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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
#1
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
#2
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-hotspots-in-the-aurora-a-tpx2-interaction-using-biochemical-biophysical-and-fragment-based-approaches
#3
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 anti-cancer drugs that exploit the increased sensitivity of cancer cells to mitotic stress. Here, we investigate the interface using co-precipitation assays and isothermal titration calorimetry to quantify the energetic contribution of individual residues of TPX2...
October 18, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28993511/cell-cycle-dependent-tumor-engraftment-and-migration-are-enabled-by-aurora-a
#4
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
#5
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...
September 28, 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
#6
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-mtoc-assembly-by-recruiting-plk1-and-aurora-a-during-meiotic-maturation
#7
HaiYang Wang, Min Ho Choe, In-Won Lee, Suk Namgoong, Jae-Sung Kim, Nam-Hyung Kim, Jeong Su Oh
In contrast to somatic cells where spindle microtubules are nucleated from centrosomes acting as major microtubule organizing centers (MTOCs), oocytes form meiotic spindles by assembling multiple acentriolar MTOCs without canonical centrosomes. Although Aurora A and Plk1 are required for these events, the underlying mechanisms remain largely unknown. Here we show that cancerous inhibitor of protein phosphatase 2A (CIP2A) regulates MTOC organization by recruiting Aurora A and Plk1 at spindle poles during meiotic maturation...
September 21, 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
#8
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
#9
Tsung-Ying Yang, Chieh-Lin 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
https://www.readbyqxmd.com/read/28881819/apio-ee-9-is-a-novel-aurora-a-and-b-antagonist-that-suppresses-esophageal-cancer-growth-in-a-pdx-mouse-model
#10
Guoguo Jin, Ke Yao, Zhiping Guo, Zhenjiang Zhao, Kangdong Liu, Fangfang Liu, Hanyong Chen, Dhilli Rao Gorja, Kanamata Reddy, Ann M Bode, Ziming Dong, Zigang Dong
Esophageal cancer (EC) is one of the most aggressive malignancies of the upper aerodigestive tract. Over the past three decades, with advances in surgical techniques and treatment, the prognosis of esophageal cancer has only slowly improved. Thus identifying novel molecular targets and developing therapeutic agents are critical. Aurora kinases play a crucial role in mitosis and selective inhibitors might provide an effective therapeutic treatment for cancer. However, the role of Aurora kinases in EC is still inadequately studied...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881569/aurora-a-kinase-regulates-non-homologous-end-joining-and-poly-adp-ribose-polymerase-function-in-ovarian-carcinoma-cells
#11
Thuy-Vy Do, Jeff Hirst, Stephen Hyter, Katherine F Roby, Andrew K Godwin
Ovarian cancer is usually diagnosed at late stages when cancer has spread beyond the ovary and patients ultimately succumb to the development of drug-resistant disease. There is an urgent and unmet need to develop therapeutic strategies that effectively treat ovarian cancer and this requires a better understanding of signaling pathways important for ovarian cancer progression. Aurora A kinase (AURKA) plays an important role in ovarian cancer progression by mediating mitosis and chromosomal instability. In the current study, we investigated the role of AURKA in regulating the DNA damage response and DNA repair in ovarian carcinoma cells...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28869606/kctd12-promotes-tumorigenesis-by-facilitating-cdc25b-cdk1-aurora-a-dependent-g2-m-transition
#12
Y Zhong, J Yang, W W Xu, Y Wang, C-C Zheng, B Li, Q-Y He
Cell cycle dysregulation leads to uncontrolled cell proliferation and tumorigenesis. Understanding the molecular mechanisms underlying cell cycle progression can provide clues leading to the identification of key proteins involved in cancer development. In this study, we performed proteomics analysis to identify novel regulators of the cell cycle. We found that potassium channel tetramerization domain containing 12 (KCTD12) was significantly upregulated in M phase compared with S phase. We also found that KCTD12 overexpression not only facilitated the G2/M transition and induced cancer cell proliferation, but also promoted the growth of subcutaneous tumors and Ki-67 proliferation index in mice...
September 4, 2017: Oncogene
https://www.readbyqxmd.com/read/28861148/a-proteomics-based-investigation-on-the-anticancer-activity-of-alisertib-an-aurora-kinase-a-inhibitor-in-hepatocellular-carcinoma-hep3b-cells
#13
Qiaohua Zhu, Meihua Luo, Chengyu Zhou, Zhiwei Zhou, Zhixu He, Xinfa Yu, Shufeng Zhou
Targeted therapy may provide survival benefit for advanced hepatocellular carcinoma (HCC) and Aurora A kinase (AURKA) represents a feasible target in cancer treatment. The purpose of this study is to investigate the anticancer activity of alisertib (ALS) on Hep3B cells based on a proteomic study conducted with the stable-isotope labeling by amino acids in cell culture (SILAC). The proteomic response to ALS was obtained with SILAC-based proteomic study. Cell cycle distribution and apoptosis were assessed using flow cytometry and autophagy was determined using flow cytometry and confocal microscopy...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28855673/aurora-a-phosphorylation-of-yy1-during-mitosis-inactivates-its-dna-binding-activity
#14
Karen E Alexander, Raed Rizkallah
Successful execution of mitotic cell division requires the tight synchronisation of numerous biochemical pathways. The underlying mechanisms that govern chromosome segregation have been thoroughly investigated. However, the mechanisms that regulate transcription factors in coordination with mitotic progression remain poorly understood. In this report, we identify the transcription factor YY1 as a novel mitotic substrate for the Aurora A kinase, a key regulator of critical mitotic events, like centrosome maturation and spindle formation...
