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https://www.readbyqxmd.com/read/27827996/the-bromodomain-and-extra-terminal-domain-bet-family-functional-anatomy-of-bet-paralogous-proteins
#1
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/27815670/novel-rice-mutants-overexpressing-the-brassinosteroid-catabolic-gene-cyp734a4
#2
Wenjing Qian, Chao Wu, Yaping Fu, Guocheng Hu, Zhengquan He, Wenzhen Liu
Moderate overexpression of CYP734A4 improves grain number per main panicle and seed setting rate. Brassinosteroid (BR) homeostasis and signaling are crucial for plant growth and development. CYP734A genes encode cytochrome P450 monooxygenases that control the level of bioactive BRs by degrading BRs. However, fertile plants overexpressing CYP734As have not been reported in rice. Here, we isolated a novel semi-dominant mutant brd3-D, in which T-DNA was inserted approximately 4 kb upstream of the CYP734A4 gene (GenBank Accession AB488667), causing its overexpression...
November 4, 2016: Plant Molecular Biology
https://www.readbyqxmd.com/read/27783056/metabolic-response-to-xd14-treatment-in-human-breast-cancer-cell-line-mcf-7
#3
Daqiang Pan, Michel Kather, Lucas Willmann, Manuel Schlimpert, Christoph Bauer, Simon Lagies, Karin Schmidtkunz, Steffen U Eisenhardt, Manfred Jung, Stefan Günther, Bernd Kammerer
XD14 is a 4-acyl pyrrole derivative, which was discovered by a high-throughput virtual screening experiment. XD14 inhibits bromodomain and extra-terminal domain (BET) proteins (BRD2, BRD3, BRD4 and BRDT) and consequently suppresses cell proliferation. In this study, metabolic profiling reveals the molecular effects in the human breast cancer cell line MCF-7 (Michigan Cancer Foundation-7) treated by XD14. A three-day time series experiment with two concentrations of XD14 was performed. Gas chromatography-mass spectrometry (GC-MS) was applied for untargeted profiling of treated and non-treated MCF-7 cells...
October 24, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27769357/clinical-trials-for-bet-inhibitors-run-ahead-of-the-science
#4
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/27769353/erythropoiesis-provides-a-brd-s-eye-view-of-bet-protein-function
#5
REVIEW
Aaron J Stonestrom, Sarah C Hsu, Michael T Werner, Gerd A Blobel
Pharmacologic inhibitors of the bromodomain and extra-terminal motif (BET) protein family are in clinical trials for the treatment of hematologic malignancies, yet the functions of individual BET proteins remain largely uncharacterized. We review the molecular roles of BETs in the context of erythropoiesis. Studies in this lineage have provided valuable insights into their mechanisms of action, and helped define the individual and overlapping functions of BET protein family members BRD2, BRD3, and BRD4. These studies have important ramifications for our understanding of the molecular and physiologic roles of BET proteins, and provide a framework for elucidating some of the beneficial and adverse effects of pharmacologic inhibitors...
March 2016: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/27769352/phospho-brd4-transcription-plasticity-and-drug-targeting
#6
REVIEW
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
https://www.readbyqxmd.com/read/27764794/the-bet-bromodomain-inhibitor-exerts-the-most-potent-synergistic-anticancer-effects-with-quinone-containing-compounds-and-anti-microtubule-drugs
#7
Pei Y Liu, Nicholas Sokolowski, Su T Guo, Faraz Siddiqi, Bernard Atmadibrata, Thomas J Telfer, Yuting Sun, Lihong Zhang, Denise Yu, Joshua Mccarroll, Bing Liu, Rui H Yang, Xiang Y Guo, Andrew E Tee, Ken Itoh, Jenny Wang, Maria Kavallaris, Michelle Haber, Murray D Norris, Belamy B Cheung, Jennifer A Byrne, David S Ziegler, Glenn M Marshall, Marcel E Dinger, Rachel Codd, Xu D Zhang, Tao Liu
BET bromodomain inhibitors are very promising novel anticancer agents, however, single therapy does not cause tumor regression in mice, suggesting the need for combination therapy. After screening a library of 2697 small molecule compounds, we found that two classes of compounds, the quinone-containing compounds such as nanaomycin and anti-microtubule drugs such as vincristine, exerted the best synergistic anticancer effects with the BET bromodomain inhibitor JQ1 in neuroblastoma cells. Mechanistically, the quinone-containing compound nanaomycin induced neuroblastoma cell death but also activated the Nrf2-antioxidant signaling pathway, and the BET bromodomain proteins BRD3 and BRD4 formed a protein complex with Nrf2...
October 13, 2016: Oncotarget
https://www.readbyqxmd.com/read/27667451/-brd3-promotes-il-6-production-via-enhancing-acetylase-cbp-recruitment-and-histone-3-acetylation-within-il6-promoter
#8
Wenhui Ren, Donghao Sun, Chunmei Wang, Nan Li
Objective To investigate the role of bromodomain containing 3 (Brd3) in LPS-triggered interleukin-6 (IL-6) production in macrophages and the underlying mechanism. Methods CRISPR-Cas9 technology was used to screen an RAW264.7 cell line with Brd3 knockout (Brd3(-/-)). The Brd3(-/-) cells were used as an experimental group, and the parential cells expressing wide-type Brd3 as a control group. The IL-6 level in cell culture supernatant was detected by ELISA after 100 ng/mL LPS challenging. Effect of Brd3 knockout on the expression and activation of signal pathways involved in IL-6 expression, including the NF-κB and mitogen-activated protein kinase (MAPK) pathways were examined by Western blot analysis...
