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Ruiting Lin, Siyuan Xia, Changliang Shan, Dong Chen, Yijie Liu, Xue Gao, Mei Wang, Hee-Bum Kang, Yaozhu Pan, Shuangping Liu, Young Rock Chung, Omar Abdel-Wahab, Taha Merghoub, Michael Rossi, Ragini R Kudchadkar, David H Lawson, Fadlo R Khuri, Sagar Lonial, Jing Chen
Dietary supplements such as vitamins and minerals are widely used in the hope of improving health but may have unidentified risks and side effects. In particular, a pathogenic link between dietary supplements and specific oncogenes remains unknown. Here we report that chondroitin-4-sulfate (CHSA), a natural glycosaminoglycan approved as a dietary supplement used for osteoarthritis, selectively promotes the tumor growth potential of BRAF V600E-expressing human melanoma cells in patient- and cell line-derived xenograft mice and confers resistance to BRAF inhibitors...
March 15, 2018: Molecular Cell
Hyeonseok Ko, Seongrak Kim, Kyungmi Yang, Kunhong Kim
Epithelial-mesenchymal transition (EMT) is a critical process in invasion and metastasis of cancer cells. E-cadherin to N-cadherin switching is considered a molecular hallmark of EMT. Recently, we reported that increased CK2 activity fully induces E-cadherin to N-cadherin switching, but the molecular mechanisms of N-cadherin upregulation are unknown. In this study, we examined how N-cadherin is upregulated by CK2. N-cadherin promoter analysis and ChIP analysis identified and confirmed myeloid zinc finger 1 (MZF1) as an N-cadherin transcription factor...
March 13, 2018: Oncogenesis
Lie Wang, Giri Kumar Chandaka, Robert C Foehring, Joseph C Callaway, William E Armstrong
Oxytocin (OT) neurons exhibit larger afterhyperpolarizations (AHPs) following spike trains during pregnancy and lactation, when these neurons burst and release more OT. Calcium-dependent AHPs mediated by SK channels show this plasticity, and are reduced when the channel is phosphorylated by casein kinase 2 (CK2), and increased when dephosphorylated by protein phosphatase 2A (PP2A), by altering Ca2+ sensitivity. We compared AHP currents in supraoptic OT neurons after CK2 inhibition with 4,5,6,7-tetrabromobenzotriazole (TBB), or PP1-PP2A inhibition with okadaic acid (OA) focusing on the peak current at 100 ms representing the SK-mediated, medium AHP (ImAHP )...
March 14, 2018: Journal of Neurophysiology
Jordi Vilardell, Cristina Girardi, Oriano Marin, Giorgio Cozza, Lorenzo A Pinna, Maria Ruzzene
CK2 is a pleiotropic S/T protein kinase (formerly known as casein kinase 2) which is attracting increasing interest as therapeutic target, and the identification of its substrates is a crucial step in determining its involvement in different pathological conditions. We recently found that S131 of Akt2 (homologous to the well established CK2 target S129 of Akt1) is not phosphorylated by CK2 either in vitro or in vivo, although the consensus sequence recognized by CK2 (S/T-x-x-E/D/pS/pT) is conserved in it. Here, by exploiting synthetic peptides, in cell transfection experiments, and computational analysis, we show that a single sequence element, a T at position n+1, hampers phosphorylation, causing an α-helix structure organization which prevents the recognition of its own consensus by CK2...
2018: PloS One
Julie K Horton, Donna F Stefanick, Melike Çağlayan, Ming-Lang Zhao, Agnes K Janoshazi, Rajendra Prasad, Natalie R Gassman, Samuel H Wilson
Aprataxin (APTX) is a DNA-adenylate hydrolase that removes 5'-AMP blocking groups from abortive ligation repair intermediates. XRCC1, a multi-domain protein without catalytic activity, interacts with a number of known repair proteins including APTX, modulating and coordinating the various steps of DNA repair. CK2-phosphorylation of XRCC1 is thought to be crucial for its interaction with the FHA domain of APTX. In light of conflicting reports, the importance of XRCC1 phosphorylation and APTX function is not clear...
