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https://www.readbyqxmd.com/read/28077651/bromodomain-containing-4-brd4-couples-nf%C3%AE%C2%BAb-rela-with-airway-inflammation-and-the-irf-rig-i-amplification-loop-in-respiratory-syncytial-virus-infection
#1
Bing Tian, Jun Yang, Yingxin Zhao, Teodora Ivanciuc, Hong Sun, Roberto P Garofalo, Allan R Brasier
: The airway mucosa expresses protective interferon (IFN) and inflammatory cytokines in response to Respiratory Syncytial Virus (RSV) infection. In this study, we examine the role of bromodomain containing 4 (BRD4) in mediating this innate immune response in human small airway epithelial cells. We observe that RSV induces BRD4 to complex with NFκB/RelA. BRD4 is functionally required for expression of the NFκB-dependent inflammatory gene regulatory network (GRN), including the IFN Response Factor (IRFs)-1 and -7 that mediate a cross-talk pathway for RIG-I upregulation...
January 11, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28076398/identification-of-a-novel-mutation-in-brd4-that-causes-autosomal-dominant-syndromic-congenital-cataracts-associated-with-other-neuro-skeletal-anomalies
#2
Hyun-Seok Jin, Jeonhyun Kim, Woori Kwak, Hyeonsoo Jeong, Gyu-Bin Lim, Cha Gon Lee
Congenital cataracts can occur as a non-syndromic isolated ocular disease or as a part of genetic syndromes accompanied by a multi-systemic disease. Approximately 50% of all congenital cataract cases have a heterogeneous genetic basis. Here, we describe three generations of a family with an autosomal dominant inheritance pattern and common complex phenotypes, including bilateral congenital cataracts, short stature, macrocephaly, and minor skeletal anomalies. We did not find any chromosomal aberrations or gene copy number abnormalities using conventional genetic tests; accordingly, we conducted whole-exome sequencing (WES) to identify disease-causing genetic alterations in this family...
2017: PloS One
https://www.readbyqxmd.com/read/28073847/identification-of-ccr2-and-cd180-as-robust-pharmacodynamic-tumor-and-blood-biomarkers-for-clinical-use-with-brd4-bet-inhibitors
#3
Tammie C Yeh, Greg O'Connor, Philip Petteruti, Austin Dulak, Maureen Hattersley, J Carl Barrett, Huawei Chen
PURPOSE: AZD5153 is a novel BRD4/BET inhibitor with a distinctive bivalent bromodomain binding mode. To support its clinical development, we identified pharmacodynamic (PD) biomarkers for use in clinical trials to establish target engagement. EXPERIMENTAL DESIGN: CCR2 and CD180 mRNAs, initially identified from whole transcriptome profiling, were further evaluated by quantitative PCR in hematologic cell lines, xenografts, and whole blood from rat, healthy volunteers, and patients with cancer...
January 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28063381/brd4-inhibition-attenuates-unilateral-ureteral-obstruction-induced-fibrosis-by-blocking-tgf-%C3%AE-mediated-nox4-expression
#4
Baoshang Zhou, Jiao Mu, Yi Gong, Caibao Lu, Youguang Zhao, Ting He, Zhexue Qin
Uncovering new therapeutic targets for renal fibrosis holds promise for the treatment of chronic kidney diseases. Bromodomain and extra-terminal (BET) protein inhibitors have been shown to effectively ameliorate pathological fibrotic responses. However, the pharmacological effects and underlying mechanisms of these inhibitors in renal fibrosis remain elusive. In this study, we determined that the inhibition of Brd4, a BET family member, with a selective potent chemical inhibitor, JQ1, could prevent the development of renal fibrosis and block the progression of fibrosis in rats that have undergone unilateral ureteral obstruction (UUO)...
December 30, 2016: Redox Biology
https://www.readbyqxmd.com/read/28062857/positive-feedback-loop-mediated-by-protein-phosphatase-1%C3%AE-mobilization-of-p-tefb-and-basal-cdk1-drives-androgen-receptor-in-prostate-cancer
#5
Xiaming Liu, Yanfei Gao, HuiHui Ye, Sean Gerrin, Fen Ma, Yiming Wu, Tengfei Zhang, Joshua Russo, Changmeng Cai, Xin Yuan, Jihong Liu, Shaoyong Chen, Steven P Balk
P-TEFb (CDK9/cyclin T) plays a central role in androgen receptor (AR)-mediated transactivation by phosphorylating both RNA polymerase 2 complex proteins and AR at S81. CDK9 dephosphorylation mobilizes P-TEFb from an inhibitory 7SK ribonucleoprotein complex, but mechanisms targeting phosphatases to P-TEFb are unclear. We show that AR recruits protein phosphatase 1α (PP1α), resulting in P-TEFb mobilization and CDK9-mediated AR S81 phosphorylation. This increased pS81 enhances p300 recruitment, histone acetylation, BRD4 binding and subsequent further recruitment of P-TEFb, generating a positive feedback loop that sustains transcription...
