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https://www.readbyqxmd.com/read/28720575/hsp72-and-nek6-cooperate-to-cluster-amplified-centrosomes-in-cancer-cells
#1
Josephina Sampson, Laura O'Regan, Martin Js Dyer, Richard Bayliss, Andrew M Fry
Cancer cells frequently possess extra amplified centrosomes clustered into two poles whose pseudo-bipolar spindles exhibit reduced fidelity of chromosome segregation and promote genetic instability. Inhibition of centrosome clustering triggers multipolar spindle formation and mitotic catastrophe, offering an attractive therapeutic approach to selectively kill cells with amplified centrosomes. However, mechanisms of centrosome clustering remain poorly understood. Here, we identify a new pathway that acts through NIMA-related kinase 6 (Nek6) and Hsp72 to promote centrosome clustering...
July 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28706138/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...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28700980/aurora-a-kinase-regulates-non-homologous-end-joining-and-poly-adp-ribose-polymerase-function-in-ovarian-carcinoma-cells
#3
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...
July 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28700101/dynamic-equilibrium-of-the-aurora-a-kinase-activation-loop-revealed-by-single-molecule-spectroscopy
#4
James A H Gilburt, Hajrah Sarkar, Peter Sheldrake, Julian Blagg, Liming Ying, Charlotte Dodson
The conformation of the activation loop (T-loop) of protein kinases underlies enzymatic activity and influences the binding of small molecule inhibitors. Using single molecule fluorescence spectroscopy, we have determined that phosphorylated Aurora-A kinase is in dynamic equilibrium between a DFG-in-like active T-loop conformation and a DFG-out-like inactive conformation and have measured the rate constants of interconversion. Addition of the Aurora-A activating protein TPX2 shifts the equilibrium towards an active T-loop conformation, whereas addition of the inhibitors MLN8054 and CD532 favors an inactive T-loop...
July 12, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28685608/what-s-new-in-small-cell-lung-cancer-extensive-disease-an-overview-on-advances-of-systemic-treatment-in-2016
#5
Andreas Seeber, Christoph Leitner, Kathrin Philipp-Abbrederis, Gilbert Spizzo, Florian Kocher
Systemic therapy options for small cell lung cancer patients with extensive disease remain poor. After an initial response on first-line therapy, virtually all patients develop disease progression. For those who showed an initial response only few therapy options with low response rates are currently available. Until now, many experimental and targeted agents have failed to yield convincing clinical benefits, and new therapy options are clearly warranted for these patients. In this year's oncological congresses, several new therapy strategies, including checkpoint inhibition, showed promising results in ongoing trials...
July 7, 2017: Future Oncology
https://www.readbyqxmd.com/read/28654908/apio-ee-9-is-a-novel-aurora-a-and-b-antagonist-that-suppresses-esophageal-cancer-growth-in-a-pdx-mouse-model
#6
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...
June 16, 2017: Oncotarget
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
#7
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/28620032/a-moving-target-structure-and-disorder-in-pursuit-of-myc-inhibitors
#8
REVIEW
Richard Bayliss, Selena G Burgess, Eoin Leen, Mark W Richards
The Myc proteins comprise a family of ubiquitous regulators of gene expression implicated in over half of all human cancers. They interact with a large number of other proteins, such as transcription factors, chromatin-modifying enzymes and kinases. Remarkably, few of these interactions have been characterized structurally. This is at least in part due to the intrinsically disordered nature of Myc proteins, which adopt a defined conformation only in the presence of binding partners. Owing to this behaviour, crystallographic studies on Myc proteins have been limited to short fragments in complex with other proteins...
June 15, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28610844/overexpression-of-eif4f-components-in-meningiomas-and-suppression-of-meningioma-cell-growth-by-inhibiting-translation-initiation
#9
Janet L Oblinger, Sarah S Burns, Jie Huang, Li Pan, Yulin Ren, Rulong Shen, A Douglas Kinghorn, D Bradley Welling, Long-Sheng Chang
Meningiomas frequently display activation of the PI3K/AKT/mTOR pathway, leading to elevated levels of phospho-eukaryotic translation initiation factor 4E binding proteins, which enhances protein synthesis; however, it is not known whether inhibition of protein translation is an effective treatment option for meningiomas. We found that human meningiomas expressed high levels of the three components of the eukaryotic initiation factor 4F (eIF4F) translation initiation complex, eIF4A, eIF4E, and eIF4G. The expression of eIF4A and eIF4E was important in sustaining the growth of NF2-deficient benign meningioma Ben-Men-1 cells, as shRNA-mediated knockdown of these proteins strongly reduced cell proliferation...
