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Aurora kinase

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https://www.readbyqxmd.com/read/29340707/vrk1-and-aurkb-form-a-complex-that-cross-inhibit-their-kinase-activity-and-the-phosphorylation-of-histone-h3-in-the-progression-of-mitosis
#1
David S Moura, Ignacio Campillo-Marcos, Marta Vázquez-Cedeira, Pedro A Lazo
Regulation of cell division requires the integration of signals implicated in chromatin reorganization and coordination of its sequential changes in mitosis. Vaccinia-related kinase 1 (VRK1) and Aurora B (AURKB) are two nuclear kinases involved in different steps of cell division. We have studied whether there is any functional connection between these two nuclear kinases, which phosphorylate histone H3 in Thr3 and Ser10, respectively. VRK1 and AURKB are able to form a stable protein complex, which represents only a minor subpopulation of each kinase within the cell and is detected following nocodazole release...
January 16, 2018: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29339483/hells-and-cdca7-comprise-a-bipartite-nucleosome-remodeling-complex-defective-in-icf-syndrome
#2
Christopher Jenness, Simona Giunta, Manuel M Müller, Hiroshi Kimura, Tom W Muir, Hironori Funabiki
Mutations in CDCA7, the SNF2 family protein HELLS (LSH), or the DNA methyltransferase DNMT3b cause immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome. While it has been speculated that DNA methylation defects cause this disease, little is known about the molecular function of CDCA7 and its functional relationship to HELLS and DNMT3b. Systematic analysis of how the cell cycle, H3K9 methylation, and the mitotic kinase Aurora B affect proteomic profiles of chromatin in Xenopus egg extracts revealed that HELLS and CDCA7 form a stoichiometric complex on chromatin, in a manner sensitive to Aurora B...
January 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29333101/variations-in-the-aurka-gene-biomarkers-for-the-development-and-progression-of-hepatocellular-carcinoma
#3
Bin Wang, Chin-Jung Hsu, Chia-Hsuan Chou, Hsiang-Lin Lee, Whei-Ling Chiang, Chen-Ming Su, Hsiao-Chi Tsai, Shun-Fa Yang, Chih-Hsin Tang
Hepatocellular carcinoma (HCC) is a liver malignancy and a major cause of cancer mortality worldwide. AURKA (aurora kinase A) is a mitotic serine/threonine kinase that functions as an oncogene and plays a critical role in hepatocarcinogenesis. We report on the association between 4 single nucleotide polymorphisms (SNPs) of the AURKA gene (rs1047972, rs2273535, rs2064836, and rs6024836) and HCC susceptibility as well as clinical outcomes in 312 patients with HCC and in 624 cancer-free controls. We found that carriers of the TT allele of the variant rs1047972 were at greater risk of HCC compared with wild-type (CC) carriers...
2018: International Journal of Medical Sciences
https://www.readbyqxmd.com/read/29332580/aurora-kinase-inhibitors-in-head-and-neck-cancer
#4
Guangying Qi, Jing Liu, Sisi Mi, Takaaki Tsunematsu, Shengjian Jin, Wenhua Shao, Tian Liu, Naozumi Ishimaru, Bo Tang, Yasusei Kudo
Aurora kinases are a group of serine/threonine kinases responsible for the regulation of mitosis. In recent years, with the increase in Aurora kinase-related research, the important role of Aurora kinases in tumorigenesis has been gradually recognized. Aurora kinases have been regarded as a new target for cancer therapy, resulting in the development of Aurora kinase inhibitors. The study and application of these small-molecule inhibitors, especially in combination with chemotherapy drugs, represents a new direction in cancer treatment...
January 12, 2018: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/29325268/-clinical-significance-of-targeting-drug-based-molecular-biomarkers-expression-in-ovarian-clear-cell-carcinoma
#5
M J Li, H R Li, X Cheng, R Bi, X Y Tu, F Liu, L H Chen
Objective: To assess the expression level of targeting drug-based molecular biomarkers in ovarian clear cell carcinoma (OCCC) tissues and its clinical significance. Methods: A total of 63 OCCC patients included 40 primary OCCC and 23 recurrent OCCC for secondary cytoreductive surgery (SCS), who had received primary surgeries at Fudan University Shanghai Cancer Center between January, 2008 and December, 2015 were enrolled, and immunohistochemistry SP method was used to test human epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-2 (HER2), aurora kinase A (AURKA), breast cancer susceptibility gene 1 (BRCA1), BRCA2 and programmed death-ligand 1 (PD-L1)protein expression in paraffin-embedded tissues...
