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https://www.readbyqxmd.com/read/27879331/brd4-activates-early-viral-transcription-upon-human-papillomavirus-18-infection-of-primary-keratinocytes
#1
Caleb C McKinney, Min Jung Kim, Dan Chen, Alison A McBride
: Human papillomaviruses (HPVs) replicate in the cutaneous and mucosal epithelia, and the infectious cycle is synchronous with the differentiation program of the host keratinocytes. The virus initially infects dividing cells in the lower layers of the epithelium, where it establishes a persistent infection. The viral genome is maintained as a low-copy-number, extrachromosomal element in these proliferating cells but switches to the late stage of the life cycle in differentiated cells...
November 22, 2016: MBio
https://www.readbyqxmd.com/read/27827996/the-bromodomain-and-extra-terminal-domain-bet-family-functional-anatomy-of-bet-paralogous-proteins
#2
REVIEW
Yasushi Taniguchi
The Bromodomain and Extra-Terminal Domain (BET) family of proteins is characterized by the presence of two tandem bromodomains and an extra-terminal domain. The mammalian BET family of proteins comprises BRD2, BRD3, BRD4, and BRDT, which are encoded by paralogous genes that may have been generated by repeated duplication of an ancestral gene during evolution. Bromodomains that can specifically bind acetylated lysine residues in histones serve as chromatin-targeting modules that decipher the histone acetylation code...
November 7, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27769357/clinical-trials-for-bet-inhibitors-run-ahead-of-the-science
#3
REVIEW
Guillaume Andrieu, Anna C Belkina, Gerald V Denis
Several cancer clinical trials for small molecule inhibitors of BET bromodomain proteins have been initiated. There is enthusiasm for the anti-proliferative effect of inhibiting BRD4, one of the targets of these inhibitors, which is thought to cooperate with MYC, a long-desired target for cancer therapeutics. However, no current inhibitor is selective for BRD4 among the three somatic BET proteins, which include BRD2 and BRD3; their respective functions are partially overlapping and none are functionally redundant with BRD4...
March 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27669656/inhibition-of-bet-proteins-and-epigenetic-signaling-as-a-potential-treatment-for-osteoporosis
#4
Marc Baud'huin, François Lamoureux, Camille Jacques, Lidia Rodriguez Calleja, Thibaut Quillard, Céline Charrier, Jérome Amiaud, Martine Berreur, Bénédicte Brounais-LeRoyer, Robert Owen, Gwendolen C Reilly, James E Bradner, Dominique Heymann, Benjamin Ory
Histone modifications are important for maintaining the transcription program. BET proteins, an important class of "histone reading proteins", have recently been described as essential in bone biology. This study presents the therapeutic opportunity of BET protein inhibition in osteoporosis. We find that the pharmacological BET protein inhibitor JQ1 rescues pathologic bone loss in a post-ovariectomy osteoporosis model by increasing the trabecular bone volume and restoring mechanical properties. The BET protein inhibition suppresses osteoclast differentiation and activity as well as the osteoblastogenesis in vitro...
January 2017: Bone
https://www.readbyqxmd.com/read/27651452/brd4-localization-to-lineage-specific-enhancers-is-associated-with-a-distinct-transcription-factor-repertoire
#5
Zeynab Najafova, Roberto Tirado-Magallanes, Malayannan Subramaniam, Tareq Hossan, Geske Schmidt, Sankari Nagarajan, Simon J Baumgart, Vivek Kumar Mishra, Upasana Bedi, Eric Hesse, Stefan Knapp, John R Hawse, Steven A Johnsen
Proper temporal epigenetic regulation of gene expression is essential for cell fate determination and tissue development. The Bromodomain-containing Protein-4 (BRD4) was previously shown to control the transcription of defined subsets of genes in various cell systems. In this study we examined the role of BRD4 in promoting lineage-specific gene expression and show that BRD4 is essential for osteoblast differentiation. Genome-wide analyses demonstrate that BRD4 is recruited to the transcriptional start site of differentiation-induced genes...
September 19, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27600312/brd4-is-associated-with-raccoon-polyomavirus-genome-and-mediates-viral-gene-transcription-and-maintenance-of-a-stem-cell-state-in-neuroglial-tumour-cells
#6
Molly E Church, Marko Estrada, Christian M Leutenegger, Florante N Dela Cruz, Patricia A Pesavento, Kevin D Woolard
Polyomavirus infection often results in persistence of the viral genome with little or no virion production. However, infection of certain cell types can result in high viral gene transcription and either cytolysis or neoplastic transformation. While infection by polyomavirus is common in humans and many animals, major questions regarding viral persistence of most polyomaviruses remain unanswered. Specifically, identification of target cells for viral infection and the mechanisms polyomaviruses employ to maintain viral genomes within cells are important not only in ascribing causality to polyomaviruses in disease, but in understanding specific mechanisms by which they cause disease...
