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https://www.readbyqxmd.com/read/28738012/evaluation-of-protein-kinase-ck2-as-a-therapeutic-target-for-squamous-cell-carcinoma-of-cats
#1
Claire M Cannon, Janeen H Trembley, Betsy T Kren, Gretchen M Unger, M Gerard O'Sullivan, Ingrid Cornax, Jaime F Modiano, Khalil Ahmed
OBJECTIVE To investigate protein kinase CK2 (CK2) expression in squamous cell carcinoma (SCC) of cats and to examine effects of CK2 downregulation on in vitro apoptosis and viability in SCC. SAMPLE Biopsy specimens of oral mucosa and testis and blood samples from clinically normal cats, biopsy specimens of oral SCC from cats, and feline SCC (SCCF1) and mammary gland carcinoma (K12) cell lines. PROCEDURES Immunohistochemical labeling for CK2α was performed on biopsy specimens. Sequences of the CK2α subunit gene and CK2α' subunit gene in feline blood and feline cancer cell lines were determined by use of PCR and reverse-transcription PCR assays followed by direct Sanger sequencing...
August 2017: American Journal of Veterinary Research
https://www.readbyqxmd.com/read/28698370/g9a-coordinates-with-the-rpa-complex-to-promote-dna-damage-repair-and-cell-survival
#2
Qiaoyan Yang, Qian Zhu, Xiaopeng Lu, Yipeng Du, Linlin Cao, Changchun Shen, Tianyun Hou, Meiting Li, Zhiming Li, Chaohua Liu, Di Wu, Xingzhi Xu, Lina Wang, Haiying Wang, Ying Zhao, Yang Yang, Wei-Guo Zhu
Histone methyltransferase G9a has critical roles in promoting cancer-cell growth and gene suppression, but whether it is also associated with the DNA damage response is rarely studied. Here, we report that loss of G9a impairs DNA damage repair and enhances the sensitivity of cancer cells to radiation and chemotherapeutics. In response to DNA double-strand breaks (DSBs), G9a is phosphorylated at serine 211 by casein kinase 2 (CK2) and recruited to chromatin. The chromatin-enriched G9a can then directly interact with replication protein A (RPA) and promote loading of the RPA and Rad51 recombinase to DSBs...
July 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28683323/identification-of-a-druggable-pathway-controlling-glioblastoma-invasiveness
#3
Nora Pencheva, Mark C de Gooijer, Daniel J Vis, Lodewyk F A Wessels, Tom Würdinger, Olaf van Tellingen, René Bernards
Diffuse and uncontrollable brain invasion is a hallmark of glioblastoma (GBM), but its mechanism is understood poorly. We developed a 3D ex vivo organotypic model to study GBM invasion. We demonstrate that invading GBM cells upregulate a network of extracellular matrix (ECM) components, including multiple collagens, whose expression correlates strongly with grade and clinical outcome. We identify interferon regulatory factor 3 (IRF3) as a transcriptional repressor of ECM factors and show that IRF3 acts as a suppressor of GBM invasion...
July 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/28674151/kinase-activity-ranking-using-phosphoproteomics-data-karp-quantifies-the-contribution-of-protein-kinases-to-the-regulation-of-cell-viability
#4
Edmund Wilkes, Pedro Casado, Vinothini Rajeeve, Pedro Rodriguez Cutillas
Cell survival is regulated by a signaling network driven by the activity of protein kinases; however, determining the contribution that each kinase in the network makes to such regulation remains challenging. Here, we report a computational approach that uses mass spectrometry-based phosphoproteomics data to rank protein kinases based on their contribution to cell regulation. We found that the scores returned by this algorithm, which we have termed Kinase Activity Ranking using Phosphoproteomics data (KARP), were a quantitative measure of the contribution that individual kinases make to the signaling output...
July 3, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28672764/interaction-of-tubulin-and-protein-kinase-ck2-in-trypanosoma-equiperdum
#5
Beatriz E Boscán, Graciela L Uzcanga, Maritza Calabokis, Rocío Camargo, Frank Aponte, José Bubis
A polypeptide band with an apparent molecular weight of 55,000 was phosphorylated in vitro in whole-cell lysates of Trypanosoma equiperdum. This band corresponds to tubulin as demonstrated by immunoprecipitation of the phosphorylated polypeptide from T. equiperdum extracts when anti-α and anti-β tubulin monoclonal antibodies were employed. A parasite protein kinase CK2 was in charge of modifying tubulin given that common mammalian CK2 inhibitors such as emodin and GTP, hindered the phosphorylation of tubulin and exogenously added casein...