February 15, 2018: DNA Repair
Jordi Vilardell, Estefania Alcaraz, Eduard Sarró, Enric Trilla, Thaïs Cuadros, Inés de Torres, Maria Plana, Santiago Ramón Y Cajal, Lorenzo A Pinna, Maria Ruzzene, Juan Morote, Anna Meseguer, Emilio Itarte
Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of renal cancer. STAT3 pathway is altered in these tumors and p-STAT3 Ser727 is an independent prognostic factor for ccRCC. Protein kinase CK2 is altered in different types of tumors and overexpression of CK2α is considered predictive of bad prognosis and metastatic risk. CK2 subunits analyses in ccRCC samples showed increased CK2α/α' nuclear content in all cases, but decreased cytosolic CK2β (CK2βcyt) levels in the more advanced tumors...
January 19, 2018: Oncotarget
Alexander Schnitzler, Andreas Gratz, Andre Bollacke, Michael Weyrich, Uwe Kuckländer, Bernhard Wünsch, Claudia Götz, Karsten Niefind, Joachim Jose
Human protein kinase CK2 is an emerging target for neoplastic diseases. Potent lead structures for human CK2 inhibitors are derived from dibenzofuranones. Two new derivatives, 7,9-dichloro-1,2-dihydro-8-hydroxy-4-[(4-methoxyphenylamino)-methylene]dibenzo[ b , d ]furan-3(2 H )-one ( 4a ) and ( E )-1,3-dichloro-6-[(4-methoxyphenylimino)-methyl]dibenzo[ b , d ]furan-2,7-diol ( 5 ) were tested for inhibition of CK2 and induction of apoptosis in LNCaP cells. Both turned out to be tight binding inhibitors, with IC50 values of 7 nM ( 4a ) and 5 nM ( 5 ) and an apparent Ki value of 0...
February 17, 2018: Pharmaceuticals
Tomoko Takai, Tomokazu Matsuda, Yuki Matsuura, Kaho Inoue, Emi Suzuki, Ayumi Kanno, Maki Kimura-Koyanagi, Shun-Ichiro Asahara, Naoya Hatano, Wataru Ogawa, Yoshiaki Kido
During the development of type 2 diabetes, endoplasmic reticulum (ER) stress leads to pancreatic β cell failure. CCAAT/enhancer-binding protein (C/EBP) β is highly induced by ER stress and AMP-activated protein kinase (AMPK) suppression in pancreatic β cells, and its accumulation reduces pancreatic β cell mass. We investigated the phosphorylation state of C/EBPβ under these conditions. Casein kinase 2 (CK2) was found to co-localize with C/EBPβ in MIN6 cells. It phosphorylated S222 of C/EBPβ, a previously unidentified phosphorylation site...
February 12, 2018: Biochemical and Biophysical Research Communications
Feihong Chen, Xiufeng Jin, Jian Zhao, Shaohua Gou
DN604, a carboplatin analogue with a functional dicarboxylato ligand, was deeply investigated to explore its ability to induce apoptosis as well as its antitumor mechanism of action. Both in vitro and in vivo assays indicated that DN604 could effectively inhibit cell viability of SGC-7901 gastric cancer cells and exhibited stronger antitumor activity than carboplatin and comparable activity to cisplatin. Significantly in contrast to cisplatin, DN604 resulted in negligible toxic effects in vivo with the same tumor growth inhibition effect as cisplatin...
January 31, 2018: Experimental Cell Research
Xuehui Hong, He Huang, Xingfeng Qiu, Zhijie Ding, Xing Feng, Yuekun Zhu, Huiqin Zhuo, Jingjing Hou, Jiabao Zhao, Wangyu Cai, Ruihua Sha, Xinya Hong, Yongxiang Li, Hongjiang Song, Zhiyong Zhang
RIOK1 has recently been shown to play important roles in cancers, but its posttranslational regulation is largely unknown. Here we report that RIOK1 is methylated at K411 by SETD7 methyltransferase and that lysine-specific demethylase 1 (LSD1) reverses its methylation. The mutated RIOK1 (K411R) that cannot be methylated exhibits a longer half-life than does the methylated RIOK1. FBXO6 specifically interacts with K411-methylated RIOK1 through its FBA domain to induce RIOK1 ubiquitination. Casein kinase 2 (CK2) phosphorylates RIOK1 at T410, which stabilizes RIOK1 by antagonizing K411 methylation and impeding the recruitment of FBXO6 to RIOK1...
