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Aurora kinase

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https://www.readbyqxmd.com/read/28079881/translational-upregulation-of-aurora-a-by-hnrnp-q1-contributes-to-cell-proliferation-and-tumorigenesis-in-colorectal-cancer
#1
Chien-Hsien Lai, Yu-Chuan Huang, Jenq-Chang Lee, Joseph Ta-Chien Tseng, Kung-Chao Chang, Yen-Ju Chen, Nai-Jhu Ding, Pao-Hsuan Huang, Wen-Chang Chang, Bo-Wen Lin, Ruo-Yu Chen, Yu-Chu Wang, Yi-Chien Lai, Liang-Yi Hung
By using RNA-immunoprecipitation assay following next-generation sequencing, a group of cell cycle-related genes targeted by hnRNP Q1 were identified, including Aurora-A kinase. Overexpressed hnRNP Q1 can upregulate Aurora-A protein, but not alter the mRNA level, through enhancing the translational efficiency of Aurora-A mRNA, either in a cap-dependent or -independent manner, by interacting with the 5'-UTR of Aurora-A mRNA through its RNA-binding domains (RBDs) 2 and 3. By ribosomal profiling assay further confirmed the translational regulation of Aurora-A mRNA by hnRNP Q1...
January 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28077684/targeting-aurora-kinase-a-and-jak2-prevents-gvhd-while-maintaining-treg-and-antitumor-ctl-function
#2
Brian C Betts, Anandharaman Veerapathran, Joseph Pidala, Hua Yang, Pedro Horna, Kelly Walton, Christopher L Cubitt, Steven Gunawan, Harshani R Lawrence, Nicholas J Lawrence, Said M Sebti, Claudio Anasetti
Graft-versus-host disease (GVHD) is a leading cause of nonrelapse mortality after allogeneic hematopoietic cell transplantation. T cell costimulation by CD28 contributes to GVHD, but prevention is incomplete when targeting CD28, downstream mammalian target of rapamycin (mTOR), or Aurora A. Likewise, interleukin-6 (IL-6)-mediated Janus kinase 2 (JAK2) signaling promotes alloreactivity, yet JAK2 inhibition does not eliminate GVHD. We provide evidence that blocking Aurora A and JAK2 in human T cells is synergistic in vitro, prevents xenogeneic GVHD, and maintains antitumor responses by cytotoxic T lymphocytes (CTLs)...
January 11, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28073841/activation-of-eif4e-by-aurora-kinase-a-depicts-a-novel-druggable-axis-in-everolimus-resistant-cancer-cells
#3
Ahmed Katsha, Lihong Wang, Janet Arras, Omar M Omar, Jeffrey A Ecsedy, Abbes Belkhiri, Wael El-Rifai
PURPOSE: In this study, we investigated the role of Aurora kinase A (AURKA) in regulating EIF4E, cap-dependent translation, and resistance to mTOR inhibitor, RAD001 (everolimus). EXPERIMENTAL DESIGN: Tumor xenografts and in vitro cell models of upper gastrointestinal adenocarcinomas (UGCs) were used to determine the role of AURKA in activation of EIF4E and cap-dependent translation. Overexpression, knockdown, and pharmacologic inhibition of AURKA were used in vitro and in vivo...
January 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28069132/molecular-regulation-of-the-spindle-assembly-checkpoint-by-kinases-and-phosphatases
#4
G Manic, F Corradi, A Sistigu, S Siteni, I Vitale
The spindle assembly checkpoint (SAC) is a surveillance mechanism contributing to the preservation of genomic stability by monitoring the microtubule attachment to, and/or the tension status of, each kinetochore during mitosis. The SAC halts metaphase to anaphase transition in the presence of unattached and/or untensed kinetochore(s) by releasing the mitotic checkpoint complex (MCC) from these improperly-oriented kinetochores to inhibit the anaphase-promoting complex/cyclosome (APC/C). The reversible phosphorylation of a variety of substrates at the kinetochore by antagonistic kinases and phosphatases is one major signaling mechanism for promptly turning on or turning off the SAC...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28049706/coordination-of-cell-cycle-progression-and-mitotic-spindle-assembly-involves-histone-h3-lysine-4-methylation-by-set1-compass
#5
Traude H Beilharz, Paul F Harrison, Douglas Maya Miles, Michael Ming See, Uyen Minh Merry Le, Ming Kalanon, Melissa Jane Curtis, Qambar Hasan, Julie Saksouk, Thanasis Margaritis, Frank Holstege, Vincent Geli, Bernhard Dichtl
Methylation of histone H3 lysine 4 (H3K4) by Set1 complex/COMPASS is a hallmark of eukaryotic chromatin, but it remains poorly understood how this post-translational modification contributes to the regulation of biological processes like the cell cycle. Here, we report a H3K4 methylation-dependent pathway in Saccharomyces cerevisiae that governs toxicity toward benomyl, a microtubule destabilizing drug. Benomyl-sensitive growth of wild-type cells required mono- and dimethylation of H3K4 and Pho23, a PHD-containing subunit of the Rpd3L complex...