August 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28852909/effects-of-rifampin-itraconazole-and-esomeprazole-on-the-pharmacokinetics-of-alisertib-an-investigational-aurora-a-kinase-inhibitor-in-patients-with-advanced-malignancies
#15
Xiaofei Zhou, Shubham Pant, John Nemunaitis, A Craig Lockhart, Gerald Falchook, Todd M Bauer, Manish Patel, John Sarantopoulos, Michael Bargfrede, Andreas Muehler, Lakshmi Rangachari, Bin Zhang, Karthik Venkatakrishnan
Aim Two studies investigated the effect of gastric acid reducing agents and strong inducers/inhibitors of CYP3A4 on the pharmacokinetics of alisertib, an investigational Aurora A kinase inhibitor, in patients with advanced malignancies. Methods In Study 1, patients received single doses of alisertib (50 mg) in the presence and absence of either esomeprazole (40 mg once daily [QD]) or rifampin (600 mg QD). In Study 2, patients received single doses of alisertib (30 mg) in the presence and absence of itraconazole (200 mg QD)...
August 30, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28819760/effect-of-alisertib-an-investigational-aurora-a-kinase-inhibitor-on-the-qtc-interval-in-patients-with-advanced-malignancies
#16
Xiaofei Zhou, John Nemunaitis, Shubham Pant, Todd M Bauer, Manish Patel, John Sarantopoulos, A Craig Lockhart, Daniel Goodman, Dirk Huebner, Diane R Mould, Karthik Venkatakrishnan
Aims A primary objective of this study was to investigate the effect of single and multiple doses of alisertib, an investigational Aurora A kinase inhibitor, on the QTc interval in patients with advanced malignancies. The dose regimen used was the maximum tolerated dose which was also the recommended phase 3 dose (50 mg twice daily [BID] for 7 days in 21-day cycles). Methods Patients received a single dose of alisertib (50 mg) on Day 1, and multiple doses of alisertib (50 mg BID) on Days 4 through to the morning of Day 10 of the first cycle of treatment...
August 18, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28818446/characterization-of-a-highly-selective-inhibitor-of-the-aurora-kinases
#17
Fleur M Ferguson, Zainab M Doctor, Apirat Chaikuad, Taebo Sim, Nam Doo Kim, Stefan Knapp, Nathanael S Gray
Aurora kinases play an essential role in mitosis and cell cycle regulation. In recent years Aurora kinases have proved popular cancer targets and many inhibitors have been developed. The majority of these clinical candidates are multi-targeted, rendering them inappropriate as tools for studying Aurora kinase mediated signaling. Here we report discovery of a highly selective inhibitor of Aurora kinases A, B and C, with potent cellular activity and minimal off-target activity (PLK4). The X-ray co-crystal structure of Aurora A in complex with compound 2 is reported, and provides insights into the structural determinants of ligand binding and selectivity...
September 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28808254/ikk2-regulates-cytokinesis-during-vertebrate-development
#18
Hongyuan Shen, Eun Myoung Shin, Serene Lee, Sinnakaruppan Mathavan, Hiromi Koh, Motomi Osato, Hyungwon Choi, Vinay Tergaonkar, Vladimir Korzh
NFκB signaling has a pivotal role in regulation of development, innate immunity, and inflammation. Ikk2 is one of the two critical kinases that regulate the NFκB signaling pathway. While the role of Ikk2 in immunity, inflammation and oncogenesis has received attention, an understanding of the role of Ikk2 in vertebrate development has been compounded by the embryonic lethality seen in mice lacking Ikk2. We find that despite abnormal angiogenesis in IKK2 zygotic mutants of zebrafish, the maternal activity of Ikk2 supports embryogenesis and maturation of fertile animals and allows to study the role of IKK2 in development...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28763871/-the-function-of-aurora-a-and-its-role-in-the-development-of-liver-cancer
#19
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/28761362/targeted-tpx2-increases-chromosome-missegregation-and-suppresses-tumor-cell-growth-in-human-prostate-cancer
#20
Hung-Wei Pan, Hsing-Hao Su, Chao-Wen Hsu, Guan-Jin Huang, Tony Tong-Lin Wu
Prostate cancer is a complex disease that can be relatively harmless or extremely aggressive. Although androgen-deprivation therapy is a commonly used treatment for men with prostate cancer, the adverse effects can be detrimental to patient health and quality of life. Therefore, identifying new target genes for tumor growth will enable the development of novel therapeutic intervention. TPX2 plays a critical role in chromosome segregation machinery during mitosis. Low rates of chromosome missegregation can promote tumor development, whereas higher levels might promote cell death and suppress tumorigenesis...
2017: OncoTargets and Therapy
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