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Cheng-Ming Chiang
BRD4 is an epigenetic regulator and transcription cofactor whose phosphorylation by CK2 and dephosphorylation by PP2A modulates its function in chromatin targeting, factor recruitment, and cancer progression. While the bromodomains of BET family proteins, including BRD4, BRD2, BRD3 and BRDT, have been the primary targets of small compounds such as JQ1, I-BET and MS417 that show promising anticancer effects against some hematopoietic cancer and solid tumors, drug resistance upon prolonged treatment necessitates a better understanding of alternative pathways underlying not only the resistance but also persistent BET protein dependence for identifying new targets and effective combination therapy strategies...
March 2016: Drug Discovery Today. Technologies
Haiwei Lian, Dun Li, Yun Zhou, Esther Landesman-Bollag, Guanglan Zhang, Nicole M Anderson, Kevin Charles Tang, Justine E Roderick, Michelle A Kelliher, David C Seldin, Hui Fu, Hui Feng
No abstract text is available yet for this article.
October 6, 2016: Haematologica
Jiang Zhu, Wen-Shu Wang, Dan Ma, Lin-Yu Zhang, Feng Ren, Ting-Ting Yuan
Protein kinase CK2, which consists of two α and two β subunits, plays an essential role in plant development and is implicated in plant responses to abiotic stresses, including salt and heat. However, the function of CK2 in response to heavy metals such as cadmium (Cd) has not yet been established. In this study, the transgenic line CKB4ox, which overexpresses CKB4 encoding the CK2β subunit and has elevated CK2 activity, was used to investigate the potential role of CK2 in response to Cd stress in Arabidopsis thaliana...
October 8, 2016: Plant Physiology and Biochemistry: PPB
Chandrika Gowda, Mansi Sachdev, Sunil Muthisami, Malika Kapadia, Lidija Petrovic-Dovat, Melanie Hartman, Yali Ding, Chunhua Song, Jonathon L Payne, Bi-Hua Tan, Sinisa Dovat
BACKGROUND: Casein kinase II (CK2) is a pro-oncogenic protein, which is emerging as a promising therapeutic target in cancer. Recent studies have revealed an important role for CK2 in tumorigenesis. High levels of CK2 are noted in many malignancies including leukemia. Use of CK2 inhibitors in various malignancies including breast, prostate, and lung cancer are being tested. Although many CK2 inhibitors exist, only a few have emerged as selective inhibitors that are potent and effective...
October 6, 2016: Current Pharmaceutical Design
Mrigendra Bir Karmacharya, Binika Hada, So Ra Park, Byung Hyune Choi
Many studies have shown that mitochondrial dysfunction and the subsequent oxidative stress caused by excessive reactive oxygen species (ROS) generation play a central role in the pathogenesis of Parkinson's disease (PD). We have previously shown that low-intensity ultrasound (LIUS) could reduce ROS generation by L-buthionine-(S,R)-sulfoximine (BSO) in retinal pigment epithelial cells. In this study, we studied the effects of LIUS stimulation on the ROS-dependent α-synuclein aggregation in 1-methyl-4-phenylpyridinium ion (MPP(+))-treated PC12 cells...
October 6, 2016: Molecular Neurobiology
Marie de Bourayne, Yann Gallais, Zeina El Ali, Philippe Rousseau, Marie-Hélène Damiens, Claude Cochet, Odile Filhol, Sylvie Chollet-Martin, Marc Pallardy, Saadia Kerdine-Römer
Allergic contact dermatitis (ACD) represents a severe health problem with increasing worldwide prevalence. It is a T-cell-mediated inflammatory skin disease caused by chemicals present in the daily or professional environment. NiSO4 and 2,4-dinitrochlorobenzene (DNCB) are 2 chemicals involved in ACD. These contact sensitizers are known to induce an up-regulation of phenotypic markers and cytokine secretion in dendritic cells (DCs; professional APCs), leading to the generation of CD8(+) Tc1/Tc17 and CD4(+) Th1/Th17 effector T cells...
