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https://www.readbyqxmd.com/read/28512243/plk1-phosphorylation-of-mre11-antagonizes-the-dna-damage-response
#1
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 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). Phosphorylation of Mre11 at S649/S688 inhibited loading of the MRN complex to damaged DNA, leading to both premature DNA damage checkpoint termination and inhibition of DNA repair...
May 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28501934/cx-4945-the-protein-kinase-ck2-inhibitor-and-anti-cancer-drug-shows-anti-fungal-activity
#2
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
#3
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 down-stream 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 consisting of a) reduced basal NHE3 activity: specifically, inhibition of the PI3-K/ AKT-dependent component. b) reduced acute stimulation of NHE3 activity by LPA/LPA5R stimulation...
May 11, 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
#4
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...
April 30, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28489572/ck2-and-pi3k-are-direct-molecular-targets-of-quercetin-in-chronic-lymphocytic-leukaemia
#5
Maria Russo, Alfonsina Milito, Carmela Spagnuolo, Virginia Carbone, Anders Rosén, Paola Minasi, Fabio Lauria, Gian Luigi Russo
Despite the encouraging results of the innovative therapeutic treatments, complete remission is uncommon in patients affected by chronic lymphocytic leukaemia, which remains an essentially incurable disease. Recently, clinical trials based on BH3-mimetic drugs showed positive outcomes in subjects with poor prognostic features. However, resistance to treatments occurs in a significant number of patients. We previously reported that the multi-kinase inhibitor quercetin, a natural flavonol, restores sensitivity to ABT-737, a BH3-mimetic compound, in both leukemic cell lines and B-cells isolated from patients...
April 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28487119/the-mammalian-ste20-like-kinase-1-mst1-is-a-substrate-for-the-apoptosis-inhibiting-protein-kinase-ck2
#6
Christina Servas, Sandra Kiehlmeier, Julia Hach, Rebecca Gross, Claudia Götz, Mathias Montenarh
Apoptosis and the response to cell stress are evolutionary highly conserved mechanisms. Both processes require strict regulation, which is often performed by protein kinases. The mammalian Sterile 20-like kinase 1 (MST1) is a pro-apoptotic protein kinase, which is activated and cleaved by caspases upon the induction of cell stress. Being a phosphoprotein itself, the activity of MST1 is regulated by phosphorylation. Protein kinase CK2 is an anti-apoptotic protein kinase which seems to be involved in the regulation of many different cellular processes including apoptosis...
May 6, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28485934/discovery-of-pyrazolo-1-5-a-pyrimidine-b-cell-lymphoma-6-bcl6-binders-and-optimization-to-high-affinity-macrocyclic-inhibitors
#7
William McCoull, Roman D Abrams, Erica Anderson, Kevin Blades, Peter Barton, Matthew Box, Jonathan Burgess, Kate Byth, Qing Cao, Claudio Chuaqui, Rodrigo J Carbajo, Tony Cheung, Erin Code, Andrew D Ferguson, Shaun Fillery, Nathan O Fuller, Eric Gangl, Ning Gao, Matthew Grist, David Hargreaves, Martin R Howard, Jun Hu, Paul D Kemmitt, Jennifer E Nelson, Nichole O'Connell, D Bryan Prince, Piotr Raubo, Philip B Rawlins, Graeme R Robb, Junjie Shi, Michael J Waring, David Whittaker, Marta Wylot, Xiahui Zhu
Inhibition of the protein-protein interaction between B-cell lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic target in diffuse large B-cell lymphoma (DLBCL) cancers and profiling of potent and selective BCL6 inhibitors are critical to test this hypothesis. We identified a pyrazolo[1,5-a]pyrimidine series of BCL6 binders from a fragment screen in parallel with a virtual screen. Using structure-based drug design, binding affinity was increased 100000-fold. This involved displacing crystallographic water, forming new ligand-protein interactions and a macrocyclization to favor the bioactive conformation of the ligands...
