold-for-cep192-mediated-microtubule-organizing-center-assembly-by-recruiting-plk1-and-aurora-a-during-meiotic-maturation
#18
HaiYang Wang, Min Ho Choe, In-Won Lee, Suk Namgoong, Jae-Sung Kim, Nam-Hyung Kim, Jeong Su Oh
In somatic cells spindle microtubules are nucleated from centrosomes that act as major microtubule organizing centers (MTOCs), whereas oocytes form meiotic spindles by assembling multiple acentriolar MTOCs without canonical centrosomes. Aurora A and Plk1 are required for these events, but the underlying mechanisms remain largely unknown. Here we show that CIP2A regulates MTOC organization by recruiting aurora A and Plk1 at spindle poles during meiotic maturation. CIP2A colocalized with pericentrin at spindle poles with a few distinct cytoplasmic foci...
October 15, 2017: Development
https://www.readbyqxmd.com/read/28891222/global-population-pharmacokinetics-of-the-investigational-aurora-a-kinase-inhibitor-alisertib-in-cancer-patients-rationale-for-lower-dosage-in-asia
#19
X Zhou, D R Mould, T Takubo, E Sheldon-Waniga, D Huebner, A Milton, K Venkatakrishnan
AIMS: This population pharmacokinetic analysis was conducted to quantitatively describe the regional differences and sources of inter-patient variability on the apparent oral clearance of alisertib. METHODS: A population pharmacokinetic analysis was performed on data from 671 cancer patients in Western countries and in Japan/ East Asia administered alisertib 5-150 mg once or twice daily in multiple dosing schedules. The final model was used to simulate alisertib pharmacokinetics in patients in the West and East Asian regions in the single agent schedule of 7 days of dosing in a 21 day cycle...
September 11, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28884479/transcriptional-repression-of-aurora-a-gene-by-wild-type-p53-through-directly-binding-to-its-promoter-with-histone-deacetylase-1-and-msin3a
#20
Tsung-Ying Yang, Chieh-Lin Jerry Teng, Tsung-Chieh Chester Lin, Kun-Chieh Chen, Shih-Lan Hsu, Chun-Chi Wu
In this study, we firstly showed that p53 transcriptionally represses Aurora-A gene expression through directly binding to its promoter. DNA affinity precipitation assay and chromatin immunoprecipitation assay indicated that p53 physically bound to the Aurora-A promoter. Moreover, the in vitro and in vivo assays showed that p53 directly bound to the Aurora-A promoter together with histone deacetylase 1 (HDAC1) and mSin3a as corepressors. Furthermore, we identified that the nucleotides -360 to -354 (CCTGCCC), upstream of the Aurora-A transcriptional start site, was responsible for the p53-mediated repression...
September 7, 2017: International Journal of Cancer. Journal International du Cancer
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