October 5, 2016: Journal of Leukocyte Biology
Chandrika Gowda, Chunhua Song, Malika Kapadia, Jonathon L Payne, Tommy Hu, Yali Ding, Sinisa Dovat
The IKZF1 gene encodes the Ikaros protein, a zinc finger transcriptional factor that acts as a master regulator of hematopoiesis and a tumor suppressor in leukemia. Impaired activity of Ikaros is associated with the development of high-risk acute lymphoblastic leukemia (ALL) with a poor prognosis. The molecular mechanisms that regulate Ikaros' function as a tumor suppressor and regulator of cellular proliferation are not well understood. We demonstrated that Ikaros is a substrate for Casein Kinase II (CK2), an oncogenic kinase that is overexpressed in ALL...
September 18, 2016: Advances in Biological Regulation
Anatolii R Syniugin, Olga V Ostrynska, Maksym O Chekanov, Galyna P Volynets, Sergiy A Starosyla, Volodymyr G Bdzhola, Sergiy M Yarmoluk
In this article, the derivatives of 3-quinoline carboxylic acid were studied as inhibitors of protein kinase CK2. Forty-three new compounds were synthesized. Among them 22 compounds inhibiting CK2 with IC50 in the range from 0.65 to 18.2 μM were identified. The most active inhibitors were found among tetrazolo-quinoline-4-carboxylic acid and 2-aminoquinoline-3-carboxylic acid derivatives.
September 2, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Tanvi Shekhar-Guturja, G M Kamal B Gunaherath, E M Kithsiri Wijeratne, Jean-Philippe Lambert, Anna F Averette, Soo Chan Lee, Taeyup Kim, Yong-Sun Bahn, Farida Tripodi, Ron Ammar, Katja Döhl, Karolina Niewola-Staszkowska, Lutz Schmitt, Robbie J Loewith, Frederick P Roth, Dominique Sanglard, David Andes, Corey Nislow, Paola Coccetti, Anne-Claude Gingras, Joseph Heitman, A A Leslie Gunatilaka, Leah E Cowen
There is an urgent need for new strategies to treat invasive fungal infections, which are a leading cause of human mortality. Here, we establish two activities of the natural product beauvericin, which potentiates the activity of the most widely deployed class of antifungal against the leading human fungal pathogens, blocks the emergence of drug resistance, and renders antifungal-resistant pathogens responsive to treatment in mammalian infection models. Harnessing genome sequencing of beauvericin-resistant mutants, affinity purification of a biotinylated beauvericin analog, and biochemical and genetic assays reveals that beauvericin blocks multidrug efflux and inhibits the global regulator TORC1 kinase, thereby activating the protein kinase CK2 and inhibiting the molecular chaperone Hsp90...
October 2016: Nature Chemical Biology
Khalil Ahmed, Betsy T Kren, Md Joynal Abedin, Rachel I Vogel, Daniel P Shaughnessy, Lucas Nacusi, Vicci L Korman, Yingming Li, Scott M Dehm, Cheryl L Zimmerman, Gloria A Niehans, Gretchen M Unger, Janeen H Trembley
CK2, a protein serine/threonine kinase, promotes cell proliferation and suppresses cell death. This essential-for-survival signal demonstrates elevated expression and activity in all cancers examined, and is considered an attractive target for cancer therapy. Here, we present data on the efficacy of a tenfibgen (TBG) coated nanocapsule which delivers its cargo of siRNA (siCK2) or single stranded RNA/DNA oligomers (RNAi-CK2) simultaneously targeting CK2α and α' catalytic subunits. Intravenous administration of TBG-siCK2 or TBG-RNAi-CK2 resulted in significant xenograft tumor reduction at low doses in PC3-LN4 and 22Rv1 models of prostate cancer...