October 2016: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/27651315/brd4-regulates-breast-cancer-dissemination-through-jagged1-notch1-signaling
#9
Guillaume Andrieu, Anna H Tran, Katherine J Strissel, Gerald V Denis
The bromodomain and extraterminal (BET) proteins are epigenetic "readers" of acetylated histones in chromatin and have been identified as promising therapeutic targets in diverse cancers. However, it remains unclear how individual family members participate in cancer progression and small molecule inhibitors such as JQ1 can target functionally independent BET proteins. Here, we report a signaling pathway involving BRD4 and the ligand/receptor pair Jagged1/Notch1 that sustains triple-negative breast cancer migration and invasion...
September 20, 2016: Cancer Research
https://www.readbyqxmd.com/read/27591477/bet-bromodomain-inhibition-promotes-neurogenesis-while-inhibiting-gliogenesis-in-neural-progenitor-cells
#10
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/27451123/small-molecule-targeting-of-bet-proteins-in-cancer
#11
C A French
BET proteins have recently become recognized for their role in a broad range of cancers and are defined by the presence of two acetyl-histone reading bromodomains and an ET domain. This family of proteins includes BRD2, BRD3, BRD4, and BRDT. BRD4 is the most-studied BET protein in cancer, and normally serves as an epigenetic reader that links active chromatin marks to transcriptional elongation through activation of RNA polymerase II. The role of BRD3 and BRD4 first became known in cancer as mutant oncoproteins fused to the p300-recruiting NUT protein in a rare aggressive subtype of squamous cell cancer known as NUT midline carcinoma (NMC)...
2016: Advances in Cancer Research
https://www.readbyqxmd.com/read/27169995/regulation-of-gli-underlies-a-role-for-bet-bromodomains-in-pancreatic-cancer-growth-and-the-tumor-microenvironment
#12
Yinshi Huang, Sabikun Nahar, Akifumi Nakagawa, Maite G Fernandez-Barrena, Jennifer A Mertz, Barbara M Bryant, Curtis E Adams, Mari Mino-Kenudson, Kate N Von Alt, Kevin Chang, Andrew R Conery, Charlie Hatton, Robert J Sims, Martin E Fernandez-Zapico, Xingpeng Wang, Keith D Lillemoe, Carlos Fernández-Del Castillo, Andrew L Warshaw, Sarah P Thayer, Andrew S Liss
PURPOSE: The initiation, progression, and maintenance of pancreatic ductal adenocarcinoma (PDAC) results from the interplay of genetic and epigenetic events. While the genetic alterations of PDAC have been well characterized, epigenetic pathways regulating PDAC remain, for the most part, elusive. The goal of this study was to identify novel epigenetic regulators contributing to the biology of PDAC. EXPERIMENTAL DESIGN: In vivo pooled shRNA screens targeting 118 epigenetic proteins were performed in two orthotopic PDAC xenograft models...
August 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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
#13
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/27078884/nonselective-inhibition-of-the-epigenetic-transcriptional-regulator-bet-induces-marked-lymphoid-and-hematopoietic-toxicity-in-mice
#14
Dong U Lee, Paula Katavolos, Gopinath Palanisamy, Arna Katewa, Charly Sioson, Janice Corpuz, Jodie Pang, Kevin DeMent, Edna Choo, Nico Ghilardi, Dolores Diaz, Dimitry M Danilenko
Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4 and BRDT) are epigenetic transcriptional regulators required for efficient expression of growth promoting, cell cycle progression and antiapoptotic genes. Through their bromodomain, these proteins bind to acetylated lysine residues of histones and are recruited to transcriptionally active chromatin. Inhibition of the BET-histone interaction provides a tractable therapeutic strategy to treat diseases that may have epigenetic dysregulation. JQ1 is a small molecule that blocks BET interaction with histones...
June 1, 2016: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/27063978/bromodomain-inhibitor-otx015-in-patients-with-lymphoma-or-multiple-myeloma-a-dose-escalation-open-label-pharmacokinetic-phase-1-study
#15
Sandy Amorim, Anastasios Stathis, Mary Gleeson, Sunil Iyengar, Valeria Magarotto, Xavier Leleu, Franck Morschhauser, Lionel Karlin, Florence Broussais, Keyvan Rezai, Patrice Herait, Carmen Kahatt, François Lokiec, Gilles Salles, Thierry Facon, Antonio Palumbo, David Cunningham, Emanuele Zucca, Catherine Thieblemont
BACKGROUND: The first-in-class small molecule inhibitor OTX015 (MK-8628) specifically binds to bromodomain motifs BRD2, BRD3, and BRD4 of bromodomain and extraterminal (BET) proteins, inhibiting them from binding to acetylated histones, which occurs preferentially at super-enhancer regions that control oncogene expression. OTX015 is active in haematological preclinical entities including leukaemia, lymphoma, and myeloma. We aimed to establish the recommended dose of OTX015 in patients with haematological malignancies...