January 31, 2018: ELife
Ceris I Owen, Ramsay Bowden, Michael J Parker, Jo Patterson, Joan Patterson, Sue Price, Ajoy Sarkar, Bruce Castle, Charulatha Deshpande, Miranda Splitt, Neeti Ghali, John Dean, Andrew J Green, Charlene Crosby, Katrina Tatton-Brown
Variants in the Protein Kinase CK2 alpha subunit, encoding the CSNK2A1 gene, have previously been reported in children with an intellectual disability and dysmorphic facial features syndrome: now termed the Okur-Chung neurodevelopmental syndrome. More recently, through trio-based exome sequencing undertaken by the Deciphering Developmental Disorders Study (DDD study), a further 11 children with de novo CSNK2A1 variants have been identified. We have undertaken detailed phenotyping of these patients. Consistent with previously reported patients, patients in this series had apparent intellectual disability, swallowing difficulties, and hypotonia...
January 31, 2018: American Journal of Medical Genetics. Part A
Jung-Hyun Na, Won-Kyu Lee, Yeon Gyu Yu
Intrinsically disordered proteins (IDPs) represent approximately 30% of the human genome and play key roles in cell proliferation and cellular signaling by modulating the function of target proteins via protein-protein interactions. In addition, IDPs are involved in various human disorders, such as cancer, neurodegenerative diseases, and amyloidosis. To understand the underlying molecular mechanism of IDPs, it is important to study their structural features during their interactions with target proteins. However, conventional biochemical and biophysical methods for analyzing proteins, such as X-ray crystallography, have difficulty in characterizing the features of IDPs because they lack an ordered three-dimensional structure...
January 27, 2018: International Journal of Molecular Sciences
Abdelhamid Nacereddine, Andre Bollacke, Eszter Róka, Christelle Marminon, Zouhair Bouaziz, Ferenc Fenyvesi, Ildikó Katalin Bácskay, Joachim Jose, Florent Perret, Marc Le Borgne
Since the approval of imatinib in 2001, kinase inhibitors have revolutionized cancer therapies. Inside this family of phosphotransferases, casein kinase 2 (CK2) is of great interest and numerous scaffolds have been investigated to design CK2 inhibitors. Recently, functionalized indeno[1,2-b]indoles have been revealed to have high potency against human cancer cell lines such as MCF-7 breast carcinoma and A-427 lung carcinoma. 4-Methoxy-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (THN7), identified as a potent inhibitor of CK2 (IC50 = 71 nM), was selected for an encapsulation study in order to evaluate its antiproliferative activity as THN7-loaded cyclodextrin nanoparticles...
January 26, 2018: Pharmaceuticals
Fei Wu, Jian Qiu, Yang Fan, Qiuling Zhang, Baohua Cheng, Yili Wu, Bo Bai
Cerebral ischemia/reperfusion (I/R) injury-induced neuronal apoptosis contributes to the death and disability in patients with ischemic stroke. However, underlying mechanisms remain elusive and it lacks effective treatment. Here we reported that the expression of casein kinase 2 (CK2) was significantly reduced in brains of middle cerebral artery occlusion/reperfusion (MACO/R) model rats and oxygen-glucose deprivation/reperfusion (OGD/R) model neurons, which was associated with the activation of eIF2-ATF4-CHOP signaling pathway, leading to neuronal apoptosis...