January 2017: Genetics
https://www.readbyqxmd.com/read/28043854/compound-selectivity-and-target-residence-time-of-kinase-inhibitors-studied-with-surface-plasmon-resonance
#6
Nicole Willemsen-Seegers, Joost C M Uitdehaag, Martine B W Prinsen, Judith R F de Vetter, Jos de Man, Masaaki Sawa, Yusuke Kawase, Rogier C Buijsman, Guido J R Zaman
Target residence time (τ) has been suggested to be a better predictor of the biological activity of kinase inhibitors than inhibitory potency (IC50) in enzyme assays. Surface plasmon resonance binding assays for 46 human protein and lipid kinases were developed. The association and dissociation constants of 80 kinase inhibitor interactions were determined. τ and equilibrium affinity constants (KD) were calculated to determine kinetic selectivity. Comparison of τ and KD or IC50 values revealed a strikingly different view on the selectivity of several kinase inhibitors, including the multi-kinase inhibitor ponatinib, which was tested on 10 different kinases...
December 30, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28043820/kinase-signaling-and-targeted-therapy-for-primary-myelofibrosis
#7
REVIEW
Qiong Yang, John D Crispino, Qiang Jeremy Wen
The myeloproliferative neoplasms (MPNs) are somatic mutation-driven hematological malignancies characterized by bone marrow fibrosis and the accumulation of atypical megakaryocytes with reduced polyploidization in the primary myelofibrosis (PMF) subtype of the MPNs. Increasing evidence points to a dominant role of abnormal megakaryocytes (MK) in disease initiation and progression. Here we review the literature related to kinase signaling pathways relevant to megakaryocyte differentiation and proliferation, including Aurora A kinase, RhoA/ROCK and JAK/STAT, as well as the activities of their targeted inhibitors in models of the disease...
December 30, 2016: Experimental Hematology
https://www.readbyqxmd.com/read/28040741/premature-silencing-of-the-spindle-assembly-checkpoint-is-prevented-by-the-bub1-h2a-sgo1-pp2a-axis-in-saccharomyces-cerevisiae
#8
Fengzhi Jin, Michael Bokros, Yanchang Wang
The spindle assembly checkpoint (SAC) monitors mistakes in kinetochore-microtubule interaction and its activation prevents anaphase entry. The SAC remains active until all chromosomes have achieved bipolar attachment that applies tension on kinetochores. Our previous data in budding yeast Saccharomyces cerevisiae show that Ipl1/Aurora B kinase and a centromere-associated protein Sgo1 are required to prevent SAC silencing prior to tension generation, but we believe that this regulatory network is incomplete...
December 30, 2016: Genetics
https://www.readbyqxmd.com/read/28034990/phase-i-study-of-the-aurora-a-kinase-inhibitor-alisertib-with-induction-chemotherapy-in-patients-with-acute-myeloid-leukemia
#9
Amir T Fathi, Seth A Wander, Traci M Blonquist, Andrew M Brunner, Philip C Amrein, Jeffrey Supko, Nicole M Hermance, Amity L Manning, Hossein Sadrzadeh, Karen K Ballen, Eyal C Attar, Timothy A Graubert, Gabriela Hobbs, Christelle Joseph, Ashley M Perry, Meghan Burke, Regina Silver, Julia Foster, Meghan Bergeron, Aura Y Ramos, Tina T Som, Kaitlyn M Fishman, Kristin L McGregor, Christine Connolly, Donna S Neuberg, Yi-Bin Chen
Aberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred via cohorts...
December 29, 2016: Haematologica
https://www.readbyqxmd.com/read/28032021/detection-of-ligand-induced-conformational-changes-in-the-activation-loop-of-aurora-a-kinase-by-peldor-spectroscopy
#10
Selena G Burgess, Maria Grazia Concilio, Richard Bayliss, Alistair J Fielding
The structure of protein kinases has been extensively studied by protein crystallography. Conformational movement of the kinase activation loop is thought to be crucial for regulation of activity; however, in many cases the position of the activation loop in solution is unknown. Protein kinases are an important class of therapeutic target and kinase inhibitors are classified by their effect on the activation loop. Here, we report the use of pulsed electron double resonance (PELDOR) and site-directed spin labeling to monitor conformational changes through the insertion of MTSL [S-(1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1 H-pyrrol-3-yl)methyl methanesulfonothioate] on the dynamic activation loop and a stable site on the outer surface of the enzyme...