May 9, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28468969/protein-kinase-ck2-controls-the-fate-between-th17-cell-and-regulatory-t-cell-differentiation
#8
Sara A Gibson, Wei Yang, Zhaoqi Yan, Yudong Liu, Amber L Rowse, Amy S Weinmann, Hongwei Qin, Etty N Benveniste
CK2 is a highly conserved and pleiotropic serine/threonine kinase that promotes many prosurvival and proinflammatory signaling pathways, including PI3K/Akt/mTOR and JAK/STAT. These pathways are essential for CD4(+) T cell activation and polarization, but little is known about how CK2 functions in T cells. In this article, we demonstrate that CK2 expression and kinase activity are induced upon CD4(+) T cell activation. Targeting the catalytic activity of CK2 using the next-generation small molecule inhibitor CX-4945 in vitro significantly and specifically inhibited mouse and human Th17 cell differentiation while promoting the generation of Foxp3(+) regulatory T cells (Tregs)...
May 3, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28460620/cx-4945-a-selective-inhibitor-of-casein-kinase-2-synergizes-with-b-cell-receptor-signaling-inhibitors-in-inducing-diffuse-large-b-cell-lymphoma-cell-death
#9
Elisa Mandato, Sara Canovas Nunes, Fortunato Zaffino, Alessandro Casellato, Paolo Macaccaro, Laura Quotti Tubi, Andrea Visentin, Livio Trentin, Gianpietro Semenzato, Francesco Piazza
BACKGROUND: Approximately one third of Diffuse Large B cell Lymphomas (DLBCL) are refractory or relapse. Novel therapeutic approaches under scrutiny include inhibitors of B-cell receptor (BCR) signaling. Protein kinase CK2 propels survival, proliferation and stress response in solid and hematologic malignancies and promotes a "non-oncogene addiction" phenotype. Whether this kinase regulates BCR signaling thus being a suitable pharmacological target in DLBCL is unknown. OBJECTIVE: To establish if CK2 controls DLBCL cell survival and the BCR signaling; to check if the combination of CK2 inhibitor CX-4945 and BCR blockers Ibrutinib and Fostamatinib is more effectively cytotoxic for DLBCL cells than the single agents; to survey the changes in signaling molecules downstream BCR upon CK2 inhibition...
April 26, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28455748/ck2-is-a-key-regulator-of-slc4a2-mediated-cl-hco3-exchange-in-human-airway-epithelia
#10
Salam H Ibrahim, Mark J Turner, Vinciane Saint-Criq, James Garnett, Iram J Haq, Malcolm Brodlie, Chris Ward, Christian Borgo, Mauro Salvi, Andrea Venerando, Michael A Gray
Transepithelial bicarbonate secretion by human airway submucosal glands and surface epithelial cells is crucial to maintain the pH-sensitive innate defence mechanisms of the lung. cAMP agonists stimulate HCO3(-) secretion via coordinated increases in basolateral HCO3(-) influx and accumulation, as well as CFTR-dependent HCO3(-) efflux at the luminal membrane of airway epithelial cells. Here, we investigated the regulation of a basolateral located, DIDS-sensitive, Cl(-)/HCO3(-) exchanger, anion exchanger 2 (AE2; SLC4A2) which is postulated to act as an acid loader, and therefore potential regulator of HCO3(-) secretion, in human airway epithelial cells...
April 28, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28453785/structural-and-functional-characterization-of-the-pnkp-xrcc4-ligiv-dna-repair-complex
#11
R Daniel Aceytuno, Cortt G Piett, Zahra Havali-Shahriari, Ross A Edwards, Martial Rey, Ruiqiong Ye, Fatima Javed, Shujuan Fang, Rajam Mani, Michael Weinfeld, Michal Hammel, John A Tainer, David C Schriemer, Susan P Lees-Miller, J N Mark Glover
Non-homologous end joining (NHEJ) repairs DNA double strand breaks in non-cycling eukaryotic cells. NHEJ relies on polynucleotide kinase/phosphatase (PNKP), which generates 5΄-phosphate/3΄-hydroxyl DNA termini that are critical for ligation by the NHEJ DNA ligase, LigIV. PNKP and LigIV require the NHEJ scaffolding protein, XRCC4. The PNKP FHA domain binds to the CK2-phosphorylated XRCC4 C-terminal tail, while LigIV uses its tandem BRCT repeats to bind the XRCC4 coiled-coil. Yet, the assembled PNKP-XRCC4-LigIV complex remains uncharacterized...
