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https://www.readbyqxmd.com/read/29778533/casein-kinase-ii-phosphorylates-the-c-terminal-region-of-lif1-to-promote-the-lif1-xrs2-interaction-needed-for-non-homologous-end-joining
#1
Kenichiro Matsuzaki, Miki Shinohara
A DNA double strand break (DSB) is one of the most cytotoxic DNA lesions, but it can be repaired by non-homologous end joining (NHEJ) or by homologous recombination. The choice between these two repair pathways depends on the cell cycle stage. Although NHEJ constitutes a simple re-ligation reaction, the regulatory mechanism(s) controlling its activity has not been fully characterized. Lif1 is a regulatory subunit of the NHEJ-specific DNA ligase IV and interacts with Xrs2 of the MRX complex which is a key factor in DSB repair...
May 17, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29760653/ck2-phosphorylating-i-2-pp2a-set-mediates-tau-pathology-and-cognitive-impairment
#2
Qing Zhang, Yiyuan Xia, Yongjun Wang, Yangping Shentu, Kuan Zeng, Yacoubou A R Mahaman, Fang Huang, Mengjuan Wu, Dan Ke, Qun Wang, Bin Zhang, Rong Liu, Jian-Zhi Wang, Keqiang Ye, Xiaochuan Wang
Casein kinase 2 (CK2) is highly activated in Alzheimer disease (AD) and is associated with neurofibrillary tangles formation. Phosphorylated SET, a potent PP2A inhibitor, mediates tau hyperphosphorylation in AD. However, whether CK2 phosphorylates SET and regulates tau pathological phosphorylation in AD remains unclear. Here, we show that CK2 phosphorylating SET at Ser9 induced tau hyperphosphorylation in AD. We found that either Aβ treatment or tau overexpression stimulated CK2 activation leading to SET Ser9 hyperphosphorylation in neurons and animal models, while inhibition of CK2 by TBB abolished this event...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29759799/novel-non-atp-competitive-small-molecules-targeting-the-ck2-%C3%AE-%C3%AE-interface
#3
Paul Brear, Andrew North, Jessica Iegre, Kathy Hadje Georgiou, Alexandra Lubin, Laura Carro, William Green, Hannah F Sore, Marko Hyvönen, David R Spring
Increased CK2 levels are prevalent in many cancers. Combined with the critical role CK2 plays in many cell-signaling pathways, this makes it a prime target for down regulation to fight tumour growth. Herein, we report a fragment-based approach to inhibiting the interaction between CK2α and CK2β at the α-β interface of the holoenzyme. A fragment, CAM187, with an IC50 of 44 μM and a molecular weight of only 257 gmol-1 has been identified as the most promising compound. Importantly, the lead fragment only bound at the interface and was not observed in the ATP binding site of the protein when co-crystallised with CK2α...
May 9, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29743645/the-protein-kinase-ck2-catalytic-domain-from-plasmodium-falciparum-crystal-structure-tyrosine-kinase-activity-and-inhibition
#4
David Ruiz-Carrillo, Jianqing Lin, Abbas El Sahili, Meng Wei, Siu Kwan Sze, Peter C F Cheung, Christian Doerig, Julien Lescar
Malaria causes every year over half-a-million deaths. The emergence of parasites resistant to available treatments makes the identification of new targets and their inhibitors an urgent task for the development of novel anti-malaria drugs. Protein kinase CK2 is an evolutionary-conserved eukaryotic serine/threonine protein kinase that in Plasmodium falciparum (PfCK2) has been characterized as a promising target for chemotherapeutic intervention against malaria. Here we report a crystallographic structure of the catalytic domain of PfCK2α (D179S inactive single mutant) in complex with ATP at a resolution of 3...
May 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29742868/modulated-gene-expression-of-toxoplasma-gondii-infected-retinal-pigment-epithelial-cell-line-arpe-19-via-pi3k-akt-or-mtor-signal-pathway
#5
Wei Zhou, Juan-Hua Quan, Fei-Fei Gao, Hassan Ahmed Hassan Ahmed Ismail, Young-Ha Lee, Guang-Ho Cha
Due to the critical location and physiological activities of the retinal pigment epithelial (RPE) cell, it is constantly subjected to contact with various infectious agents and inflammatory mediators. However, little is known about the signaling events in RPE involved in Toxoplasma gondii infection and development. The aim of the study is to screen the host mRNA transcriptional change of 3 inflammation-related gene categories, PI3K/Akt pathway regulatory components, blood vessel development factors and ROS regulators, to prove that PI3K/Akt or mTOR signaling pathway play an essential role in regulating the selected inflammation-related genes...