November 2016: Journal of General Virology
https://www.readbyqxmd.com/read/27591477/bet-bromodomain-inhibition-promotes-neurogenesis-while-inhibiting-gliogenesis-in-neural-progenitor-cells
#7
Jingjun Li, Jing Ma, Guofeng Meng, Hong Lin, Sharon Wu, Jamie Wang, Jie Luo, Xiaohong Xu, David Tough, Matthew Lindon, Inma Rioja Pastor, Jing Zhao, Hongkang Mei, Rab Prinjha, Zhong Zhong
Neural stem cells and progenitor cells (NPCs) are increasingly appreciated to hold great promise for regenerative medicine to treat CNS injuries and neurodegenerative diseases. However, evidence for effective stimulation of neuronal production from endogenous or transplanted NPCs for neuron replacement with small molecules remains limited. To identify novel chemical entities/targets for neurogenesis, we had established a NPC phenotypic screen assay and validated it using known small-molecule neurogenesis inducers...
July 20, 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27581642/structure-activity-relationship-study-of-n-6-benzoyladenine-type-brd4-inhibitors-and-their-effects-on-cell-differentiation-and-tnf-%C3%AE-production
#8
Seika Amemiya, Takao Yamaguchi, Taki Sakai, Yuichi Hashimoto, Tomomi Noguchi-Yachide
Bromodomains are epigenetic 'readers' of histone acetylation. The first potent bromodomain and extra-terminal domain (BET) inhibitors, (+)-JQ1 and I-BET762 (also known as GSK525762), were reported in 2010. Some BET inhibitors are already under clinical trial for the treatment of cancers, but so far, only a few chemical scaffolds are available. We have reported potent N(6)-benzoyladenine-based inhibitors of BRD4, a BET family member that serves as a key mediator of transcriptional elongation. Here we present an analysis of the structure-activity relationships of these inhibitors...
2016: Chemical & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/27548527/bet-bromodomain-inhibition-enhances-t-cell-persistence-and-function-in-adoptive-immunotherapy-models
#9
Yuki Kagoya, Munehide Nakatsugawa, Yuki Yamashita, Toshiki Ochi, Tingxi Guo, Mark Anczurowski, Kayoko Saso, Marcus O Butler, Cheryl H Arrowsmith, Naoto Hirano
Adoptive immunotherapy is a potentially curative therapeutic approach for patients with advanced cancer. However, the in vitro expansion of antitumor T cells prior to infusion inevitably incurs differentiation towards effector T cells and impairs persistence following adoptive transfer. Epigenetic profiles regulate gene expression of key transcription factors over the course of immune cell differentiation, proliferation, and function. Using comprehensive screening of chemical probes with defined epigenetic targets, we found that JQ1, an inhibitor of bromodomain and extra-terminal motif (BET) proteins, maintained CD8+ T cells with functional properties of stem cell-like and central memory T cells...
September 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27498864/erk5-is-a-key-regulator-of-naive-primed-transition-and-embryonic-stem-cell-identity
#10
Charles A C Williams, Rosalia Fernandez-Alonso, Jinhua Wang, Rachel Toth, Nathanael S Gray, Greg M Findlay
Embryonic stem cells (ESCs) can self-renew or differentiate into any cell type, a phenomenon known as pluripotency. Distinct pluripotent states, termed naive and primed pluripotency, have been described. However, the mechanisms that control naive-primed pluripotent transition are poorly understood. Here, we perform a targeted screen for kinase inhibitors, which modulate the naive-primed pluripotent transition. We find that XMD compounds, which selectively inhibit Erk5 kinase and BET bromodomain family proteins, drive ESCs toward primed pluripotency...
August 16, 2016: Cell Reports
https://www.readbyqxmd.com/read/27477287/brd4-phosphorylation-regulates-hpv-e2-mediated-viral-transcription-origin-replication-and-cellular-mmp-9-expression
#11
Shwu-Yuan Wu, Dawn Sijin Nin, A-Young Lee, Scott Simanski, Thomas Kodadek, Cheng-Ming Chiang
Post-translational modification can modulate protein conformation and alter binding partner recruitment within gene regulatory regions. Here, we report that bromodomain-containing protein 4 (BRD4), a transcription co-factor and chromatin regulator, uses a phosphorylation-induced switch mechanism to recruit E2 protein encoded by cancer-associated human papillomavirus (HPV) to viral early gene and cellular matrix metalloproteinase-9 (MMP-9) promoters. Enhanced MMP-9 expression, induced upon keratinocyte differentiation, occurs via BRD4-dependent recruitment of active AP-1 and NF-κB to their target sequences...
