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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 D2 dopamine and 5-HT1A receptors 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
Emiliano Zamponi, Fiamma Buratti, Gabriel Cataldi, Hector Hugo Caicedo, Yuyu Song, Lisa M Jungbauer, Mary J LaDu, Mariano Bisbal, Alfredo Lorenzo, Jiyan Ma, Pablo R Helguera, Gerardo A Morfini, Scott T Brady, Gustavo F Pigino
Prion diseases include a number of progressive neuropathies involving conformational changes in cellular prion protein (PrPc) that may be fatal sporadic, familial or infectious. Pathological evidence indicated that neurons affected in prion diseases follow a dying-back pattern of degeneration. However, specific cellular processes affected by PrPc that explain such a pattern have not yet been identified. Results from cell biological and pharmacological experiments in isolated squid axoplasm and primary cultured neurons reveal inhibition of fast axonal transport (FAT) as a novel toxic effect elicited by PrPc...
2017: PloS One
Sandip K Basu, Sook Lee, Jacqueline Salotti, Srikanta Basu, Krisada Sakchaisri, Zhen Xiao, Vijay Walia, Christopher J Westlake, Deborah K Morrison, Peter F Johnson
The precise characteristics that distinguish normal and oncogenic RAS signaling remain obscure. Here we show that oncogenic RAS and BRAF induce perinuclear re-localization of several RAS pathway proteins, including the kinases CK2 and p-ERK1/2 and the signaling scaffold KSR1. This spatial reorganization requires endocytosis, the kinase activities of MEK-ERK and CK2, and the presence of KSR1. CK2α co-localizes with KSR1 and Rab11, a marker of recycling endosomes, whereas p-ERK associates predominantly with a distinct KSR1-positive endosomal population...
December 19, 2017: Cancer Research
Richmond Muimo, Hani Mm Alothaid, Anil Mehta
NM23 proteins NDPK-A and -B bind to the cystic fibrosis (CF) protein CFTR in different ways from kinases such as PKA, CK2 and AMPK or linkers to cell calcium such as calmodulin and annexins. NDPK-A (not -B) interacts with CFTR through reciprocal AMPK binding/control, whereas NDPK-B (not -A) binds directly to CFTR. NDPK-B can activate G proteins without ligand-receptor coupling, so perhaps NDPK-B's binding influences energy supply local to a nucleotide-binding site (NBD1) needed for CFTR to function. Curiously, CFTR (ABC-C7) is a member of the ATP-binding cassette (ABC) protein family that does not obey 'clan rules'; CFTR channels anions and is not a pump, regulates disparate processes, is itself regulated by multiple means and is so pleiotropic that it acts as a hub that orchestrates calcium signaling through its consorts such as calmodulin/annexins...
December 18, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
Mirosława Koronkiewicz, Zdzisław Chilmonczyk, Zygmunt Kazimerczuk, Andrzej Orzeszko
Abnormally high levels of CK2 and PIM-1 serine/threonine kinases have been documented in many cases of cancer. The elevation of CK2 and PIM-1 in cells entails suppression of apoptosis and implies a protective role for the kinases against cell death. Downregulation of these enzymes by chemical methods promotes apoptosis in cells. The aim of the present study was to explore the anticancer activity of inhibitors of protein kinases CK2 and PIM-1 on neoplastic cell lines in vitro. We studied a series of deoxynucleosides with various tetrahalobenzimidazoles as aglycone moiety...
December 12, 2017: European Journal of Pharmacology
Ashutosh Srivastava, Tsuyoshi Hirota, Stephan Irle, Florence Tama
Protein Kinase CK2 is ubiquitously expressed and highly conserved protein kinase that shows constitutive activity. It phosphorylates a diverse set of proteins and plays crucial role in several cellular processes. The catalytic subunit of this enzyme (CK2α) shows remarkable flexibility as evidenced in numerous crystal structures determined till now. Here, using analysis of multiple crystal structures and long timescale molecular dynamics simulations, we explore the conformational flexibility of CK2α. The enzyme shows considerably higher flexibility in the solution as compared to that observed in crystal structure ensemble...
December 15, 2017: Proteins
Christian Borgo, Gabriella Milan, Francesca Favaretto, Fabio Stasi, Roberto Fabris, Valentina Salizzato, Luca Cesaro, Anna Belligoli, Marta Sanna, Mirto Foletto, Luca Prevedello, Vincenzo Vindigni, Romeo Bardini, Arianna Donella-Deana, Roberto Vettor
Insulin plays a major role in glucose metabolism and insulin-signaling defects are present in obesity and diabetes. CK2 is a pleiotropic protein kinase implicated in fundamental cellular pathways and abnormally elevated in tumors. Here we report that in human and murine adipocytes CK2-inhibition decreases the insulin-induced glucose-uptake by counteracting Akt-signaling and GLUT4-translocation to the plasma membrane. In mice CK2 acts on insulin-signaling in adipose tissue, liver and skeletal muscle and its acute inhibition impairs glucose tolerance...