April 2018: Korean Journal of Parasitology
https://www.readbyqxmd.com/read/29733298/snasp-inhibits-tlr-signaling-to-regulate-immune-response-in-sepsis
#6
Feng-Ming Yang, Yong Zuo, Wei Zhou, Chuan Xia, Bumsuk Hahm, Mark Sullivan, Jinke Cheng, Hui-Ming Chang, Edward Th Yeh
Many Toll-like receptors (TLRs) signal through TNF receptor-associated factor 6 (TRAF6) to activate innate immune responses. Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed. CK2 phosphorylates sNASP at serine 158, allowing sNASP to dissociate from TRAF6. Free TRAF6 is then autoubiquitinated, followed by activation of downstream signaling pathways...
May 7, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29732088/second-generation-ck2%C3%AE-inhibitors-targeting-the-%C3%AE-d-pocket
#7
Jessica Iegre, Paul Brear, Claudia De Fusco, Masao Yoshida, Sophie L Mitchell, Maxim Rossmann, Laura Carro, Hannah F Sore, Marko Hyvönen, David R Spring
CK2 is a critical cell cycle regulator that also promotes various anti-apoptotic mechanisms. Development of ATP-non-competitive inhibitors of CK2 is a very attractive strategy considering that the ATP binding site is highly conserved among other kinases. We have previously utilised a pocket outside the active site to develop a novel CK2 inhibitor, CAM4066 . Whilst CAM4066 bound to this new pocket it was also interacting with the ATP site: herein, we describe an example of a CK2α inhibitor that binds completely outside the active site...
March 21, 2018: Chemical Science
https://www.readbyqxmd.com/read/29725001/ablation-of-beta-subunit-of-protein-kinase-ck2-in-mouse-oocytes-causes-follicle-atresia-and-premature-ovarian-failure
#8
Qiu-Xia Liang, Zhen-Bo Wang, Fei Lin, Chun-Hui Zhang, Hong-Mei Sun, Liang Zhou, Qian Zhou, Heide Schatten, Filhol-Cochet Odile, Boldyreff Brigitte, Qing-Yuan Sun, Wei-Ping Qian
Premature ovarian failure (POF), a major cause of female infertility, is a complex disorder, but the molecular mechanisms underlying the disorder are only poorly understood. Here we report that protein kinase CK2 contributes to maintaining follicular survival through PI3K/AKT pathway and DNA damage response pathway. Targeted deletion of CK2β in mouse oocytes from the primordial follicle stage resulted in female infertility, which was attributed to POF incurring by massive follicle atresia. Downregulated PI3K/AKT signaling was found after CK2β deletion, indicated by reduced level of phosphorylated AKT (S473, T308, and S129) and altered AKT targets related to cell survival...
May 3, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29717996/crystal-structures-of-human-ck2%C3%AE-2-in-new-crystal-forms-arising-from-a-subtle-difference-in-salt-concentration
#9
Masato Tsuyuguchi, Tetsuko Nakaniwa, Takayoshi Kinoshita
The catalytic subunits of protein kinase CK2 are classified into two subtypes: CK2α1 and CK2α2. CK2α1 is an attractive drug-discovery target for various diseases such as cancers and nephritis. CK2α2 is defined as an off-target of CK2α1 and is a potential target in the development of male contraceptive drugs. High-resolution crystal structures of both isozymes are likely to provide crucial clues for the design of selective inhibitors of CK2α1 and/or CK2α2. To date, several crystal structures of CK2α1 have been solved at high resolutions of beyond 1...
May 1, 2018: Acta Crystallographica. Section F, Structural Biology Communications
https://www.readbyqxmd.com/read/29709918/biochemical-characterization-of-ferulic-acid-and-caffeic-acid-which-effectively-inhibit-melanin-synthesis-via-different-mechanisms-in-b16-melanoma-cells
#10
Hiroko Maruyama, Fumitaka Kawakami, Thet-Thet Lwin, Motoki Imai, Fazel Shamsa
In this study, we examined the inhibitory effects of ferulic acid and caffeic acid on melanin production using a murine B16 melanoma cell line. The mechanisms by which the two acids inhibit melanin production were investigated by evaluating their effects on the activity of tyrosinase, which is involved is the first step of melanin biosynthesis. Ferulic acid showed no toxicity against the melanoma cells at any dose, whereas caffeic acid exerted cellular toxicity at concentrations higher than 0.35 mM. Both ferulic and caffeic acids effectively inhibited melanin production in the B16 melanoma cells...
