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https://www.readbyqxmd.com/read/28230762/the-development-of-ck2-inhibitors-from-traditional-pharmacology-to-in-silico-rational-drug-design
#1
REVIEW
Giorgio Cozza
Casein kinase II (CK2) is an ubiquitous and pleiotropic serine/threonine protein kinase able to phosphorylate hundreds of substrates. Being implicated in several human diseases, from neurodegeneration to cancer, the biological roles of CK2 have been intensively studied. Upregulation of CK2 has been shown to be critical to tumor progression, making this kinase an attractive target for cancer therapy. Several CK2 inhibitors have been developed so far, the first being discovered by "trial and error testing". In the last decade, the development of in silico rational drug design has prompted the discovery, de novo design and optimization of several CK2 inhibitors, active in the low nanomolar range...
February 20, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28230733/ck2-molecular-targeting-tumor-cell-specific-delivery-of-rnai-in-various-models-of-cancer
#2
REVIEW
Janeen H Trembley, Betsy T Kren, Md Joynal Abedin, Rachel I Vogel, Claire M Cannon, Gretchen M Unger, Khalil Ahmed
Protein kinase CK2 demonstrates increased protein expression relative to non-transformed cells in the majority of cancers that have been examined. The elevated levels of CK2 are involved in promoting not only continued proliferation of cancer cells but also their resistance to cell death; thus, CK2 has emerged as a plausible target for cancer therapy. Our focus has been to target CK2 catalytic subunits at the molecular level using RNA interference (RNAi) strategies to achieve their downregulation. The delivery of oligonucleotide therapeutic agents warrants that they are protected and are delivered specifically to cancer cells...
February 21, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28223413/transcriptional-activation-of-lipogenesis-by-insulin-requires-phosphorylation-of-med17-by-ck2
#3
Jose A Viscarra, Yuhui Wang, Il-Hwa Hong, Hei Sook Sul
De novo lipogenesis is precisely regulated by nutritional and hormonal conditions. The genes encoding various enzymes involved in this process, such as fatty acid synthase (FASN), are transcriptionally activated in response to insulin. We showed that USF1, a key transcription factor for FASN activation, directly interacted with the Mediator subunit MED17 at the FASN promoter. This interaction recruited Mediator, which can bring POL II and other general transcription machinery to the complex. Moreover, we showed that MED17 was phosphorylated at Ser(53) by casein kinase 2 (CK2) in the livers of fed mice or insulin-stimulated hepatocytes, but not in the livers of fasted mice or untreated hepatocytes...
February 21, 2017: Science Signaling
https://www.readbyqxmd.com/read/28209983/generation-and-quantitative-proteomics-analysis-of-ck2%C3%AE-%C3%AE-cells
#4
Christian Borgo, Cinzia Franchin, Stefano Scalco, Valentina Bosello-Travain, Arianna Donella-Deana, Giorgio Arrigoni, Mauro Salvi, Lorenzo A Pinna
CK2 is a ubiquitous, constitutively active, highly pleiotropic, acidophilic Ser/Thr protein kinase whose holoenzyme is composed of two catalytic (α and/or α') subunits and a dimer of a non-catalytic β subunit. Abnormally high CK2 level/activity is often associated with malignancy and a variety of cancer cells have been shown to rely on it to escape apoptosis. To gain information about the actual "druggability" of CK2 and to dissect CK2 dependent cellular processes that are instrumental to the establishment and progression of neoplasia we have exploited the CRISPR/Cas9 genome editing technology to generate viable clones of C2C12 myoblasts devoid of either both the CK2 catalytic subunits or its regulatory β-subunit...
February 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28208768/inhibition-of-protein-kinase-ck2-prevents-adipogenic-differentiation-of-mesenchymal-stem-cells-like-c3h-10t1-2-cells
#5
Lisa Schwind, Sarah Schetting, Mathias Montenarh
Protein kinase CK2 as a holoenzyme is composed of two catalytic α- or α'-subunits and two non-catalytic β-subunits. Knock-out experiments revealed that CK2α and CK2β are required for embryonic development. Little is known about the role of CK2 during differentiation of stem cells. Mesenchymal stem cells (MSCs) are multipotent cells which can be differentiated into adipocytes in vitro. Thus, MSCs and in particular C3H/10T1/2 cells are excellent tools to study a possible role of CK2 in adipogenesis. We found downregulation of the CK2 catalytic subunits as well as a decrease in CK2 kinase activity with progression of differentiation...