August 9, 2016: Cell Reports
https://www.readbyqxmd.com/read/27338676/cytological-features-of-nut-midline-carcinoma-arising-in-sino-nasal-tract-and-parotid-gland-report-of-two-new-cases-and-review-of-the-literature
#12
Jerzy Klijanienko, Christophe Le Tourneau, José Rodriguez, Martial Caly, Stamatios Theocharis
Nuclear Protein in Testis (NUT) Midline Carcinoma (NMC) represents a recently described, uncommon, high-grade and extremely lethal malignancy mainly occurring in children and young adults. Such tumors are genetically characterized by chromosomal rearrangements of the NUT gene. Cytological description of NUT carcinoma is limited and only seven cases were reported up to date. We show here another two cases studied cytologically with molecular and immunohistochemical confirmation. In both cases smears were hypercellular and composed of isolated or clustered small to medium-sized in size with roundish and oval shape cells...
September 2016: Diagnostic Cytopathology
https://www.readbyqxmd.com/read/27292648/t-bet-activates-th1-genes-through-mediator-and-the-super-elongation-complex
#13
Arnulf Hertweck, Catherine M Evans, Malihe Eskandarpour, Jonathan C H Lau, Kristine Oleinika, Ian Jackson, Audrey Kelly, John Ambrose, Peter Adamson, David J Cousins, Paul Lavender, Virginia L Calder, Graham M Lord, Richard G Jenner
The transcription factor T-bet directs Th1 cell differentiation, but the molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood. Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator and P-TEFb in the form of the super elongation complex (SEC). Th1 genes are occupied by H3K4me3 and RNA polymerase II in Th2 cells, while T-bet-mediated recruitment of P-TEFb in Th1 cells activates transcriptional elongation. P-TEFb is recruited to both genes and enhancers, where it activates enhancer RNA transcription...
June 21, 2016: Cell Reports
https://www.readbyqxmd.com/read/27282480/rvx-297-a-novel-bd2-selective-inhibitor-of-bet-bromodomains
#14
Olesya A Kharenko, Emily M Gesner, Reena G Patel, Karen Norek, Andre White, Eric Fontano, Robert K Suto, Peter R Young, Kevin G McLure, Henrik C Hansen
Bromodomains are epigenetic readers that specifically bind to the acetyl lysine residues of histones and transcription factors. Small molecule BET bromodomain inhibitors can disrupt this interaction which leads to potential modulation of several disease states. Here we describe the binding properties of a novel BET inhibitor RVX-297 that is structurally related to the clinical compound RVX-208, currently undergoing phase III clinical trials for the treatment of cardiovascular diseases, but is distinctly different in its biological and pharmacokinetic profiles...
August 12, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27158652/preparation-data-of-the-bromodomains-brd3-1-brd3-2-brd4-1-and-brpf1b-and-crystallization-of-brd4-1-inhibitor-complexes
#15
Martin Hügle, Xavier Lucas, Gerhard Weitzel, Dmytro Ostrovskyi, Bernhard Breit, Stefan Gerhardt, Karin Schmidtkunz, Manfred Jung, Roland Schüle, Oliver Einsle, Stefan Günther, Daniel Wohlwend
This article presents detailed purification procedures for the bromodomains BRD3(1), BRD3(2), BRD4(1), and BRPF1B. In addition we provide crystallization protocols for apo BRD4(1) and BRD4(1) in complex with numerous inhibitors. The protocols described here were successfully applied to obtain affinity data by isothermal titration calorimetry (ITC) and by differential scanning fluorimetry (DSF) as well as structural characterizations of BRD4(1) inhibitor complexes (PDB codes: PDB: 4LYI, PDB: 4LZS, PDB: 4LYW, PDB: 4LZR, PDB: 4LYS, PDB: 5D24, PDB: 5D25, PDB: 5D26, PDB: 5D3H, PDB: 5D3J, PDB: 5D3L, PDB: 5D3N, PDB: 5D3P, PDB: 5D3R, PDB: 5D3S, PDB: 5D3T)...