December 2016: ChemistryOpen
https://www.readbyqxmd.com/read/28028179/functional-effects-of-akt3-on-aurora-kinase-inhibitor-induced-aneuploidy
#11
Kohji Noguchi, Keita Hongama, Shiori Hariki, Yuma Nonomiya, Kazuhiro Katayama, Yoshikazu Sugimoto
The suppression of mitotic Aurora kinases (AURKs) by AURK inhibitors frequently causes cytokinetic failure, leading to polyploidy or aneuploidy, indicating the critical role of AURK-mediated phosphorylation during cytokinesis. We demonstrate the deregulated expression of AKT3 in Aurora kinase inhibitor (AURKi)-resistant cells, which we established from human colorectal cancer HCT 116 cells. The AKT family, which includes AKT1, -2, and -3, plays multiple roles in antiapoptotic functions and drug resistance and is involved in cell growth and survival pathways...
December 27, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28017898/oxidative-stress-induces-mitotic-arrest-by-inhibiting-aurora-a-involved-mitotic-spindle-formation
#12
Guang-Fei Wang, Qincai Dong, Yuanyuan Bai, Jing Yuan, Quanbin Xu, Cheng Cao, Xuan Liu
Oxidative stress contributes to the oxidative modification of cellular components, including lipids, proteins and DNA, and results in DNA damage, cell cycle arrest, cellular dysfunction and apoptosis. However, the mechanism underlying oxidative stress-induced mitotic abnormalities is not fully understood. In this study, we demonstrated that exogenous and endogenous reactive oxygen species (ROS) promoted mitotic arrest. Delayed formation and abnormal function of the mitotic spindle, which directly impeded mitosis and promoted abnormal chromosome separation, was responsible for ROS-induced mitotic arrest...
December 23, 2016: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28013532/aurora-kinase-a-is-a-prognostic-marker-in-colorectal-adenocarcinoma
#13
Hyun Min Koh, Bo Geun Jang, Chang Lim Hyun, Young Sill Kim, Jin Won Hyun, Weon Young Chang, Young Hee Maeng
Background: Aurora kinase A (AURKA), or STK15/BTAK, is a member of the serine/threonine kinase family and plays important roles in mitosis and chromosome stability. This study investigated the clinical significance of AURKA expression in colorectal cancer patients in Korea. Materials and Methods: AURKA protein expression was evaluated by immunohistochemistry in 151 patients with colorectal adenocarcinoma using tissue microarray blocks. We analyzed the relationship between clinicopathological characteristics and AURKA expression...
December 25, 2016: Journal of Pathology and Translational Medicine
https://www.readbyqxmd.com/read/28004478/cs2164-a-novel-multi-target-inhibitor-against-tumor-angiogenesis-mitosis-chronic-inflammation-with-anti-tumor-potency
#14
You Zhou, Song Shan, Zhi-Bin Li, Li-Jun Xin, De-Si Pan, Qian-Jiao Yang, Ying-Ping Liu, Xu-Peng Yue, Xiao-Rong Liu, Ji-Zhou Gao, Jin-Wen Zhang, Zhi-Qiang Ning, Xian-Ping Lu
Although inhibitors targeting tumor angiogenic pathway have provided improvement for clinical treatment in patients with various solid tumors, the still very limited anti-cancer efficacy and acquired drug resistance demand new agents that may offer better clinical benefits. In the efforts of finding a small molecule potentially targeting several key pathways for tumor development, we designed, discovered and evaluated a novel multi-kinase inhibitor, CS2164. CS2164 inhibited the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα, and c-Kit), mitosis-related kinase Aurora B, and chronic inflammatory-related kinase CSF-1R in a high potency manner with the IC50 at a single digital nanomolar range...
December 22, 2016: Cancer Science
https://www.readbyqxmd.com/read/28002641/nestin-phosphorylation-at-threonines-315-and-1299-correlates-with-proliferation-and-metastasis-of-human-pancreatic-cancer
#15
Yoko Matsuda, Toshiyuki Ishiwata, Hisashi Yoshimura, Kazuya Yamahatsu, Toshinari Minamoto, Tomio Arai
The neuroepithelial stem cell marker nestin is a cytoskeletal protein that regulates cell proliferation, invasion, and stemness in various tumors, including pancreatic tumors. In the present study, we examined the expression and roles of phosphorylated nestin in pancreatic cancer cells. Nestin phosphorylation at threonines 315 (Thr315) and 1299 (Thr1299) was observed during mitosis in human pancreatic cancer cells. Nestin phosphorylation was positively correlated with a cell proliferation marker, MIB-1 expression in human pancreatic cancer samples...