December 25, 2017: Zhonghua Fu Chan Ke za Zhi
https://www.readbyqxmd.com/read/29311228/tpxl-1-activates-aurora-a-to-clear-contractile-ring-components-from-the-polar-cortex-during-cytokinesis
#6
Sriyash Mangal, Jennifer Sacher, Taekyung Kim, Daniel Sampaio Osório, Fumio Motegi, Ana Xavier Carvalho, Karen Oegema, Esther Zanin
During cytokinesis, a signal from the central spindle that forms between the separating anaphase chromosomes promotes the accumulation of contractile ring components at the cell equator, while a signal from the centrosomal microtubule asters inhibits accumulation of contractile ring components at the cell poles. However, the molecular identity of the inhibitory signal has remained unknown. To identify molecular components of the aster-based inhibitory signal, we developed a means to monitor the removal of contractile ring proteins from the polar cortex after anaphase onset...
January 8, 2018: Journal of Cell Biology
https://www.readbyqxmd.com/read/29301505/optimising-the-chick-chorioallantoic-membrane-xenograft-model-of-neuroblastoma-for-drug-delivery
#7
Rasha Swadi, Grace Mather, Barry L Pizer, Paul D Losty, Violaine See, Diana Moss
BACKGROUND: Neuroblastoma is a paediatric cancer that despite multimodal therapy still has a poor outcome for many patients with high risk tumours. Retinoic acid (RA) promotes differentiation of some neuroblastoma tumours and cell lines, and is successfully used clinically, supporting the view that differentiation therapy is a promising strategy for treatment of neuroblastoma. To improve treatment of a wider range of tumour types, development and testing of novel differentiation agents is essential...
January 4, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29296234/the-pyrazolyl-urea-gege3-inhibits-tumor-angiogenesis-and-reveals-dystrophia-myotonica-protein-kinase-dmpk-1-as-a-novel-angiogenesis-target
#8
Elda Meta, Beat A Imhof, Patricia Ropraz, Richard J Fish, Chiara Brullo, Olga Bruno, Adama Sidibé
The limitation of targeting VEGF/VEGFR2 signalling to stop angiogenesis in cancer therapy has been blamed on re-activation of alternative receptor tyrosine kinases by compensatory angiogenic factors. Targeting MAPK and PI3K signaling pathways in endothelial cells may be an alternative or complementary approach. Herein we aimed to evaluate the antitumor and antiangiogenic potential of a novel pyrazolyl-urea kinase inhibitor, GeGe3, and to identify its kinase targets. We found GeGe3 to inhibit the proliferation of HUVEC and endothelial tube formation...
December 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/29291012/alisertib-promotes-apoptosis-and-autophagy-in-melanoma-through-p38-mapk-mediated-aurora-a-signaling
#9
Yuan-Yuan Shang, Ming Yao, Zhi-Wei Zhou, Jian-Cui, Li-Xia, Rong-Ying Hu, Ying-Yao Yu, Qiong-Gao, Biao-Yang, Yu-Xi Liu, Jie Dang, Shu-Feng Zhou, Nan-Yu
We investigated the efficacy of Alisertib (ALS), a selective Aurora kinase A (AURKA) inhibitor, in melanoma. We found that ALS exerts anti-proliferative, pro-apoptotic, and pro-autophagic effects on A375 and skmel-5 melanoma cells by inhibiting p38 MAPK signaling. SB202190, a p38 MAPK-selective inhibitor, enhanced ALS-induced apoptosis and autophagy in both cell lines. ALS induced cell cycle arrest in melanoma cells through activation of the p53/p21/cyclin B1 pathway. Knockdown of p38 MAPK enhanced ALS-induced apoptosis and reduced ALS-induced autophagy...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29289986/phase-i-trial-to-evaluate-the-addition-of-alisertib-to-fulvestrant-in-women-with-endocrine-resistant-er-metastatic-breast-cancer
#10
Tufia C Haddad, Antonino D'Assoro, Vera Suman, Mateusz Opyrchal, Prema Peethambaram, Minetta C Liu, Matthew P Goetz, James N Ingle
PURPOSE: In estrogen receptor-positive (ER+) breast cancer models, activation of Aurora A kinase (AURKA) is associated with downregulation of ERα expression and resistance to endocrine therapy. Alisertib is an oral selective inhibitor of AURKA. The primary objectives of this phase I trial were to determine the recommended phase II dose (RP2D) and evaluate the toxicities and clinical activity of alisertib combined with fulvestrant in patients with ER+ metastatic breast cancer (MBC). METHODS: In this standard 3 + 3 dose-escalation phase I study, postmenopausal patients with endocrine-resistant, ER+ MBC previously treated with endocrine therapy were assigned to one of two dose levels of alisertib (40 or 50 mg) in combination with fixed-dose fulvestrant...