2018: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/29708304/casein-kinase-2-inhibition-impairs-spontaneous-and-oxytocin-induced-contractions-in-late-pregnant-mouse-uterus
#11
K S Suhas, Subhashree Parida, Chandrasekaran Gokul, Vivek Srivastava, E Prakash, Sakshi Chauhan, Thakur Uttam Singh, Manjit Panigrahi, Avinash G Telang, Santosh K Mishra
NEW FINDINGS: What is the central question of this study? Does the inhibition of the protein kinase casein kinase 2 (CK2) alter the uterine contractility? What is the main finding and its importance? Inhibition of CK2 impaired the spontaneous and oxytocin-induced contractility in late pregnant mouse uterus. This finding suggests that CK2 is a novel pathway mediating oxytocin-induced contractility in the uterus and thus opens up the possibility for this class of drugs to be developed as a new class of tocolytics...
May 1, 2018: Experimental Physiology
https://www.readbyqxmd.com/read/29683096/novel-anthraquinone-derivatives-as-dual-inhibitors-of-topoisomerase-2-and-casein-kinase-2-in-silico-studies-synthesis-and-biological-evaluation-on-leukemic-cell-lines
#12
Abbas Kabir, Kalpana Tilekar, Neha Upadhyay, C S Ramaa
Background - Cancer being a complex disease, single targeting agents remains unsuccessful. This calls for "multiple targeting", wherein a single drug is so designed that it will modulate the activity of multiple protein targets. Topoisomerase 2 (Top2) helps in removing DNA tangles and super-coiling during cellular replication, Casein Kinase 2 (CK2) is involved in the phosphorylation of multitude of protein targets. Thus, in the present work, we have tried to develop dual inhibitors of Top2 and CK2...
April 22, 2018: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/29676523/characterization-of-low-abundance-species-in-the-active-pharmaceutical-ingredient-of-cigb-300-a-clinical-grade-anticancer-synthetic-peptide
#13
Hilda Garay, Luis Ariel Espinosa, Yasser Perera, Aniel Sánchez, David Diago, Silvio E Perea, Vladimir Besada, Osvaldo Reyes, Luis Javier González
CIGB-300 is a first-in-class synthetic peptide-based drug of 25 amino acids currently undergoing clinical trials in cancer patients. It contains an amidated disulfide cyclic undecapeptide fused to the TAT cell-penetrating peptide through a beta-alanine spacer. CIGB-300 inhibits the CK2-mediated phosphorylation leading to apoptosis of tumor cells in vitro, and in vivo in cancer patients. Despite the clinical development of CIGB-300, the characterization of peptide-related impurities present in the active pharmaceutical ingredient has not been reported earlier...
April 20, 2018: Journal of Peptide Science: An Official Publication of the European Peptide Society
https://www.readbyqxmd.com/read/29666759/phosphoproteomic-insights-into-processes-influenced-by-the-kinase-like-protein-dia1-c3orf58
#14
Agnieszka Hareza, Magda Bakun, Bianka Świderska, Małgorzata Dudkiewicz, Alicja Koscielny, Anna Bajur, Jacek Jaworski, Michał Dadlez, Krzysztof Pawłowski
Many kinases are still 'orphans,' which means knowledge about their substrates, and often also about the processes they regulate, is lacking. Here, DIA1/C3orf58, a member of a novel predicted kinase-like family, is shown to be present in the endoplasmic reticulum and to influence trafficking via the secretory pathway. Subsequently, DIA1 is subjected to phosphoproteomics analysis to cast light on its signalling pathways. A liquid chromatography-tandem mass spectrometry proteomic approach with phosphopeptide enrichment is applied to membrane fractions of DIA1-overexpressing and control HEK293T cells, and phosphosites dependent on the presence of DIA1 are elucidated...
2018: PeerJ
https://www.readbyqxmd.com/read/29660033/phosphorylation-of-xeroderma-pigmentosum-group-c-regulates-ultraviolet-induced-dna-damage-repair
#15
Palak Shah, Baozhong Zhao, Lei Qiang, Yu-Ying He
Nucleotide excision repair (NER) is the most versatile DNA repair system that removes bulky DNA damage induced by various endogenous and exogenous factors, including UV radiation. Defects in NER can lead to the xeroderma pigmentosum (XP) syndrome, mainly characterized by increased carcinogenesis in the skin. The function of NER factors, including xeroderma pigmentosum group C (XPC), can be regulated by post-translational modifications such as ubiquitination. However, the role of phosphorylation in XPC function remains unknown...