January 6, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28062533/bet-bromodomain-proteins-as-cancer-therapeutic-targets
#6
Shaokun Shu, Kornelia Polyak
Epigenetic regulators are emerging therapeutic targets in a wide variety of human cancers. BET bromodomain proteins have been identified as key regulators of oncogenic transcription factors including MYC; therefore, their inhibition might provide a way to block these "undruggable" targets. Several BET bromodomain inhibitors are in clinical development with promising preliminary findings. However, tumors acquire resistance to these agents in several different ways. In this review, we summarize the role that BET bromodomain proteins play in tumorigenesis as well as the molecular mechanisms underlying therapeutic responses and resistance to their inhibition with emphasis on BRD4 and breast cancer...
January 6, 2017: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/28058282/protein-degradation-by-in-cell-self-assembly-of-proteolysis-targeting-chimeras
#7
Honorine Lebraud, David J Wright, Christopher N Johnson, Tom D Heightman
Selective degradation of proteins by proteolysis targeting chimeras (PROTACs) offers a promising potential alternative to protein inhibition for therapeutic intervention. Current PROTAC molecules incorporate a ligand for the target protein, a linker, and an E3 ubiquitin ligase recruiting group, which bring together target protein and ubiquitinating machinery. Such hetero-bifunctional molecules require significant linker optimization and possess high molecular weight, which can limit cellular permeation, solubility, and other drug-like properties...
December 28, 2016: ACS Central Science
https://www.readbyqxmd.com/read/28042144/novel-bet-protein-proteolysis-targeting-chimera-bet-protac-exerts-superior-lethal-activity-than-bromodomain-inhibitor-beti-against-post-myeloproliferative-neoplasm-mpn-secondary-s-aml-cells
#8
D T Saenz, W Fiskus, Y Qian, T Manshouri, K Rajapakshe, K Raina, K G Coleman, A P Crew, A Shen, C P Mill, B Sun, P Qiu, T M Kadia, N Pemmaraju, C DiNardo, M-S Kim, A J Nowak, C Coarfa, C M Crews, S Verstovsek, K N Bhalla
The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Whereas the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells...
January 2, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28032455/in-silico-design-and-bioevaluation-of-selective-benzotriazepine-brd4-inhibitors-with-potent-antiosteoclastogenic-activity
#9
Vishwa Deepak, Binglin Wang, Dwayne Koot, Abe Kasonga, Xiao Xing Stander, Magdalena Coetzee, Andre Stander
The bromodomain (BRD) and extra-terminal domain (BET) protein family binds to acetylated histones on lysine residues and act as epigenetic readers. Recently, the role of this protein family in bone loss has been gaining attention. Earlier studies have reported that benzotriazepine (Bzt) derivatives could be effective inhibitors of BET proteins. In this study by using in silico tools we designed three Bzt analogs (W49, W51, and W52). By docking, molecular simulations and chemiluminescent alpha screen binding assay we show that the studied analogs were selective at inhibiting BRD4 when compared to BRD2...
December 29, 2016: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28024472/-effect-of-brd4-inhibitor-gsk525762a-on-proliferation-and-apoptosis-of-sup-b15-cells-in-vitro-and-its-possible-mechanism
#10
Xue Wang, Na Qi, Sha Ma, Zhi-Ling Yan, Qing-Yun Wu, Lin Wang, Chong Chen, Kai-Lin Xu
OBJECTIVE: To investigate the effect of BRD4 inhibitor GSK525762A on the proliferation and apoptosis of Philadelphia chromosome-positive acute lymphoblastic leukemia SUP-B15 cells and its mechanism. METHODS: SUP-B15 cells were treated with different concentration of GSK525762A, the proliferation-inhibition curve was assayed and plotted by CCK-8 method, the cell viability and apoptosis were detected by flow cytometry with Annexin V and 7-AAD staining. The transcripts of anti-apoptotic genes C-MYC, CDK6 and BCL-2 were detected by real-time PCR...