December 14, 2017: Scientific Reports
Jennifer Hochscherf, Dirk Lindenblatt, Benedict Witulski, Robin Birus, Dagmar Aichele, Christelle Marminon, Zouhair Bouaziz, Marc Le Borgne, Joachim Jose, Karsten Niefind
Protein kinase CK2, a member of the eukaryotic protein kinase superfamily, is associated with cancer and other human pathologies and thus an attractive drug target. The indeno[1,2-b]indole scaffold is a novel lead structure to develop ATP-competitive CK2 inhibitors. Some indeno[1,2-b]indole-based CK2 inhibitors additionally obstruct ABCG2, an ABC half transporter overexpressed in breast cancer and co-responsible for drug efflux and resistance. Comprehensive derivatization studies revealed substitutions of the indeno[1,2-b]indole framework that boost either the CK2 or the ABCG2 selectivity or even support the dual inhibition potential...
December 13, 2017: Pharmaceuticals
Jian-Feng Liu, Wei-Wei Deng, Lei Chen, Yi-Cun Li, Lei Wu, Si-Rui Ma, Wen-Feng Zhang, Lin-Lin Bu, Zhi-Jun Sun
Angiogenesis is an essential event in tumor growth and metastasis, and immune system also contributes to the tumor evasion. Emerging evidences have suggested the bidirectional link between angiogenesis and immunosuppression. Myeloid-derived suppressor cell (MDSC) is a kind of immunosuppressive cells and plays an important role in this process. However, the actual regulatory mechanisms of angiogenesis and MDSCs in head and neck squamous cell carcinoma (HNSCC) were unclear. In this study, through analyzing the immunohistochemistry staining of human HNSCC tissue microarray, we found that the microvascular density (MVD) was significantly increased in HNSCC patients...
December 7, 2017: Molecular Carcinogenesis
Scott F Rusin, Mark E Adamo, Arminja N Kettenbach
Protein phosphorylation is a crucial regulatory mechanism that controls many aspects of cellular signaling. Casein kinase 2 (CK2), a constitutively expressed and active kinase, plays key roles in an array of cellular events including transcription and translation, ribosome biogenesis, cell cycle progression, and apoptosis. CK2 is implicated in cancerous transformation and is a therapeutic target in anti-cancer therapy. The specific and selective CK2 ATP competitive inhibitor, CX-4945 (silmitaseratib), is currently in phase 2 clinical trials...
2017: Frontiers in Cell and Developmental Biology
Sérgio T Ribeiro, João T Barata, Bruno Silva-Santos
No abstract text is available yet for this article.
October 31, 2017: Oncotarget
Melissa M J Chua, Migi Lee, Isabel Dominguez
A multitude of proteins are aberrantly expressed in cancer cells, including the oncogenic serine-threonine kinase CK2. In a previous report, we found increases in CK2 transcript expression that could explain the increased CK2 protein levels found in tumors from lung and bronchus, prostate, breast, colon and rectum, ovarian and pancreatic cancers. We also found that, contrary to the current notions about CK2, some CK2 transcripts were downregulated in several cancers. Here, we investigate all other cancers using Oncomine to determine whether they also display significant CK2 transcript dysregulation...
2017: PloS One
Andrea Baier, Jolanta Nazaruk, Anna Galicka, Ryszard Szyszka
CK2 is a pleiotropic, constitutively active protein kinase responsible for the phosphorylation of more than 300 physiological substrates. Typically, this enzyme is found in tetrameric form consisting of two regulatory subunits CK2β and two catalytic subunits CK2α or CK2α'. Several natural occurring flavonoids were tested for their ability to inhibit both CK2 holoenzymes, CK2α2β2 and CK2α'2β2. We identified few substances selectively inhibiting only the α' subunit. Other compounds showed similar effect towards all four isoforms...
November 29, 2017: Molecular and Cellular Biochemistry
Sarah Spohrer, Rebecca Groß, Lisa Nalbach, Lisa Schwind, Heike Stumpf, Michael D Menger, Emmanuel Ampofo, Mathias Montenarh, Claudia Götz
Glucose homeostasis is regulated by insulin, which is produced in the β-cells of the pancreas. The synthesis of insulin is controlled by several transcription factors including PDX-1, USF1 and USF2. Both, PDX-1 and USF1 were identified as substrates for protein kinase CK2. Here, we have analysed the interplay of PDX-1, USF1 and CK2 in the regulation of PDX-1 gene transcription. We found that the PDX-1 promoter is dose-dependently transactivated by PDX-1 and transrepressed by USF1. With increasing glucose concentrations the transrepression of the PDX-1 promoter by USF1 is successively abrogated...
November 27, 2017: Scientific Reports
Qianwen Li, Ke Li, Tianyang Yang, Sheng Zhang, Yu Zhou, Zhenyu Li, Jinrong Xiong, Fangzheng Zhou, Xiaoshu Zhou, Li Liu, Rui Meng, Gang Wu
Protein kinase CK2 is a highly conserved protein Ser/Thr protein kinase and plays important roles in cell proliferation, protein translation and cell survival. This study investigated the possibility of using CK2 inhibition as a new approach for increasing the efficacy of radiotherapy in non-small cell lung cancer (NSCLC) and its underlying mechanisms. Kinase inhibition of CK2 was attempted either by using the specific CK2 inhibitor, Quinalizarin or by applying siRNA interference technology to silence the expression of the catalytic subunit of CK2 in A549 and H460 cells...
November 23, 2017: Scientific Reports
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