December 30, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29283376/differential-selective-pressures-experienced-by-the-aurora-kinase-gene-family
#11
Joni M Seeling, Alexis A Farmer, Adam Mansfield, Hyuk Cho, Madhusudan Choudhary
Aurora kinases (AKs) are serine/threonine kinases that are essential for cell division. Humans have three AK genes: AKA, AKB, and AKC. AKA is required for centrosome assembly, centrosome separation, and bipolar spindle assembly, and its mutation leads to abnormal spindle morphology. AKB is required for the spindle checkpoint and proper cytokinesis, and mutations cause chromosome misalignment and cytokinesis failure. AKC is expressed in germ cells, and has a role in meiosis analogous to that of AKB in mitosis...
December 28, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29276128/tension-induced-error-correction-and-not-kinetochore-attachment-status-activates-the-sac-in-an-aurora-b-c-dependent-manner-in-oocytes
#12
Antoine Vallot, Ioanna Leontiou, Damien Cladière, Warif El Yakoubi, Susanne Bolte, Eulalie Buffin, Katja Wassmann
Cell division with partitioning of the genetic material should take place only when paired chromosomes named bivalents (meiosis I) or sister chromatids (mitosis and meiosis II) are correctly attached to the bipolar spindle in a tension-generating manner. For this to happen, the spindle assembly checkpoint (SAC) checks whether unattached kinetochores are present, in which case anaphase onset is delayed to permit further establishment of attachments. Additionally, microtubules are stabilized when they are attached and under tension...
December 16, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/29260599/alisertib-a-review-of-pharmacokinetics-efficacy-and-toxicity-in-patients-with-hematologic-malignancies-and-solid-tumors
#13
Susanne Liewer, Ashley Huddleston
Aurora kinases are essential mediators in cell mitosis. Amplification of these kinases can lead to the development of malignancy and may be associated with inferior survival. Alisertib is an oral aurora kinase inhibitor which has been shown to induce cell-cycle arrest and apoptosis in preclinical studies. It is currently under investigation for a wide variety of malignancies including hematologic (specifically Non-Hodgkin's lymphoma) and solid tumors. Areas covered: A PubMed search was performed to identify clinical studies reporting outcomes with alisertib...
December 20, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29250521/mitotic-regulation-by-nek-kinase-networks
#14
REVIEW
Andrew M Fry, Richard Bayliss, Joan Roig
Genetic studies in yeast and Drosophila led to identification of cyclin-dependent kinases (CDKs), Polo-like kinases (PLKs) and Aurora kinases as essential regulators of mitosis. These enzymes have since been found in the majority of eukaryotes and their cell cycle-related functions characterized in great detail. However, genetic studies in another fungal species, Aspergillus nidulans, identified a distinct family of protein kinases, the NEKs, that are also widely conserved and have key roles in the cell cycle, but which remain less well studied...
2017: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/29250165/evaluating-the-associations-between-human-circadian-rhythms-and-dysregulated-genes-in-liver-cancer-cells
#15
Andrea Polo, Sakshi Singh, Anna Crispo, Marilina Russo, Aldo Giudice, Maurizio Montella, Giovanni Colonna, Susan Costantini
Network analysis is a useful approach in cancer biology as it provides information regarding the genes and proteins. In our previous study, a network analysis was performed on dysregulated genes in HepG2 cells, a hepatoblastoma cell line that lacks the viral infection, compared with normal hepatocytes, identifying the presence of 26 HUB genes. The present study aimed to identify whether these previously identified HUB genes participate in the network that controls the human circadian rhythms. The results of the present study demonstrated that 20/26 HUB genes were associated with the metabolic processes that control human circadian rhythms, which supports the hypothesis that a number of cancer types are dependent from circadian cycles...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29249817/drug-induced-inhibition-of-phosphorylation-of-stat5-overrides-drug-resistance-in-neoplastic-mast-cells
#16
B Peter, S Bibi, G Eisenwort, B Wingelhofer, D Berger, G Stefanzl, K Blatt, H Herrmann, E Hadzijusufovic, G Hoermann, T Hoffmann, J Schwaab, M Jawhar, M Willmann, W R Sperr, J Zuber, K Sotlar, H-P Horny, R Moriggl, A Reiter, M Arock, P Valent
Systemic mastocytosis (SM) is a mast cell (MC) neoplasm with complex pathology and a variable clinical course. In aggressive SM (ASM) and MC leukemia (MCL), responses to conventional drugs are poor and the prognosis is dismal. R763 is a multi-kinase inhibitor that blocks the activity of Aurora-kinase-A/B, ABL1, AKT and FLT3. We examined the effects of R763 on proliferation and survival of neoplastic MC. R763 produced dose-dependent inhibition of proliferation in the human MC lines HMC-1.1 (IC50 5-50 nM), HMC-1...