December 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28024402/relative-binding-free-energy-calculations-applied-to-protein-homology-models
#11
Daniel Cappel, Michelle Lynn Hall, Eelke B Lenselink, Thijs Beuming, Jun Qi, James Bradner, Woody Sherman
A significant challenge and potential high-value application of computer-aided drug design is the accurate prediction of protein-ligand binding affinities. Free energy perturbation (FEP) using molecular dynamics (MD) sampling is among the most suitable approaches to achieve accurate binding free energy predictions, due to the rigorous statistical framework of the methodology, correct representation of the energetics, and thorough treatment of the important degrees of freedom in the system (including explicit waters)...
December 27, 2016: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/27994766/discovery-of-new-bromodomain-scaffolds-by-biosensor-fragment-screening
#12
Iva Navratilova, Tonia Aristotelous, Sarah Picaud, Apirat Chaikuad, Stefan Knapp, Panagis Filappakopoulos, Andrew L Hopkins
The discovery of novel bromodomain inhibitors by fragment screening is complicated by the presence of dimethyl sulfoxide (DMSO), an acetyl-lysine mimetic, that can compromise the detection of low affinity fragments. We demonstrate surface plasmon resonance as a primary fragment screening approach for the discovery of novel bromodomain scaffolds, by describing a protocol to overcome the DMSO interference issue. We describe the discovery of several novel small molecules scaffolds that inhibit the bromodomains PCAF, BRD4, and CREBBP, representing canonical members of three out of the seven subfamilies of bromodomains...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27991587/a-bromodomain-dna-interaction-facilitates-acetylation-dependent-bivalent-nucleosome-recognition-by-the-bet-protein-brdt
#13
Thomas C R Miller, Bernd Simon, Vladimir Rybin, Helga Grötsch, Sandrine Curtet, Saadi Khochbin, Teresa Carlomagno, Christoph W Müller
Bromodomains are critical components of many chromatin modifying/remodelling proteins and are emerging therapeutic targets, yet how they interact with nucleosomes, rather than acetylated peptides, remains unclear. Using BRDT as a model, we characterized how the BET family of bromodomains interacts with site-specifically acetylated nucleosomes. Here we report that BRDT interacts with nucleosomes through its first (BD1), but not second (BD2) bromodomain, and that acetylated histone recognition by BD1 is complemented by a bromodomain-DNA interaction...
December 19, 2016: Nature Communications
https://www.readbyqxmd.com/read/27990121/targeting-mechanotransduction-at-the-transcriptional-level-yap-and-brd4-are-novel-therapeutic-targets-for-the-reversal-of-liver-fibrosis
#14
REVIEW
Altynbek Zhubanchaliyev, Aibar Temirbekuly, Kuralay Kongrtay, Leah C Wanshura, Jeannette Kunz
Liver fibrosis is the result of a deregulated wound healing process characterized by the excessive deposition of extracellular matrix. Hepatic stellate cells (HSCs), which are activated in response to liver injury, are the major source of extracellular matrix and drive the wound healing process. However, chronic liver damage leads to perpetual HSC activation, progressive formation of pathological scar tissue and ultimately, cirrhosis and organ failure. HSC activation is triggered largely in response to mechanosignaling from the microenvironment, which induces a profibrotic nuclear transcription program that promotes HSC proliferation and extracellular matrix secretion thereby setting up a positive feedback loop leading to matrix stiffening and self-sustained, pathological, HSC activation...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27980063/brd4-promotes-p63-and-grhl3-expression-downstream-of-foxo-in-mammary-epithelial-cells
#15
Sankari Nagarajan, Upasana Bedi, Anusha Budida, Feda H Hamdan, Vivek Kumar Mishra, Zeynab Najafova, Wanhua Xie, Malik Alawi, Daniela Indenbirken, Stefan Knapp, Cheng-Ming Chiang, Adam Grundhoff, Vijayalakshmi Kari, Christina H Scheel, Florian Wegwitz, Steven A Johnsen
Bromodomain-containing protein 4 (BRD4) is a member of the bromo- and extraterminal (BET) domain-containing family of epigenetic readers which is under intensive investigation as a target for anti-tumor therapy. BRD4 plays a central role in promoting the expression of select subsets of genes including many driven by oncogenic transcription factors and signaling pathways. However, the role of BRD4 and the effects of BET inhibitors in non-transformed cells remain mostly unclear. We demonstrate that BRD4 is required for the maintenance of a basal epithelial phenotype by regulating the expression of epithelial-specific genes including TP63 and Grainy Head-like transcription factor-3 (GRHL3) in non-transformed basal-like mammary epithelial cells...