June 27, 2017: Zeitschrift Für Naturforschung. C, A Journal of Biosciences
https://www.readbyqxmd.com/read/28671992/signaling-pathways-induced-by-serine-proteases-to-increase-intestinal-epithelial-barrier-function
#6
Kelcie A Lahey, Natalie J Ronaghan, Judie Shang, Sébastien P Dion, Antoine Désilets, Richard Leduc, Wallace K MacNaughton
Changes in barrier function of the gastrointestinal tract are thought to contribute to the inflammatory bowel diseases Crohn's disease and ulcerative colitis. Previous work in our lab demonstrated that apical exposure of intestinal epithelial cell lines to serine proteases results in an increase in transepithelial electrical resistance (TER). However, the underlying mechanisms governing this response are unclear. We aimed to determine the requirement for proteolytic activity, epidermal growth factor receptor (EGFR) activation, and downstream intracellular signaling in initiating and maintaining enhanced barrier function following protease treatment using a canine intestinal epithelial cell line (SCBN)...
2017: PloS One
https://www.readbyqxmd.com/read/28649667/impact-of-protein-kinase-ck2-inhibitors-on-proliferation-and-differentiation-of-neural-stem-cells
#7
Melanie Bender, Lisa Schwind, David Grundmann, Monika Martin, Markus Klotz, Claudia Götz, Mathias Montenarh, Karl-Herbert Schäfer
BACKGROUND: Protein kinases play central roles in cell and tissue development. Protein kinase CK2, an ubiquitously expressed serine/threonine kinase has severe impacts on embryo- and spermatogenesis. Since its role in neurogenesis has so far only been investigated in very few studies, we analysed the role of CK2 in neural stem cells by using two specific inhibitors. METHODS: Neural stem cells were isolated from the subventricular zone of neonatal mice, using a neurosphere approach...
June 2017: Heliyon
https://www.readbyqxmd.com/read/28623166/casein-kinase-ii-ck2-glycogen-synthase-kinase-3-gsk-3-and-ikaros-mediated-regulation-of-leukemia
#8
REVIEW
Chandrika Gowda, Mario Soliman, Malika Kapadia, Yali Ding, Kimberly Payne, Sinisa Dovat
Signaling networks that regulate cellular proliferation often involve complex interactions between several signaling pathways. In this manuscript we review the crosstalk between the Casein Kinase II (CK2) and Glycogen Synthase Kinase-3 (GSK-3) pathways that plays a critical role in the regulation of cellular proliferation in leukemia. Both CK2 and GSK-3 are potential targets for anti-leukemia treatment. Previously published data suggest that CK2 and GSK-3 act synergistically to promote the phosphatidylinositol-3 kinase (PI3K) pathway via phosphorylation of PTEN...
June 13, 2017: Advances in Biological Regulation
https://www.readbyqxmd.com/read/28623000/medical-ozone-promotes-nrf2-phosphorylation-reducing-oxidative-stress-and-pro-inflammatory-cytokines-in-multiple-sclerosis-patients
#9
Livan Delgado-Roche, Mario Riera-Romo, Fernando Mesta, Yanet Hernández-Matos, Juan M Barrios, Gregorio Martínez-Sánchez, Said M Al-Dalaien
Oxidative stress and inflammation play key roles in the pathogenesis of Multiple sclerosis (MS). Different drugs have been used in the clinical practice, however, there is not a completely effective treatment. Due to its potential therapeutic action, medical ozone represents a promising approach for neurodegenerative disorders. The aim of the present study was to address the role of ozone therapy on the cellular redox state in MS patients. Ozone (20μg/ml) was administered three times per week during a month by rectal insufflation...
June 13, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28604763/proline-rich-homeodomain-protein-prh-hhex-is-a-suppressor-of-breast-tumour-growth
#10
R M Kershaw, D Roberts, J Wragg, A M Shaaban, E Humphreys, J Halsall, L Price, R Bicknell, K Gaston, P-S Jayaraman
Breast tumours progress from hyperplasia to ductal carcinoma in situ (DCIS) and invasive breast carcinoma (IBC). PRH/HHEX (proline-rich homeodomain/haematopoietically expressed homeobox) is a transcription factor that displays both tumour suppressor and oncogenic activity in different disease contexts; however, the role of PRH in breast cancer is poorly understood. Here we show that nuclear localization of the PRH protein is decreased in DCIS and IBC compared with normal breast. Our previous work has shown that PRH phosphorylation by protein kinase CK2 prevents PRH from binding to DNA and regulating the transcription of multiple genes encoding growth factors and growth factor receptors...