June 10, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28601256/aurora-a-kinase-is-a-priority-pharmaceutical-target-for-the-treatment-of-cancers
#10
REVIEW
Arun Prasath Damodaran, Lucie Vaufrey, Olivia Gavard, Claude Prigent
Aurora kinases control multiple events during cell cycle progression and are essential for mitotic and meiotic bipolar spindle assembly and function. There are three Aurora kinases in mammals, some of which have oncogenic properties and all of which are overexpressed in multiple cancers. Pharmaceutical companies quickly made these kinases priority targets for the development of inhibitors to be used as cancer treatments. In this review, we focus on Aurora A, against which several inhibiting compounds have been discovered and made available; however, even though some of these compounds underwent clinical trials, none have yet gone beyond Phase III trials...
June 7, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28586053/hdac6-inhibition-suppresses-chondrosarcoma-by-restoring-the-expression-of-primary-cilia
#11
Wei Xiang, Fengjing Guo, Weiting Cheng, Jiaming Zhang, Junming Huang, Rui Wang, Zhongxi Ma, Kai Xu
Chondrosarcoma is a bone tumor characterized by the secretion of a cartilage-like extracellular matrix. It has been proved to lack extracellular sensor primary cilia. This study aimed to illustrate a feasible therapeutic method for chondrosarcoma by regulating primary cilia assembly through inhibiting histone deacetylases 6 (HDAC6) activation. In order to detect the interaction between primary cilia and HDAC6 in human chondrosarcoma, Tubastatin A and small interfering RNA (siRNA) were used to inhibit the endogenous expression of HDAC6...
June 2, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28552528/peroxiredoxins-are-required-for-spindle-assembly-chromosome-organization-and-polarization-in-mouse-oocytes
#12
Hyuk-Joon Jeon, Yong Seok Park, Dong-Hyung Cho, Jae-Sung Kim, Eunji Kim, Ho Zoon Chae, Sang-Young Chun, Jeong Su Oh
Peroxiredoxins (Prxs) are highly conserved antioxidant enzymes and are implicated in multiple biological processes; however, their function in oocyte meiosis has not been studied. Here we show that inhibition of Prx I and II results in spindle defects, chromosome disorganization, and impaired polarization in mouse oocytes. Prx I was specifically localized at the spindle, whereas Prx II was enriched at the oocyte cortex and chromosomes. Inhibition of Prx activity with conoidin A disturbed assembly of the microtubule organizing center (MTOC) through Aurora A regulation, leading to defects in spindle formation...
May 25, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28536143/aurora-kinase-a-promotes-ar-degradation-via-the-e3-ligase-chip
#13
Sukumar Sarkar, David L Brautigan, James M Larner
Reducing the levels of the androgen receptor (AR) is one of the most viable approaches to combat castration-resistant prostate cancer (CRPC). Previously, we observed that proteasomal-dependent degradation of AR in response to 2-methoxyestradiol (2-ME) depends primarily on the E3 ligase C-terminus of HSP70-interacting protein (STUB1/CHIP). Here, 2-ME stimulation activates CHIP by phosphorylation via Aurora kinase A (AURKA). Aurora A kinase inhibitors and RNAi knockdown of Aurora A transcript selectively blocked CHIP phosphorylation and AR degradation...
May 23, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28529042/optimization-and-biological-evaluation-of-2-aminobenzothiazole-derivatives-as-aurora-b-kinase-inhibitors
#14
Eun Lee, Ying An, Junhee Kwon, Keun Il Kim, Raok Jeon
A strong relationship between abnormal functions of Aurora kinases and tumorigenesis has been reported for decades. Consequently, Aurora kinases serve as potential targets for anticancer agents. Here, we identified aminobenzothiazole derivatives as novel inhibitors of Aurora B kinase through bioisosteric replacement of the previous inhibitors, aminobenzoxazole derivatives. Most of the urea-linked aminobenzothiazole derivatives showed potent and selective inhibitory activity against Aurora B kinase over Aurora A kinase...