April 27, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28445141/downregulation-of-protein-kinase-ck2-activity-induces-age-related-biomarkers-in-c-elegans
#12
Jeong-Hwan Park, Joo-Hyun Lee, Jeong-Woo Park, Dong-Yun Kim, Jeong-Hoon Hahm, Hong Gil Nam, Young-Seuk Bae
Studies show that a decrease in protein kinase CK2 (CK2) activity is associated with cellular senescence. However, the role of CK2 in organism aging is still poorly understood. Here, we investigated whether protein kinase CK2 (CK2) modulated longevity in Caenorhabditis elegans. CK2 activity decreased with advancing age in the worms. Knockdown of kin-10 (the ortholog of CK2β) led to a short lifespan phenotype and induced age-related biomarkers, including retardation of locomotion, decreased pharyngeal pumping rate, increased lipofuscin accumulation, and reduced resistance to heat and oxidative stress...
April 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28442011/-ck2%C3%AE-regulates-the-metastases-and-migration-of-lung-adenocarcinoma-%C3%A2-a549-cell-line-through-pi3k-akt-gsk-3%C3%AE-signal-pathway
#13
Aibing Wu, Mingchun Li, Zongjiong Mai, Shujun Li, Zhixiong Yang
BACKGROUND: Lung cancer is the leading cancer-related death worldwide. Patients with lung cancer mainly died of tumor metastasis and invasion. Protein kinase CK2 is an ubiquitous serine/threonine protein kinase and is frequently upregulated in various human tumors. This study aims to explore the effect and molecular mechanism of the invasion and migration of lung adenocarcinoma A549 cells after knock-down of CK2α expression. METHODS: The pSilencerTM 4.1-siCK2α-eGFP of lentiviral-mediated shRNA was constructed...
April 20, 2017: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/28436950/mre11-stability-is-regulated-by-ck2-dependent-interaction-with-r2tp-complex
#14
P von Morgen, K Burdova, T G Flower, N J O'Reilly, S J Boulton, S J Smerdon, L Macurek, Z Hořejší
The MRN (MRE11-RAD50-NBS1) complex is essential for repair of DNA double-strand breaks and stalled replication forks. Mutations of the MRN complex subunit MRE11 cause the hereditary cancer-susceptibility disease ataxia-telangiectasia-like disorder (ATLD). Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1...
April 24, 2017: Oncogene
https://www.readbyqxmd.com/read/28428257/the-size-speed-force-relationship-governs-migratory-cell-response-to-tumorigenic-factors
#15
Aldo Leal-Egaña, Gaelle Letort, Jean-Louis Martiel, Andreas Christ, Timothée Vignaud, Caroline Roelants, Odile Filhol, Manuel Théry
Tumor development progresses through a complex path of biomechanical changes leading first to cell growth and contraction followed by cell de-adhesion, scattering and invasion. Tumorigenic factors may act specifically on one of these steps or have wider spectrum of actions, leading to a variety of effects and thus sometimes to apparent contradictory outcomes. Here we used micropatterned lines of collagen type-I/fibronectin on deformable surfaces to standardize cell behavior and to measure simultaneously cell size, speed of motion and the magnitude of the associated traction forces at the level of a single cell...
April 20, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28420447/ck2-1-a-bone-morphogenetic-protein-receptor-type-ia-mimetic-peptide-repairs-cartilage-in-mice-with-destabilized-medial-meniscus
#16
Hemanth Akkiraju, Padma Pradeepa Srinivasan, Xian Xu, Xinqiao Jia, Catherine B Kirn Safran, Anja Nohe
BACKGROUND: Osteoarthritis (OA) of the knee involves degeneration of articular cartilage of the diarthrodial joints. Current treatment options temporarily relieve the joint pain but do not restore the lost cartilage. We recently designed a novel bone morphogenetic protein receptor type I (BMPRI) mimetic peptide, CK2.1, that activates BMPRIa signaling in the absence of bone morphogenetic protein (BMP). Our previous research demonstrated that CK2.1 induced chondrogenesis in vitro and in vivo; however, it is unknown if CK2...