August 20, 2016: Oncotarget
Alexander Ulges, Esther J Witsch, Gautam Pramanik, Matthias Klein, Katharina Birkner, Ulrike Bühler, Beatrice Wasser, Felix Luessi, Natascha Stergiou, Sarah Dietzen, Till-Julius Brühl, Toszka Bohn, Georg Bündgen, Horst Kunz, Ari Waisman, Hansjörg Schild, Edgar Schmitt, Frauke Zipp, Tobias Bopp
T helper 17 (TH17) cells represent a discrete TH cell subset instrumental in the immune response to extracellular bacteria and fungi. However, TH17 cells are considered to be detrimentally involved in autoimmune diseases like multiple sclerosis (MS). In contrast to TH17 cells, regulatory T (Treg) cells were shown to be pivotal in the maintenance of peripheral tolerance. Thus, the balance between Treg cells and TH17 cells determines the severity of a TH17 cell-driven disease and therefore is a promising target for treating autoimmune diseases...
September 6, 2016: Proceedings of the National Academy of Sciences of the United States of America
Xia Liu, Manman Dong, Honglan Qi, Qiang Gao, Chengxiao Zhang
A sensitive electrogenerated chemiluminescence (ECL) bioassay was developed for the detection of two protein kinases incorporating the peptide phosphorylation and a versatile ECL probe. Cyclic adenosine monophosphate-dependent protein kinase (PKA) and casein kinase II (CK2) were used as proof-of-concept targets while a PKA-specific peptide (CLRRASLG) and a CK2-specific peptide (CRRRADDSDDDDD) were used as the recognition substrates. Taking advantage of the ability of protein A binding with the Fc region of a variety of antibodies with high affinity, a ruthenium derivative-labeled protein A was utilized as a versatile ECL probe for bioassay of multiple protein kinases...
September 6, 2016: Analytical Chemistry
Na Zhang, Wen-Juan Chen, Yue Zhou, Hongtao Zhao, Ru-Gang Zhong
Design of novel coumarin derivatives as CK2 inhibitors were attempted by targeting the interaction with the hinge region. A set of substituents capable of forming a hydrogen bond or halogen bond with the hinge region were screened in silico, and trifluoromethyl emerges as a promising motif by forming favorable electrostatic interaction and a presumable halogen bond with the hinge region. As proof of concept, three trifluoromethyl derivatives of coumarin were synthesized and tested in vitro. The results indicated that replacement of methyl by trifluoromethyl leads to a modest 5-fold improvement in potency, with the most active compound being 0...
January 2016: Molecular Informatics
L Q Tubi, S C Nunes, A Brancalion, E D Breatta, S Manni, E Mandato, F Zaffino, P Macaccaro, M Carrino, K Gianesin, L Trentin, G Binotto, R Zambello, G Semenzato, C Gurrieri, F Piazza
Protein kinase CK2 sustains acute myeloid leukemia cell growth, however, its role in leukemia stem cells is largely unknown. Here, we discovered that the CK2 catalytic  and regulatory β subunits are consistently expressed in leukemia stem cells isolated from acute myeloid leukemia patients and cell lines. CK2 inactivation with the selective inhibitor CX-4945 or RNA interference induced an accumulation of leukemia stem cells in the late S-G2-M phases of the cell cycle and triggered late-onset apoptosis. As a result leukemia stem cells displayed an increased sensitivity to the chemotherapeutic agent doxorubicin...
August 1, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Alice Melão, Maureen Spit, Bruno A Cardoso, Joao T Barata
Interleukin-7 and IL7R are essential for normal T-cell development and homeostasis, whereas excessive interleukin-7/IL7R-mediated signaling promotes leukemogenesis. Protein kinase CK2 is overexpressed and hyperactivated in cancer, including T-cell acute lymphoblastic leukemia. Here, we show that while interleukin-7 had a minor but significant positive effect on CK2 activity in leukemia T-cells, CK2 activity was mandatory for optimal interleukin-7/IL7R-mediated signaling. CK2 pharmacological inhibition impaired STAT5 and PI3K/Akt pathway activation triggered by interleukin-7 or by mutational activation of IL7R...