February 9, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28208677/targeting-protein-kinase-ck2-evaluating-cx-4945-potential-for-gl261-glioblastoma-therapy-in-immunocompetent-mice
#6
Laura Ferrer-Font, Lucia Villamañan, Nuria Arias-Ramos, Jordi Vilardell, Maria Plana, Maria Ruzzene, Lorenzo A Pinna, Emilio Itarte, Carles Arús, Ana Paula Candiota
Glioblastoma (GBM) causes poor survival in patients even with aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment but resistance always ensues. Protein kinase CK2 (CK2) contributes to tumour development and proliferation in cancer, and it is overexpressed in human GBM. Accordingly, targeting CK2 in GBM may benefit patients. Our goal has been to evaluate whether CK2 inhibitors (iCK2s) could increase survival in an immunocompetent preclinical GBM model. Cultured GL261 cells were treated with different iCK2s including CX-4945, and target effects evaluated in vitro...
February 12, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28201649/a-ck2-rnf4-interplay-coordinates-non-canonical-sumoylation-and-degradation-of-nuclear-receptor-fxr
#7
Stéphanie Bilodeau, Véronique Caron, Jonathan Gagnon, Alexandre Kuftedjian, André Tremblay
No abstract text is available yet for this article.
February 15, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/28196025/autophagy-induced-by-cx-4945-a-casein-kinase-2-inhibitor-enhances-apoptosis-in-pancreatic-cancer-cell-lines
#8
Dae Wook Hwang, Kwang Sup So, Song Cheol Kim, Kwang-Min Park, Young-Joo Lee, Sun-Whe Kim, Chang-Min Choi, Jin Kyung Rho, Yun Jung Choi, Jae Cheol Lee
OBJECTIVES: Pancreatic cancer is the most lethal malignancy with only a few effective chemotherapeutic drugs. Because the inhibition of casein kinase 2 (CK2) has been reported as a novel therapeutic strategy for many cancers, we investigated the effects of CK2 inhibitors in pancreatic cancer cell lines. METHODS: The BxPC3, 8902, Mia PaCa-2 human pancreatic cancer cell lines, and CX-4945, a novel CK2 inhibitor, were used. Autophagy was analyzed by acridine orange staining, fluorescence microscope detection of punctuate patterns of GFP-tagged LC3 and immunoblotting for LC3...
February 14, 2017: Pancreas
https://www.readbyqxmd.com/read/28194465/unravelling-the-role-of-protein-kinase-ck2-in-metal-toxicity-using-gene-deletion-mutants
#9
Adam J Johnson, Mohammad S Zaman, Filip Veljanoski, Alex A Phrakaysone, Suhua Li, Patrick J O'Doherty, Gayani Petersingham, Gabriel G Perrone, Mark P Molloy, Ming J Wu
Metal ions, biologically essential or toxic, are present in the surrounding environment of living organisms. Understanding their uptake, homeostasis or detoxification is critical in cell biology and human health. In this study, we investigated the role of protein kinase CK2 in metal toxicity using gene deletion strains of Saccharomyces cerevisiae against a panel of six metal ions. The deletion of CKA2, the yeast orthologue of mammalian CK2α', leads to a pronounced resistant phenotype against Zn(2+) and Al(3+), whilst the deletion of CKB1 or CKB2 results in tolerance to Cr(6+) and As(3+)...
February 14, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28181418/mathematical-modeling-of-the-effects-of-ck2-3-on-mineralization-in-osteoporotic-bone
#10
A Lisberg, R Ellis, K Nicholson, P Moku, A Swarup, P Dhurjati, A Nohe
Osteoporosis is caused by decreased bone mineral density (BMD) and new treatments for this disease are desperately needed. Bone morphogenetic protein 2 (BMP2) is crucial for bone formation. The mimetic peptide CK2.3 acts downstream of BMP2 and increases BMD when injected systemically into the tail vein of mice. However, the most effective dosage needed to induce BMD in humans is unknown. We developed a mathematical model for CK2.3-dependent bone mineralization. We used a physiologically based pharmacokinetic (PBPK) model to derive the CK2...