April 6, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28522591/inhibition-of-aurora-a-and-aurora-b-is-required-for-the-sensitivity-of-hpv-driven-cervical-cancers-to-aurora-kinase-inhibitors
#15
David Martin, Sora Fallaha, Martina Proctor, Alexander Stevenson, Lewis Perrin, Nigel McMillan, Brian Gabrielli
The activity and efficacy of Aurora inhibitors have been reported in a wide range of cancer types.   The most prominent Aurora inhibitor is Alisertib, an investigational Aurora inhibitor that has been the subject of more than 30 clinical trials.   Alisertib has inhibitory activity against both Aurora A and B, although it is considered to be primarily an Aurora A inhibitor in vivo.  Here we show that Alisertib inhibits both Aurora A and B in vivo in preclinical models of HPV-driven cervical cancer, and that it is the inhibition of Aurora A and B that provide the selectivity and efficacy of this drug in vivo in this disease setting...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28470610/production-of-protein-kinases-in-e-coli
#16
Charlotte A Dodson
Recombinant protein expression is widely used to generate milligram quantities of protein kinases for crystallographic, enzymatic, or other biophysical assays in vitro. Expression in E. coli is fast, cheap, and reliable. Here I present a detailed protocol for the production of human Aurora-A kinase. I begin with transformation of a suitable plasmid into an expression strain of E. coli, followed by growth and harvesting of bacterial cell cultures. Finally, I describe the purification of Aurora-A to homogeneity using immobilized metal affinity and size exclusion chromatographies...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28465536/metformin-disrupts-malignant-behavior-of-oral-squamous-cell-carcinoma-via-a-novel-signaling-involving-late-sv40-factor-aurora-a
#17
Chang-Han Chen, Hsin-Ting Tsai, Hui-Ching Chuang, Li-Yen Shiu, Li-Jen Su, Tai-Jan Chiu, Sheng-Dean Luo, Fu-Min Fang, Chao-Cheng Huang, Chih-Yen Chien
Conventional therapeutic processes in patient with OSCC are associated with several unfavorable effects leading to patients with poor survival rate. Metformin has been shown to protect against a variety of specific diseases, including cancer. However, the precise roles and mechanisms underlying the therapeutic effects of metformin on OSCC remain elusive. In the current study, in vitro and xenograft model experiments revealed that metformin inhibited growth and metastasis of oral cancer cells. Importantly, metformin-restrained tumorigenesis of oral cancer was accompanied with strong decrease of both Aurora-A and Late SV40 Factor (LSF) expressions...
May 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28446271/-expression-of-aurora-family-genes-in-acute-leukemia-and-its-clinical-significance
#18
Zi-Lei Liu, Ying Xing, Tao Li, Chong Wang, Su-Fang Liu, Hua-Yan Zhao, Rong-Hui Zhang, Ya-Jing Ma, Xin-Ye Zhang, Wen-Liang Tian, Liu Liu, Hui Sun, Ling Sun
OBJECTIVE: To explore the mRNA expression of Aurora-A,B,C(AUR-A,B,C) in acute leukemia(AL) and their correlations with the clinical indications. METHODS: The mRNA expression levels of AUR-A,B,C in 73 cases of newly diagnosed AL (untreated group), 20 cases of AL with remission (remission group) and 14 healthy volunteers as control (healthy group) were detected by QRT-PCR, and the difference of expression levels in difference groups, their correlations with clinical indicators and the correlation between the AUR-A,B,C mRNA expression levels themselves were analyzed...
April 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28444399/development-of-a-multipurpose-scaffold-for-the-display-of-peptide-loops
#19
Maxim Rossmann, Sandra J Greive, Tommaso Moschetti, Michael Dinan, Marko Hyvönen
Protein-protein interactions (PPIs) determine a wide range of biological processes and analysis of these dynamic networks is increasingly becoming a mandatory tool for studying protein function. Using the globular ATPase domain of recombinase RadA as a scaffold, we have developed a peptide display system (RAD display), which allows for the presentation of target peptides, protein domains or full-length proteins and their rapid recombinant production in bacteria. The design of the RAD display system includes differently tagged versions of the scaffold, which allows for flexibility in the protein purification method, and chemical coupling for small molecule labeling or surface immobilization...
April 24, 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/28431392/characterization-of-aurora-a-and-its-impact-on-the-effect-of-cisplatin-based-chemotherapy-in-patients-with-non-small-cell-lung-cancer
#20
Peng Kuang, Zuhua Chen, JiaYuan Wang, Zhentao Liu, Jingyuan Wang, Jing Gao, Lin Shen
BACKGROUND AND OBJECTIVE: Aurora A, as a member of serine/threonine kinase family and a common characteristic of epithelial cancers, plays a critical role in cell mitosis. However, the clinical significance of Aurora A in non-small cell lung cancer (NSCLC) remains undetermined. METHODS: The expression of Aurora A in NSCLC and paired normal adjacent lung tissues was determined by immunohistochemistry, Western blot, and reverse transcriptase polymerase chain reaction...
June 2017: Translational Oncology
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