July 28, 2016: Haematologica
Seong-Yeol Park, Young-Seuk Bae
We previously showed that protein kinase CK2 downregulation mediates senescence through the reactive oxygen species (ROS)-p53-p21(Cip1/WAF1) pathway in various human cells. In the present study, we investigated whether the FoxO3a transcription factor is associated with ROS production during CK2 downregulation-induced senescence in human colon cancer HCT116 and breast cancer MCF-7 cells. FoxO3a overexpression suppressed ROS production and p53 stabilization induced by a CK2α knockdown. CK2α downregulation induced nuclear export of FoxO3a through stimulation of AKT-mediated phosphorylation of FoxO3a and decreased transcription of its target genes (Cu/ZnSOD, MnSOD, and catalase)...
September 9, 2016: Biochemical and Biophysical Research Communications
Jed J Kendall, Katherine E Chaney, Ami V Patel, Tilat A Rizvi, David A Largaespada, Nancy Ratner
Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that are a major cause of mortality of Neurofibromatosis type 1 (NF1) patients. MPNST patients have few therapeutic options available and only complete surgical resection can be curative. MPNST formation and survival are dependent on activated β-catenin signaling. The goal of this study was to determine if inhibition of the CK2 enzyme can be therapeutically exploited in MPNSTs, given CK2's role in mainta ining oncogenic phenotypes including stabilization of β-catenin...
July 18, 2016: Oncotarget
Georges Teto, Julius Y Fonsah, Claude T Tagny, Dora Mbanya, Emilienne Nchindap, Leopoldine Kenmogne, Joseph Fokam, Dora M Njamnshi, Charles Kouanfack, Alfred K Njamnshi, Georgette D Kanmogne
HIV-1 Tat plays a critical role in viral transactivation. Subtype-B Tat has potential use as a therapeutic vaccine. However, viral genetic diversity and population genetics would significantly impact the efficacy of such a vaccine. Over 70% of the 37-million HIV-infected individuals are in sub-Saharan Africa (SSA) and harbor non-subtype-B HIV-1. Using specimens from 100 HIV-infected Cameroonians, we analyzed the sequences of HIV-1 Tat exon-1, its functional domains, post-translational modifications (PTMs), and human leukocyte antigens (HLA)-binding epitopes...
2016: Viruses
Fatima Qaiser, Janeen H Trembley, Sarah Sadiq, Iqbal Muhammad, Rubina Younis, Shoaib Naiyar Hashmi, Badar Murtaza, Thomas S Rector, Abdul Khaliq Naveed, Khalil Ahmed
Protein kinase CK2 plays a critical role in cell growth, proliferation, and suppression of cell death. CK2 is overexpressed, especially in the nuclear compartment, in the majority of cancers, including prostate cancer (PCa). CK2-mediated activation of transcription factor nuclear factor kappa B (NF-κB) p65 is a key step in cellular proliferation, resulting in translocation of NF-κB p65 from the cytoplasm to the nucleus. As CK2 expression and activity are also elevated in benign prostatic hyperplasia (BPH), we sought to increase the knowledge of CK2 function in benign and malignant prostate by examination of the relationships between nuclear CK2 and nuclear NF-κB p65 protein expression...
September 2016: Molecular and Cellular Biochemistry
Sang Hwa Kim, Anthony T Trinh, Michele Campaigne Larsen, Adam S Mastrocola, Colin R Jefcoate, Pierre R Bushel, Randal S Tibbetts
cAMP response element binding protein (CREB) is a key regulator of glucose metabolism and synaptic plasticity that is canonically regulated through recruitment of transcriptional coactivators. Here we show that phosphorylation of CREB on a conserved cluster of Ser residues (the ATM/CK cluster) by the DNA damage-activated protein kinase ataxia-telangiectasia-mutated (ATM) and casein kinase1 (CK1) and casein kinase2 (CK2) positively and negatively regulates CREB-mediated transcription in a signal dependent manner...
July 18, 2016: Nucleic Acids Research
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