April 2016: Lancet Haematology
https://www.readbyqxmd.com/read/27063977/bromodomain-inhibitor-otx015-in-patients-with-acute-leukaemia-a-dose-escalation-phase-1-study
#16
Céline Berthon, Emmanuel Raffoux, Xavier Thomas, Norbert Vey, Carlos Gomez-Roca, Karen Yee, David Christopher Taussig, Keyvan Rezai, Christophe Roumier, Patrice Herait, Carmen Kahatt, Bruno Quesnel, Mauricette Michallet, Christian Recher, François Lokiec, Claude Preudhomme, Hervé Dombret
BACKGROUND: Bromodomain and extraterminal (BET) proteins are chromatin readers that preferentially affect the transcription of genes with super-enhancers, including oncogenes. BET proteins bind acetylated histone tails via their bromodomain, bringing the elongation complex to the promoter region. OTX015 (MK-8628) specifically binds to BRD2, BRD3, and BRD4, preventing BET proteins from binding to the chromatin, thus inhibiting gene transcription. OTX015 inhibits proliferation in many haematological malignancy cell lines and patient cells, in vitro and in vivo...
April 2016: Lancet Haematology
https://www.readbyqxmd.com/read/27008626/bet-bromodomain-proteins-brd2-brd3-and-brd4-selectively-regulate-metabolic-pathways-in-the-pancreatic-%C3%AE-cell
#17
Jude T Deeney, Anna C Belkina, Orian S Shirihai, Barbara E Corkey, Gerald V Denis
Displacement of Bromodomain and Extra-Terminal (BET) proteins from chromatin has promise for cancer and inflammatory disease treatments, but roles of BET proteins in metabolic disease remain unexplored. Small molecule BET inhibitors, such as JQ1, block BET protein binding to acetylated lysines, but lack selectivity within the BET family (Brd2, Brd3, Brd4, Brdt), making it difficult to disentangle contributions of each family member to transcriptional and cellular outcomes. Here, we demonstrate multiple improvements in pancreatic β-cells upon BET inhibition with JQ1 or BET-specific siRNAs...
2016: PloS One
https://www.readbyqxmd.com/read/26947130/the-acetyllysine-reader-brd3r-promotes-human-nuclear-reprogramming-and-regulates-mitosis
#18
Zhicheng Shao, Ruowen Zhang, Alireza Khodadadi-Jamayran, Bo Chen, Michael R Crowley, Muhamad A Festok, David K Crossman, Tim M Townes, Kejin Hu
It is well known that both recipient cells and donor nuclei demonstrate a mitotic advantage as observed in the traditional reprogramming with somatic cell nuclear transfer (SCNT). However, it is not known whether a specific mitotic factor plays a critical role in reprogramming. Here we identify an isoform of human bromodomain-containing 3 (BRD3), BRD3R (BRD3 with Reprogramming activity), as a reprogramming factor. BRD3R positively regulates mitosis during reprogramming, upregulates a large set of mitotic genes at early stages of reprogramming, and associates with mitotic chromatin...
2016: Nature Communications
https://www.readbyqxmd.com/read/26733615/the-bromodomain-inhibitor-jq1-and-the-histone-deacetylase-inhibitor-panobinostat-synergistically-reduce-n-myc-expression-and-induce-anticancer-effects
#19
Jeyran Shahbazi, Pei Y Liu, Bernard Atmadibrata, James E Bradner, Glenn M Marshall, Richard B Lock, Tao Liu
PURPOSE: Patients with neuroblastoma associated with MYCN oncogene amplification experience a very poor prognosis. BET bromodomain inhibitors are among the most promising novel anticancer agents as they block BRD3 and BRD4 from activating oncogene transcription. However, treatment with BET bromodomain inhibitors alone does not result in cancer remission in many murine models. EXPERIMENTAL DESIGN: MYCN-amplified neuroblastoma cells were treated with vehicle control, the BET bromodomain inhibitor JQ1, the histone deacetylase inhibitor panobinostat, or the combination of JQ1 and panobinostat...
May 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/26668635/bet-protein-inhibition-mitigates-acute-myocardial-infarction-damage-in-rats-via-the-tlr4-traf6-nf-%C3%AE%C2%BAb-pathway
#20
Yangli Sun, Jie Huang, Kunpeng Song
Acute myocardial infarction (AMI) is among the most serious cardiovascular diseases and is a leading cause of mortality in developed countries. Previous studies have indicated the central role played by the bromodomain (BRD) proteins, which belong to the BRD and extra-terminal (BET) family, in gene control during heart failure pathogenesis. In addition, BET inhibition has been shown to suppress cardiomyocyte hypertrophy. However, the role of BET proteins in myocardial infarction remains unclear. The present study aimed to investigate whether BETs inhibition mitigates AMI, and explore the molecular mechanism underlying this effect...
December 2015: Experimental and Therapeutic Medicine
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