June 12, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28597245/protein-kinase-ck2-regulates-redox-homeostasis-through-nf-%C3%AE%C2%BAb-and-bcl-xl-in-cardiomyoblasts
#11
Susanne Schaefer, Barbara Guerra
Oxygen consumption is particularly elevated in cardiac cells as they are equipped with a large number of mitochondria and high levels of respiratory chain components. Consequently, production of reactive oxygen species (ROS) is tightly controlled as an imbalance in redox reactions can lead to irreversible cellular damage. siRNA-mediated down-regulation of protein kinase CK2 has been implicated in the accumulation of ROS in cells. The present study was undertaken in order to investigate the role of CK2 in redox homeostasis in cardiomyoblasts...
June 8, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28585349/csnk2b-splice-site-mutations-in-patients-cause-intellectual-disability-with-or-without-myoclonic-epilepsy
#12
Karine Poirier, Laurence Hubert, Géraldine Viot, Marlène Rio, Pierre Billuart, Claude Besmond, Thierry Bienvenu
De novo mutations are a frequent cause of disorders related to brain development. We report the results from the screening of two patients diagnosed with intellectual disability (ID) using exome sequencing to identify new causative de novo mutations. Exome sequencing was conducted in two patient-parent trios to identify de novo variants. In silico and expression studies were also performed to evaluate the functional consequences of these variants. The two patients presented developmental delay with minor facial dysmorphy...
August 2017: Human Mutation
https://www.readbyqxmd.com/read/28572157/characterization-of-the-oligomeric-states-of-the-ck2-%C3%AE-2%C3%AE-2-holoenzyme-in-solution
#13
Graziano Lolli, Denise Naressi, Stefania Sarno, Roberto Battistutta
The regulatory mechanism of protein kinase CK2 has still to be fully clarified. The prevailing hypothesis is that CK2 is controlled by a self-polymerisation mechanism leading to inactive supramolecular assemblies that, when needed, can be disassembled into the α2β2 monomer, the active form of the holoenzyme. In vitro , monomeric α2β2 seems present only at high ionic strengths, typically 0.35-0.50 M NaCl, while at lower salt concentrations oligomers are formed. Here Size Exclusion Chromatography (SEC), Dynamic Light Scattering (DLS), Small Angle X-ray Scattering (SAXS) and mutagenesis have been employed for the characterization of the oligomeric states of CK2 in solution...
June 1, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28534839/exploring-the-pivotal-role-of-the-ck2-hinge-region-sub-pocket-in-binding-with-tricyclic-quinolone-analogues-by-computational-analysis
#14
Yue Zhou, Na Zhang, Shan Tang, Xiaoqian Qi, Lijiao Zhao, Rugang Zhong, Yongzhen Peng
Protein kinase CK2 has been considered as an attractive therapeutic target of cancer therapy. The tricyclic quinoline compound CX-4945 is the first representative of CK2 inhibitors used in human clinical trials. The binding of non-2,6-naphtyridine substituted compounds 27e (IC50 > 500 nM) and 27h (IC50 > 1000 nM) to CK2 is abolished. However, the unbinding mechanisms due to the key pharmacophore group replacement of compounds 27e and 27h are unveiled. In the present work, combined computational analysis was performed to investigate the underlying structural basis of the low-affinity of two systems...
May 19, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28533810/tc003132-is-essential-for-the-follicle-stem-cell-lineage-in-telotrophic-tribolium-oogenesis
#15
Matthias Teuscher, Nadi Ströhlein, Markus Birkenbach, Dorothea Schultheis, Michael Schoppmeier
BACKGROUND: Stem cells are undifferentiated cells with a potential for self-renewal, which are essential to support normal development and homeostasis. To gain insight into the molecular mechanisms underlying adult stem cell biology and organ evolution, we use the telotrophic ovary of the beetle Tribolium. To this end, we participated in a large-scale RNAi screen in the red flour beetle Tribolium, which identified functions in embryonic and postembryonic development for more than half of the Tribolium genes...