February 9, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28181315/emodin-a-natural-inhibitor-of-protein-kinase-ck2-suppresses-growth-hyphal-development-and-biofilm-formation-of-candida-albicans
#11
Monika Janeczko, Maciej Masłyk, Konrad Kubiński, Hieronim Golczyk
Emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) is a natural secondary plant product, originally isolated from the rhizomes of Rheum palmatum. Many reports show its diuretic, vasorelaxant, anti-bacterial, anti-viral, anti-ulcerogenic, immunosuppressive, hepatoprotective, anti-inflammatory, and anti-cancer potential. Emodin is a pleiotropic molecule capable of interacting with several major molecular targets, e.g. NF-κB, AKT/mTOR, and STAT3. The compound can also act as an inhibitor of some protein kinases, with special affinity to protein kinase CK2...
February 8, 2017: Yeast
https://www.readbyqxmd.com/read/28181105/protein-kinase-ck2-is-important-for-the-function-of-glioblastoma-brain-tumor-initiating-cells
#12
Amber L Rowse, Sara A Gibson, Gordon P Meares, Rajani Rajbhandari, Susan E Nozell, Kory J Dees, Anita B Hjelmeland, Braden C McFarland, Etty N Benveniste
Protein kinase CK2 is a ubiquitously expressed serine/threonine kinase composed of two catalytic subunits (α) and/or (α') and two regulatory (β) subunits. The expression and kinase activity of CK2 is elevated in many different cancers, including glioblastoma (GBM). Brain tumor initiating cells (BTICs) are a subset of cells that are highly tumorigenic and promote the resistance of GBM to current therapies. We previously reported that CK2 activity promotes prosurvival signaling in GBM. In this study, the role of CK2 signaling in BTIC function was examined...
February 8, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28178206/the-link-between-protein-kinase-ck2-and-atypical-kinase-rio1
#13
REVIEW
Konrad Kubiński, Maciej Masłyk
The atypical kinase Rio1 is widespread in many organisms, ranging from Archaebacteria to humans, and is an essential factor in ribosome biogenesis. Little is known about the protein substrates of the enzyme and small-molecule inhibitors of the kinase. Protein kinase CK2 was the first interaction partner of Rio1, identified in yeast cells. The enzyme from various sources undergoes CK2-mediated phosphorylation at several sites and this modification regulates the activity of Rio1. The aim of this review is to present studies of the relationship between the two different kinases, with respect to CK2-mediated phosphorylation of Rio1, regulation of Rio1 activity, and similar susceptibility of the kinases to benzimidazole inhibitors...
February 7, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28165359/in-search-of-small-molecule-inhibitors-targeting-the-flexible-ck2-subunit-interface
#14
Benoît Bestgen, Zakia Belaid-Choucair, Thierry Lomberget, Marc Le Borgne, Odile Filhol, Claude Cochet
Protein kinase CK2 is a tetrameric holoenzyme composed of two catalytic (α and/or α') subunits and two regulatory (β) subunits. Crystallographic data paired with fluorescence imaging techniques have suggested that the formation of the CK2 holoenzyme complex within cells is a dynamic process. Although the monomeric CK2α subunit is endowed with a constitutive catalytic activity, many of the plethora of CK2 substrates are exclusively phosphorylated by the CK2 holoenzyme. This means that the spatial and high affinity interaction between CK2α and CK2β subunits is critically important and that its disruption may provide a powerful and selective way to block the phosphorylation of substrates requiring the presence of CK2β...
February 3, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28152014/apigenin-selective-ck2-inhibitor-increases-ikaros-expression-and-improves-t-cell-homeostasis-and-function-in-murine-pancreatic-cancer
#15
Nadine Nelson, Karoly Szekeres, Cristina Iclozan, Ivannie Ortiz Rivera, Andrew McGill, Gbemisola Johnson, Onyekachi Nwogu, Tomar Ghansah
Pancreatic cancer (PC) evades immune destruction by favoring the development of regulatory T cells (Tregs) that inhibit effector T cells. The transcription factor Ikaros is critical for lymphocyte development, especially T cells. We have previously shown that downregulation of Ikaros occurs as a result of its protein degradation by the ubiquitin-proteasome system in our Panc02 tumor-bearing (TB) mouse model. Mechanistically, we observed a deregulation in the balance between Casein Kinase II (CK2) and protein phosphatase 1 (PP1), which suggested that increased CK2 activity is responsible for regulating Ikaros' stability in our model...