June 2016: Data in Brief
https://www.readbyqxmd.com/read/27110299/the-bromodomain-inhibitor-n-methyl-pyrrolidone-reduced-fat-accumulation-in-an-ovariectomized-rat-model
#16
Bebeka Gjoksi, Chafik Ghayor, Indranil Bhattacharya, Marcy Zenobi-Wong, Franz E Weber
BACKGROUND: Weight gain is one of the consequences of estrogen deficiency and constitutes a major health problem. The present study highlights the effects of N-methyl pyrrolidone (NMP) on adipogenesis in osteoporosis induced by estrogen deficiency in an ovariectomized rat model. RESULTS: Ovariectomy resulted in body weight gain, increased femoral marrow adipocytes, and hypertrophic adipocytes in white adipose tissue, distorted serum leptin, and TNF-α and PPARγ levels...
2016: Clinical Epigenetics
https://www.readbyqxmd.com/read/27055867/bet-inhibition-represses-mir17-92-to-drive-bim-initiated-apoptosis-of-normal-and-transformed-hematopoietic-cells
#17
Z Xu, P P Sharp, Y Yao, D Segal, C H Ang, S L Khaw, B J Aubrey, J Gong, G L Kelly, M J Herold, A Strasser, A W Roberts, W S Alexander, C J Burns, D C S Huang, S P Glaser
The BET (bromodomain and extraterminal domain) bromodomain-containing proteins, such as BRD4, are highly promising targets for treating lymphoid and myeloid malignancies. They act to modulate the expression of multiple genes that control diverse cellular processes including proliferation, survival and differentiation that are consequentially disrupted by small-molecule BET bromodomain inhibitors such as JQ1. By assessing the impact of these inhibitors on normal mouse hematopoietic cells or their transformed counterparts, we establish definitively that their cytotoxic action in vitro and in vivo relies predominantly on the activation of BAX/BAK-dependent mitochondrial (intrinsic) apoptosis...
July 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27007052/differential-regulation-of-the-c-myc-lin28-axis-discriminates-subclasses-of-rearranged-mll-leukemia
#18
Lili Chen, Yuqing Sun, Jingya Wang, Hui Jiang, Andrew G Muntean
MLL rearrangements occur in myeloid and lymphoid leukemias and are generally associated with a poor prognosis, however this varies depending on the fusion partner. We modeled acute myeloid leukemia (AML) in mice using various MLL fusion proteins (MLL-FPs) and observed significantly different survival outcomes. To better understand the differences between these leukemias, we examined the genome wide expression profiles of leukemic cells transformed with different MLL-FPs. RNA-sequencing and pathway analysis identified the c-Myc transcriptional program as one of the top distinguishing features...
May 3, 2016: Oncotarget
https://www.readbyqxmd.com/read/26976114/clinical-response-of-carcinomas-harboring-the-brd4-nut-oncoprotein-to-the-targeted-bromodomain-inhibitor-otx015-mk-8628
#19
Anastasios Stathis, Emanuele Zucca, Mohamed Bekradda, Carlos Gomez-Roca, Jean-Pierre Delord, Thibault de La Motte Rouge, Emmanuelle Uro-Coste, Filippo de Braud, Giuseppe Pelosi, Christopher A French
UNLABELLED: The antineoplastic, prodifferentiative effects of bromodomain and extra-terminal (BET) bromodomain (BRD) inhibitors were initially discovered in NUT midline carcinoma (NMC), an aggressive subtype of squamous cancer driven by the BRD4-NUT fusion oncoprotein. BRD4-NUT blocks differentiation and maintains tumor growth through a potent chromatin-modifying mechanism. OTX015/MK-8628, a novel oral BET inhibitor, targets BRD2/3/4/T with preclinical activity in NMC and several other tumor types and is currently in clinical development...
May 2016: Cancer Discovery
https://www.readbyqxmd.com/read/26847871/histone-h4-acetylation-and-the-epigenetic-reader-brd4-are-critical-regulators-of-pluripotency-in-embryonic-stem-cells
#20
Michelle Gonzales-Cope, Simone Sidoli, Natarajan V Bhanu, Kyoung-Jae Won, Benjamin A Garcia
BACKGROUND: Pluripotent cells can be differentiated into many different cell types in vitro. Successful differentiation is guided in large part by epigenetic reprogramming and regulation of critical gene expression patterns. Recent genome-wide studies have identified the distribution of different histone-post-translational modifications (PTMs) in various conditions and during cellular differentiation. However, our understanding of the abundance of histone PTMs and their regulatory mechanisms still remain unknown...
2016: BMC Genomics
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