2017: Frontiers in Zoology
https://www.readbyqxmd.com/read/28533219/obesity-linked-phosphorylation-of-sirt1-by-ck2-inhibits-its-nuclear-localization-and-promotes-fatty-liver
#16
Sung E Choi, Sanghoon Kwon, Sunmi Seok, Zhen Xiao, Kwan-Woo Lee, Yup Kang, Xiaoling Li, Kosaku Shinoda, Shingo Kajimura, Byron Kemper, Jongsook Kim Kemper
Sirtuin1 (SIRT1) deacetylase delays and improves many obesity-related diseases, including non-alcoholic fatty liver disease (NAFLD) and diabetes, and has received great attention as a drug target. SIRT1 function is aberrantly low in obesity, so understanding the underlying mechanisms is important for drug development. Here, we show that obesity-linked phosphorylation of SIRT1 inhibits its function and promotes pathological symptoms of NAFLD. In proteomic analysis, Ser-164 was identified as a major serine phosphorylation site in SIRT1 in obese, but not lean, mice, and this phosphorylation was catalyzed by casein kinase-2 (CK2), the levels of which were dramatically elevated in obesity...
May 22, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28512243/plk1-phosphorylation-of-mre11-antagonizes-the-dna-damage-response
#17
Zhiguo Li, Jie Li, Yifan Kong, Shan Yan, Nihal Ahmad, Xiaoqi Liu
The mitotic kinase Plk1 contributes to the DNA damage response (DDR) by targeting multiple factors downstream of the core responder kinase ATM/ATR. In this study, we show that Polo-like kinase 1 (Plk1) also phosphorylates key factors upstream of ATM/ATR and regulates their DDR-related functions. Plk1 phosphorylated Mre11, a component of the Mre11/Rad50/Nbs1 (MRN) complex, at serine 649 (S649) during DDR. Phosphorylation of Mre11-S649 by Plk1 primed subsequent CK2-mediated phosphorylation at Mre11-serine 688 (S688)...
June 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28501934/cx-4945-the-protein-kinase-ck2-inhibitor-and-anti-cancer-drug-shows-anti-fungal-activity
#18
Maciej Masłyk, Monika Janeczko, Aleksandra Martyna, Konrad Kubiński
CX-4945 is a selective inhibitor of protein kinase CK2 exhibiting clinical significance. Its antitumor properties arise from the abrogation of CK2-mediated pro-survival cellular pathways. The presented data reveal the influence of CX-4945 on the growth of yeast cells showing variable potency against Saccharomyces cerevisiae deletion strains with different contents of CK2 subunits. The catalytic subunit CK2α appears to sensitize yeast to the CX-4945 action. Moreover, the compound suppresses hyphal growth and cell adhesion of Candida albicans, thereby abolishing some hallmarks of invasiveness of the pathogen...
May 13, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28495796/phosphorylation-of-nhe3-s-719-regulates-nhe3-activity-through-the-formation-of-multiple-signaling-complexes
#19
Rafiquel Sarker, Boyoung Cha, Olga Kovbasnjuk, Robert Cole, Sandra Gabelli, Chung Ming Tse, Mark Donowitz
Casein kinase 2 (CK2) binds to the NHE3 C-terminus and constitutively phosphorylates a downstream site (S719) that accounts for 40% of basal NHE3 activity. The role of CK2 in regulation of NHE3 activity in polarized Caco-2/bbe cells was further examined by mutation of NHE3-S(719) to A (not phosphorylated) or D (phosphomimetic). NHE3-S719A but not -S719D had multiple changes in NHE3 activity: 1) reduced basal NHE3 activity-specifically, inhibition of the PI3K/AKT-dependent component; 2) reduced acute stimulation of NHE3 activity by LPA/LPA5R stimulation; and 3) reduced acute inhibition of NHE3 activity-specifically, elevated Ca(2+) related (carbachol/Ca(2+) ionophore), but there was normal inhibition by forskolin and hyperosmolarity...
July 1, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28495381/a-fragment-based-approach-leading-to-the-discovery-of-a-novel-binding-site-and-the-selective-ck2-inhibitor-cam4066
#20
Claudia De Fusco, Paul Brear, Jessica Iegre, Kathy Hadje Georgiou, Hannah F Sore, Marko Hyvönen, David R Spring
Recently we reported the discovery of a potent and selective CK2α inhibitor CAM4066. This compound inhibits CK2 activity by exploiting a pocket located outside the ATP binding site (αD pocket). Here we describe in detail the journey that led to the discovery of CAM4066 using the challenging fragment linking strategy. Specifically, we aimed to develop inhibitors by linking a high-affinity fragment anchored in the αD site to a weakly binding warhead fragment occupying the ATP site. Moreover, we describe the remarkable impact that molecular modelling had on the development of this novel chemical tool...
July 1, 2017: Bioorganic & Medicinal Chemistry
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