November 29, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29245981/co-targeting-aurora-kinase-with-pd-l1-and-pi3k-abrogates-immune-checkpoint-mediated-proliferation-in-peripheral-t-cell-lymphoma-a-novel-therapeutic-strategy
#17
Shariful Islam, Eric Vick, Bryan Huber, Carla Morales, Catherine Spier, Laurence Cooke, Eric Weterings, Daruka Mahadevan
Peripheral T-cell non-Hodgkin lymphoma (PTCL) are heterogeneous, rare, and aggressive diseases mostly incurable with current cell cycle therapies. Aurora kinases (AKs) are key regulators of mitosis that drive PTCL proliferation. Alisertib (AK inhibitor) has a response rate ∼30% in relapsed and refractory PTCL (SWOG1108). Since PTCL are derived from CD4+/CD8+ cells, we hypothesized that Program Death Ligand-1 (PD-L1) expression is essential for uncontrolled proliferation. Combination of alisertib with PI3Kα (MLN1117) or pan-PI3K inhibition (PF-04691502) or vincristine (VCR) was highly synergistic in PTCL cells...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29238913/phthalazinone-pyrazole-enhances-the-hepatic-functions-of-human-embryonic-stem-cell-derived-hepatocyte-like-cells-via-suppression-of-the-epithelial-mesenchymal-transition
#18
Young-Jun Choi, Hyemin Kim, Ji-Woo Kim, Chang-Woo Song, Dae-Sung Kim, Seokjoo Yoon, Han-Jin Park
During liver development, nonpolarized hepatic progenitor cells differentiate into mature hepatocytes with distinct polarity. This polarity is essential for maintaining the intrinsic properties of hepatocytes. The balance between the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) plays a decisive role in differentiation of polarized hepatocytes. In this study, we found that phthalazinone pyrazole (PP), a selective inhibitor of Aurora-A kinase (Aurora-A), suppressed the EMT during the differentiation of hepatocyte-like cells (HLCs) from human embryonic stem cells...
December 13, 2017: Stem Cell Reviews
https://www.readbyqxmd.com/read/29229671/h3s10ph-broadly-marks-early-replicating-domains-in-interphase-escs-and-shows-reciprocal-antagonism-with-h3k9me2
#19
Carol C L Chen, Preeti Goyal, Mohammad M Karimi, Marie H Abildgaard, Hiroshi Kimura, Matthew C Lorincz
Phosphorylation of histone H3 at serine 10 (H3S10ph) by Aurora kinases plays an important role in mitosis; however, H3S10ph also marks regulatory regions of inducible genes in interphase mammalian cells, implicating mitosis-independent functions. Using the fluorescent ubiquitin-mediated cell cycle indicator (FUCCI), we found that 30% of the genome in interphase mouse embryonic stem cells (ESCs) is marked with H3S10ph. H3S10ph broadly demarcates gene-rich regions in G1 and is positively correlated with domains of early DNA replication timing (RT) but negatively correlated with H3K9me2 and lamin-associated domains (LADs)...
December 11, 2017: Genome Research
https://www.readbyqxmd.com/read/29227678/an-old-story-in-the-parallel-synthesis-world-an-approach-to-hydantoin-libraries
#20
Andrey Bogolubsky, Yurii S Moroz, Olena Savych, Sergey Pipko, Angelika Konovets, Maxim O Platonov, Oleksandr V Vasylchenko, Vasyl V Hurmach, Oleksandr O Grygorenko
An approach to the parallel synthesis of hydantoin libraries by reaction of in situ generated 2,2,2-trifluoroethylcarbamates and α-amino esters was developed. To demonstrate utility of the method, a library of 1158 hydantoins designed according to the lead-likeness criteria (MW 200…350, cLogP -1…3) was prepared. The success rate of the method was analyzed as a function of physico-chemical parameters of the products, and it was found that the method can be considered as a tool for lead-oriented synthesis...
December 11, 2017: ACS Combinatorial Science
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