April 6, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29658601/silencing-of-casein-kinase-2-inhibits-pkc%C3%A2-induced-cell-invasion-by-targeting-mmp%C3%A2-9-in-mcf%C3%A2-7-cells
#16
Jeong-Mi Kim, Eun-Mi Noh, Hyun-Kyung Song, Yong-Ouk You, Sung Hoo Jung, Jong-Suk Kim, Kang-Beom Kwon, Young-Rae Lee, Hyun Jo Youn
Casein kinase 2 (CK2) is a serine/threonine protein kinase that has been considered to represent an important factor in mammary tumorigenesis. Increased expression of matrix metalloproteinase‑9 (MMP‑9) via nuclear factor‑κB (NF‑κB) activation has been demonstrated to promote breast cancer cell invasion. In the present study, the involvement of CK2 in protein kinase C (PKC) induced cell invasion in MCF‑7 breast cancer cells was investigated as well as the underlying molecular mechanisms. The mRNA and protein levels of MMP‑9 in MCF‑7 cells were investigated using reverse transcription‑quantitative polymerase chain reaction, western blot analyses and a zymography assay...
April 13, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29622768/role-of-phospholipase-d-in-the-lifespan-of-caenorhabditis-elegans
#17
Jeong-Hwan Park, Jeong-Woo Park, Ju-Hyeon Lee, Dong-Yun Kim, Jeong-Hoon Hahm, Young-Seuk Bae
We have previously shown that phospholipase D (PLD) downregulation accelerates cellular senescence, which is widely believed to play an important role in aging, by stimulating reactive oxygen species (ROS) accumulation in human cells. In this study, we examined the role of PLD in aging using the nematode Caenorhabditis elegans. The mRNA level of pld-1 was found to be inversely correlated with aging. RNAi-mediated knockdown of pld-1 expression in nematodes enhanced ROS and lipofuscin accumulation and decreased lifespan, motility, and resistance to stress compared to that in nematodes treated with control RNAi...
April 6, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29622027/correction-to-role-of-protein-kinases-ck1%C3%AE-and-ck2-in-multiple-myeloma-regulation-of-pivotal-survival-and-stress-managing-pathways
#18
Sabrina Manni, Marilena Carrino, Francesco Piazza
The original article [1] contains an inadvertent error in the following sentence in the Abstract regarding the erroneous description of Ser/Thr kinases as 'phylogenetically related'.
April 5, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29619377/roles-of-nucks1-in-diseases-susceptibility-potential-biomarker-and-regulatory-mechanisms
#19
REVIEW
Pengru Huang, Yujie Cai, Bin Zhao, Lili Cui
Nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) is a 27 kD chromosomal, highly conserved, and vertebrate-specific protein. NUCKS1 gene encodes a nuclear protein and the conserved regions of NUCKS1 contain several consensus phosphorylation sites for casein kinase II (CK2) and cyclin-dependent kinases (Cdk) and a basic DNA-binding domain. NUCKS1 is similar to the high mobility group (HMG) family which dominates chromatin remodeling and regulates gene transcription. Meanwhile, NUCKS1 is a RAD51 associated protein 1 (RAD51AP1) paralog that is significant for homologous recombination (HR) and genome stability and also a transcriptional regulator of the insulin signaling components...
2018: BioMed Research International
https://www.readbyqxmd.com/read/29609684/synthesis-and-biological-evaluation-of-novel-2-4-hydroxynaphthyl-chromen-4-one-as-a-ck2-inhibitor
#20
S Haidar, M Jabbour, M A Al-Khayat, D Aichele, J Jose
Protein kinase CK2 is a potential drug target for many diseases including cancer, inflammatory disorders, Alzheimer's disease, Parkinson's disease and viral infections. Significant efforts have been made for the discovery of potent inhibitors of this enzyme. Herein, we report on the synthesis, characterization, and biological evaluation of novel flavonoid compounds as CK2 inhibitors. The tested compounds were 2 (4`-hydroxynaphthyl) chromen-4-one which is a naphthyl backbone flavonoid with an IC50 value of 0...
April 2, 2018: Die Pharmazie
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