January 11, 2018: Experimental Neurology
Emily A McMillan, Sheila M Longo, Michael D Smith, Sarah Broskin, Baicheng Lin, Nisha K Singh, Todd I Strochlic
Lipid metabolism plays a critical role in female reproduction. During oogenesis, maturing oocytes accumulate high levels of neutral lipids that are essential for both energy production and for the synthesis of other lipid molecules. Metabolic pathways within the ovary are partially regulated by protein kinases that link metabolic status to oocyte development. While the functions of several kinases in this process are well established, the roles that many other kinases play in coordinating metabolic state with female germ cell development are unknown...
January 11, 2018: Journal of Biological Chemistry
Yue Zhou, Na Zhang, Xiaoqian Qi, Shan Tang, Guohui Sun, Lijiao Zhao, Rugang Zhong, Yongzhen Peng
Protein kinase is a novel therapeutic target for human diseases. The off-target and side effects of ATP-competitive inhibitors preclude them from the clinically relevant drugs. The compounds targeting the druggable allosteric sites outside the highly conversed ATP binding pocket have been identified as promising alternatives to overcome current barriers of ATP-competitive inhibitors. By simultaneously interacting with the αD region (new allosteric site) and sub-ATP binding pocket, the attractive compound CAM4066 was named as allosteric inhibitor of CK2α...
January 1, 2018: International Journal of Molecular Sciences
So Youn Park, Hwa Kyoung Shin, Won Suk Lee, Sun Sik Bae, Koanhoi Kim, Ki Whan Hong, Chi Dae Kim
Psychosis is reported over 30% of patients with Alzheimer's disease (AD) in clinics. Aripiprazole is an atypical antipsychotic drug with partial agonist activity at the D2dopamine and 5-HT1Areceptors with low side-effect profile. We identified aripiprazole is able to overcome the amyloid-β (Aβ)-evoked neurotoxicity and then increase the cell viability. This study elucidated the mechanism(s) by which aripiprazole ameliorates Aβ1-42-induced decreased neurite outgrowth and viability in neuronal cells. Pretreatment with aripiprazole increased Brain-derived neurotrophic factor (BDNF) mRNA and protein expressions in N2a cells...
December 15, 2017: Oncotarget
Pedro Martín-Acosta, Samer Haider, Ángel Amesty, Dagmar Aichele, Joachim Jose, Ana Estévez-Braun
A new series of 2-amino-4-phenyl-6-hydroxy-7-alkyl-pyranobenzoquinones was synthesized as ATP-competitive CK2 inhibitors. They were readily synthesized through a three-component Knoevenagel condensation-Michael addition-heterocyclization reaction from aldehydes, malononitrile, and 3-alkyl-2,5-dihydroxybenzoquinones. Some of the synthesized compounds presented interesting inhibitory activity with IC50 values in the submicromolar range. A structure-activity relationship study was carried out and the mode of binding was analysed by docking studies and supported by ATP competition assays...
December 18, 2017: European Journal of Medicinal Chemistry
Zhe Wei, Guangyu Wu, Bo-Shiun Chen
Synapse-associated protein 102 (SAP102) is a scaffolding protein highly expressed early in development and plays a critical role in mediating glutamate receptor trafficking during synaptogenesis. Mutations in human SAP102 have been reported to cause intellectual disability, which is thought to be due to mislocalization of the mutant protein. However, little is known about the regulation of SAP102 synaptic targeting. Here, we investigate the role of phosphorylation of SAP102 in regulating its synaptic targeting...
December 27, 2017: Molecular Neurobiology
Jung-Il Jung, Kyeong-Yong Park, Soon Ae Kim, Jiyeon Kim
Human acute T-lymphocytic leukemia (T-ALL) is one of the most commonly diagnosed hematological disorders, and is characterized by poor prognosis and survival rate. Despite the development of new therapeutic approaches, leukemia treatment options remain limited. In this study, we investigated the immunosuppressive and anti-proliferative effects of the synthetic estrogen diethylstilbestrol (DES), both alone and combined with the casein kinase 2 (CK2) inhibitor CX-4945. Our results indicated that DES induced caspase-dependent apoptosis in a human T-ALL cell line (Jurkat cells), while exerting no significant cytotoxicity in normal peripheral blood mononuclear cells (PBMCs)...
December 20, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
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