2017: PloS One
https://www.readbyqxmd.com/read/28134934/ck2-abrogates-the-inhibitory-effects-of-prh-hhex-on-prostate-cancer-cell-migration-and-invasion-and-acts-through-prh-to-control-cell-proliferation
#16
Y H Siddiqui, R M Kershaw, E H Humphreys, E M Assis Junior, S Chaudhri, P-S Jayaraman, K Gaston
PRH/HHEX (proline-rich homeodomain protein/haematopoietically expressed homeobox protein) is a transcription factor that controls cell proliferation, cell differentiation and cell migration. Our previous work has shown that in haematopoietic cells, Protein Kinase CK2-dependent phosphorylation of PRH results in the inhibition of PRH DNA-binding activity, increased cleavage of PRH by the proteasome and the misregulation of PRH target genes. Here we show that PRH and hyper-phosphorylated PRH are present in normal prostate epithelial cells, and that hyper-phosphorylated PRH levels are elevated in benign prostatic hyperplasia, prostatic adenocarcinoma, and prostate cancer cell lines...
January 30, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28134850/ck2-in-cancer-cellular-and-biochemical-mechanisms-and-potential-therapeutic-target
#17
REVIEW
Melissa M J Chua, Charina E Ortega, Ayesha Sheikh, Migi Lee, Hussein Abdul-Rassoul, Kevan L Hartshorn, Isabel Dominguez
CK2 genes are overexpressed in many human cancers, and most often overexpression is associated with worse prognosis. Site-specific expression in mice leads to cancer development (e.g., breast, lymphoma) indicating the oncogenic nature of CK2. CK2 is involved in many key aspects of cancer including inhibition of apoptosis, modulation of signaling pathways, DNA damage response, and cell cycle regulation. A number of CK2 inhibitors are now available and have been shown to have activity against various cancers in vitro and in pre-clinical models...
January 28, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28133777/ns5atp13-promotes-liver-fibrogenesis-via-activation-of-hepatic-stellate-cells
#18
Yaru Li, Shunai Liu, Ming Han, Hongping Lu, Qi Wang, Yu Zhang, Kelbinur Tursun, Zhongshu Li, Shenghu Feng, Jun Cheng
Liver fibrosis is a reversible wound-healing response to any etiology of chronic hepatic injuries. Activation of hepatic stellate cells (HSCs) is the key event in liver fibrogenesis. Generally, persistent activation and proliferation of HSCs results in liver fibrosis progression, while primary mechanisms of liver fibrosis resolution are apoptosis and reversion to a quiescent phenotype of activated HSCs. NS5ATP13 (HCV NS5A-transactivated protein 13) is involved in nucleologenesis and tumorigenesis, but its role in liver fibrosis and HSC activation remains unclear...
January 29, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28130399/constitutive-phosphorylation-of-stat3-by-the-ck2-blnk-cd5-complex
#19
Uri Rozovski, David M Harris, Ping Li, Zhiming Liu, Preetesh Jain, Ivo Veletic, Alessandra Ferrajoli, Jan Burger, Susan O'Brien, Prithviraj Bose, Philip Thompson, Nitin Jain, William Wierda, Michael J Keating, Zeev Estrov
: In chronic lymphocytic leukemia (CLL), STAT3 is constitutively phosphorylated on serine 727 and plays a role in the pathobiology of CLL. However, what induces constitutive phosphorylation of STAT3 is currently unknown. Mass spectrometry was used to identify casein kinase 2 (CK2), a serine/threonine kinase that co-immunoprecipitated with serine phosphorylated STAT3 (pSTAT3). Furthermore, activated CK2 incubated with recombinant STAT3 induced phosphorylation of STAT3 on serine 727. Although STAT3 and CK2 are present in normal B- and T-cells, STAT3 is not constitutively phosphorylated in these cells...
January 27, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28117670/exploring-the-ck2-paradox-restless-dangerous-dispensable
#20
REVIEW
Cinzia Franchin, Christian Borgo, Silvia Zaramella, Luca Cesaro, Giorgio Arrigoni, Mauro Salvi, Lorenzo A Pinna
The history of protein kinase CK2 is crowded with paradoxes and unanticipated findings. Named after a protein (casein) that is not among its physiological substrates, CK2 remained in search of its targets for more than two decades after its discovery in 1954, but it later came to be one of the most pleiotropic protein kinases. Being active in the absence of phosphorylation and/or specific stimuli, it looks unsuitable to participate in signaling cascades, but its "lateral" implication in a variety of signaling pathways is now soundly documented...
January 20, 2017: Pharmaceuticals
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