December 15, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27965149/involvement-of-brd4-in-different-steps-of-the-papillomavirus-life-cycle
#16
REVIEW
Thomas Iftner, Juliane Haedicke-Jarboui, Shwu-Yuan Wu, Cheng-Ming Chiang
Bromodomain-containing protein 4 (Brd4) is a cellular chromatin-binding factor and transcriptional regulator that recruits sequence-specific transcription factors and chromatin modulators to control target gene transcription. Papillomaviruses (PVs) have evolved to hijack Brd4's activity in order to create a facilitating environment for the viral life cycle. Brd4, in association with the major viral regulatory protein E2, is involved in multiple steps of the PV life cycle including replication initiation, viral gene transcription, and viral genome segregation and maintenance...
December 10, 2016: Virus Research
https://www.readbyqxmd.com/read/27926786/nut-midline-carcinoma-of-the-larynx-an-international-series-and-review-of-the-literature
#17
Henrik Hellquist, Christopher A French, Justin A Bishop, Andrés Coca-Pelaz, Evan J Propst, António Paiva Correia, Bo-Yee Ngan, Ronald Grant, Nicole A Cipriani, David Vokes, Rui Henrique, Fernando Pardal, Jose Ramon Vizcaino, Alessandra Rinaldo, Alfio Ferlito
AIMS: NUT midline carcinoma (NMC) is a rare undifferentiated and aggressive carcinoma that characteristically locates to the midline of the head and neck, and mediastinum. NMC is characterised by chromosomal rearrangements of the gene encoding nuclear protein in testis, NUT, at 15q14. The BRD4 gene on 19q13 is the most common translocation partner forming a fusion oncogene, BRD4-NUT. By the end of 2014, the International NUT Midline Carcinoma Registry had 48 patients treated for NMC. Laryngeal NMC are exceedingly rare and we report a case series of seven cases...
December 7, 2016: Histopathology
https://www.readbyqxmd.com/read/27913389/bet-inhibitors-target-blastic-plasmacytoid-dendritic-cell-neoplasms
#18
(no author information available yet)
Blastic plasmacytoid dendritic cell neoplasms (BPDCN) depend on a TCF4/BRD4 transcriptional program.
January 2017: Cancer Discovery
https://www.readbyqxmd.com/read/27907905/association-of-high-microvessel-%C3%AE-v%C3%AE-3-and-low-pten-with-poor-outcome-in-stage-3-neuroblastoma-rationale-for-using-first-in-class-dual-pi3k-brd4-inhibitor-sf1126
#19
Anat Erdreich-Epstein, Alok R Singh, Shweta Joshi, Francisco M Vega, Pinzheng Guo, Jingying Xu, Susan Groshen, Wei Ye, Melissa Millard, Mihaela Campan, Guillermo Morales, Joseph R Garlich, Peter W Laird, Robert C Seeger, Hiroyuki Shimada, Donald L Durden
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Our previous studies showed that the angiogenic integrin αvβ3 was increased in high-risk metastatic (stage 4) NB compared with localized neuroblastomas. Herein, we show that integrin αvβ3 was expressed on 68% of microvessels in MYCN-amplified stage 3 neuroblastomas, but only on 34% (means) in MYCN-non-amplified tumors (p < 0.001; n = 54). PTEN, a tumor suppressor involved in αvβ3 signaling, was expressed in neuroblastomas either diffusely, focally or not at all (immunohistochemistry)...
November 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27903272/inhibition-of-bromodomain-and-extra-terminal-bet-proteins-increases-nkg2d-ligand-mica-expression-and-sensitivity-to-nk-cell-mediated-cytotoxicity-in-multiple-myeloma-cells-role-of-cmyc-irf4-mir-125b-interplay
#20
Maria Pia Abruzzese, Maria Teresa Bilotta, Cinzia Fionda, Alessandra Zingoni, Alessandra Soriani, Elisabetta Vulpis, Cristiana Borrelli, Beatrice Zitti, Maria Teresa Petrucci, Maria Rosaria Ricciardi, Rosa Molfetta, Rossella Paolini, Angela Santoni, Marco Cippitelli
BACKGROUND: Anti-cancer immune responses may contribute to the control of tumors after conventional chemotherapy, and different observations have indicated that chemotherapeutic agents can induce immune responses resulting in cancer cell death and immune-stimulatory side effects. Increasing experimental and clinical evidence highlight the importance of natural killer (NK) cells in immune responses toward multiple myeloma (MM), and combination therapies able to enhance the activity of NK cells against MM are showing promise in treating this hematologic cancer...
December 1, 2016: Journal of Hematology & Oncology
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