April 18, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28418900/therapeutic-inhibition-of-usp7-pten-network-in-chronic-lymphocytic-leukemia-a-strategy-to-overcome-tp53-mutated-deleted-clones
#17
Giovanna Carrà, Cristina Panuzzo, Davide Torti, Guido Parvis, Sabrina Crivellaro, Ubaldo Familiari, Marco Volante, Deborah Morena, Marcello Francesco Lingua, Mara Brancaccio, Angelo Guerrasio, Pier Paolo Pandolfi, Giuseppe Saglio, Riccardo Taulli, Alessandro Morotti
Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disorder with either indolent or aggressive clinical course. Current treatment regiments have significantly improved the overall outcomes even if higher risk subgroups - those harboring TP53 mutations or deletions of the short arm of chromosome 17 (del17p) - remain highly challenging. In the present work, we identified USP7, a known de-ubiquitinase with multiple roles in cellular homeostasis, as a potential therapeutic target in CLL. We demonstrated that in primary CLL samples and in CLL cell lines USP7 is: i) over-expressed through a mechanism involving miR-338-3p and miR-181b deregulation; ii) functionally activated by Casein Kinase 2 (CK2), an upstream interactor known to be deregulated in CLL; iii) effectively targeted by the USP7 inhibitor P5091...
March 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28398512/mutant-spastin-proteins-promote-deficits-in-axonal-transport-through-an-isoform-specific-mechanism-involving-casein-kinase-2-activation
#18
Lanfranco Leo, Carina Weissmann, Matthew Burns, Minsu Kang, Yuyu Song, Liang Qiang, Scott T Brady, Peter W Baas, Gerardo Morfini
Mutations of various genes cause hereditary spastic paraplegia (HSP), a neurological disease involving dying-back degeneration of upper motor neurons. From these, mutations in the SPAST gene encoding the microtubule-severing protein spastin account for most HSP cases. Cumulative genetic and experimental evidence suggests that alterations in various intracellular trafficking events, including fast axonal transport (FAT), may contribute to HSP pathogenesis. However, the mechanisms linking SPAST mutations to such deficits remain largely unknown...
April 7, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28373828/the-synthetic-peptide-cigb-300-modulates-ck2-dependent-signaling-pathways-affecting-the-survival-and-chemoresistance-of-non-small-cell-lung-cancer-cell-lines
#19
Stéfano M Cirigliano, María I Díaz Bessone, Damián E Berardi, Carolina Flumian, Elisa D Bal de Kier Joffé, Silvio E Perea, Hernán G Farina, Laura B Todaro, Alejandro J Urtreger
BACKGROUND: Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer-related deaths worldwide. Up to 80% of cancer patients are classified as non-small-cell lung cancer (NSCLC) and cisplatin remains as the gold standard chemotherapy treatment, despite its limited efficacy due to both intrinsic and acquired resistance. The CK2 is a Ser/Thr kinase overexpressed in various types of cancer, including lung cancer. CIGB-300 is an antitumor peptide with a novel mechanism of action, since it binds to CK2 substrates thus preventing the enzyme activity...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/28373060/cross-talk-between-the-ck2-and-akt-signaling-pathways-in-cancer
#20
REVIEW
Maria Ruzzene, Jessika Bertacchini, Alex Toker, Sandra Marmiroli
CK2 and AKT display a high degree of cross-regulation of their respective functions, both directly, through physical interaction and phosphorylation, and indirectly, through an intense cross-talk of key downstream effectors, ultimately leading to sustained AKT activation. Being CK2 and AKT attractive targets for therapeutic intervention, here we would like to emphasize how AKT and CK2 might influence cell fate through their complex isoform-specific and contextual-dependent cross-talk, to the extent that such functional interplay should be considered when devising therapies that target one or both these key signaling kinases...
March 28, 2017: Advances in Biological Regulation
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