December 21, 2016: Cancer Science
https://www.readbyqxmd.com/read/28000901/identification-of-key-genes-in-colorectal-cancer-using-random-walk-with-restart
#16
Xiaofeng Cui, Kexin Shen, Zhongshi Xie, Tongjun Liu, Haishan Zhang
As the most common type of cancer and the second leading cause of cancer-associated mortality, colorectal cancer (CRC) has received increasing attention. The aim of the present study was to investigate the mechanisms of CRC by analyzing the microarray dataset, GSE32323. The GSE32323 dataset was downloaded from the Gene Expression Omnibus, and included 17 pairs of matched cancer and normal colorectal tissue samples. The differentially expressed genes (DEGs) were screened using the Linear Models for Microarray Data package and a search of CRC genes, also denoted as seed genes, was performed using the Online Mendelian Inheritance in Man database...
December 19, 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27999761/novel-immunotherapy-for-adult-t-cell-leukemia-lymphoma-targeting-aurora-kinase-a
#17
Nicholas Paul Casey, Hiroshi Fujiwara, Toshiki Ochi, Masaki Yasukawa
Adult T-cell leukemia/lymphoma is caused by infection with HTLV-1, following a long latent period. Immunotherapy targeting Aurora kinase A, a tumor-associated antigen over-expressed in adult T-cell leukemia/lymphoma, holds great therapeutic potential. We review the evidence in favor of a therapeutic strategy combining vaccination and TCR-gene transfer against this target.
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27995635/modulation-of-cycd3-1-cdk-complexes-by-phytohormones-and-sucrose-during-maize-germination
#18
Sara Margarita Garza-Aguilar, Aurora Lara-Núñez, Elpidio García Ramírez, Jorge M Vázquez-Ramos
Maize CycD3;1 associates to CDKA or CDKB1;1 proteins during germination and the complexes formed develop kinase activity. These complexes appear to vary in size as germination proceeds, suggesting association to different sets of proteins. CycD3;1 and associated CDK proteins respond to phytohormones and sucrose. Results revealed a reduction in the CycD3;1 protein amount along germination in the presence of IAA or ABA, although in the latter protein levels recover at the end of germination. While the levels of CDKA increase with IAA, they decrease with ABA...
December 20, 2016: Physiologia Plantarum
https://www.readbyqxmd.com/read/27981429/theoretical-studies-on-azaindoles-as-human-aurora-b-kinase-inhibitors-docking-pharmacophore-and-admet-studies
#19
Rajashekar Vadlakonda, Raghunandan Nerella, Sreenivas Enaganti
Aurora kinases are the cell cycle mitotic regulators processing multiple functions during cell division. Altered mechanism of these mitotic kinases may contribute to genomic instability that is most often correlated with tumorigenesis, which has been reported in many human cancers. Selective blockage of the aberrantly expressed Aurora kinases has the potential therapeutic assessment to control the deregulated cell cycle machinery and their associated risks of cancer. Using a combination of docking-, ligand- and structure-based pharmacophore strategies, in the present study, we have tried to predict the anticancer potentiality of our synthesized compounds (A1 to A5 and B1 to B9) against human Aurora B kinase...
December 16, 2016: Interdisciplinary Sciences, Computational Life Sciences
https://www.readbyqxmd.com/read/27939310/opposing-activities-of-aurora-b-kinase-and-b56-pp2a-phosphatase-on-mklp2-determine-abscission-timing
#20
Suet Yin Sarah Fung, Mayumi Kitagawa, Pei-Ju Liao, Jasmine Wong, Sang Hyun Lee
After cleavage furrow ingression during cytokinesis, nascent daughter cells remain connected by an intercellular bridge (ICB) and the midbody [1, 2]. The midbody becomes an assembly platform for ESCRT complexes that split apart the plasma membrane (PM) anchored to the ICB and complete abscission, which is the final step of cell division [3-5]. Aurora B governs abscission by regulating its timing as a checkpoint [6-10]. However, the underlying mechanisms for this process remain unknown. Here, we reveal the mechanism controlling abscission through integration of Aurora B kinase and B56-bound PP2A phosphatase activities on the kinesin motor protein MKlp2...
January 9, 2017: Current Biology: CB
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