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https://www.readbyqxmd.com/read/28821780/selective-inhibition-mechanism-of-rvx-208-to-the-second-bromodomain-of-bromo-and-extraterminal-proteins-insight-from-microsecond-molecular-dynamics-simulations
#1
Qianqian Wang, Ying Li, Jiahui Xu, Yuwei Wang, Elaine Lai-Han Leung, Liang Liu, Xiaojun Yao
RVX-208 is a recently reported inhibitor of bromo and extraterminal (BET) family proteins (including BRD2-4 and BRDT) with selectivity for the second bromodomain (BD2), currently in phase III clinical trials. Despite of its promising antitumor activity, due to the conserved folds of the first and second bromodomains (BD1 and BD2), the detailed selectivity mechanism of RVX-208 towards BD2 over BD1 is still unknown. To elucidate selective inhibition mechanism of RVX-208 to BD2, microsecond molecular dynamics simulations were performed in this study for BRD2-BD1, BRD2-BD2 and BRD4-BD1 with and without RVX-208, respectively...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28805822/intrinsic-bet-inhibitor-resistance-in-spop-mutated-prostate-cancer-is-mediated-by-bet-protein-stabilization-and-akt-mtorc1-activation
#2
Pingzhao Zhang, Dejie Wang, Yu Zhao, Shancheng Ren, Kun Gao, Zhenqing Ye, Shangqian Wang, Chun-Wu Pan, Yasheng Zhu, Yuqian Yan, Yinhui Yang, Di Wu, Yundong He, Jun Zhang, Daru Lu, Xiuping Liu, Long Yu, Shimin Zhao, Yao Li, Dong Lin, Yuzhuo Wang, Liguo Wang, Yu Chen, Yinghao Sun, Chenji Wang, Haojie Huang
Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising anticancer therapies. The gene encoding the E3 ubiquitin ligase substrate-binding adaptor speckle-type POZ protein (SPOP) is the most frequently mutated in primary prostate cancer. Here we demonstrate that wild-type SPOP binds to and induces ubiquitination and proteasomal degradation of BET proteins (BRD2, BRD3 and BRD4) by recognizing a degron motif common among them. In contrast, prostate cancer-associated SPOP mutants show impaired binding to BET proteins, resulting in decreased proteasomal degradation and accumulation of these proteins in prostate cancer cell lines and patient specimens and causing resistance to BET inhibitors...
August 14, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28805821/opposing-effects-of-cancer-type-specific-spop-mutants-on-bet-protein-degradation-and-sensitivity-to-bet-inhibitors
#3
Hana Janouskova, Geniver El Tekle, Elisa Bellini, Namrata D Udeshi, Anna Rinaldi, Anna Ulbricht, Tiziano Bernasocchi, Gianluca Civenni, Marco Losa, Tanya Svinkina, Craig M Bielski, Gregory V Kryukov, Luciano Cascione, Sara Napoli, Radoslav I Enchev, David G Mutch, Michael E Carney, Andrew Berchuck, Boris J N Winterhoff, Russell R Broaddus, Peter Schraml, Holger Moch, Francesco Bertoni, Carlo V Catapano, Matthias Peter, Steven A Carr, Levi A Garraway, Peter J Wild, Jean-Philippe P Theurillat
It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants...
August 14, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28805820/prostate-cancer-associated-spop-mutations-confer-resistance-to-bet-inhibitors-through-stabilization-of-brd4
#4
Xiangpeng Dai, Wenjian Gan, Xiaoning Li, Shangqian Wang, Wei Zhang, Ling Huang, Shengwu Liu, Qing Zhong, Jianping Guo, Jinfang Zhang, Ting Chen, Kouhei Shimizu, Francisco Beca, Mirjam Blattner, Divya Vasudevan, Dennis L Buckley, Jun Qi, Lorenz Buser, Pengda Liu, Hiroyuki Inuzuka, Andrew H Beck, Liewei Wang, Peter J Wild, Levi A Garraway, Mark A Rubin, Christopher E Barbieri, Kwok-Kin Wong, Senthil K Muthuswamy, Jiaoti Huang, Yu Chen, James E Bradner, Wenyi Wei
The bromodomain and extraterminal (BET) family of proteins comprises four members-BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer...
August 14, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28737745/electromagnetized-gold-nanoparticles-mediate-direct-lineage-reprogramming-into-induced-dopamine-neurons-in-vivo-for-parkinson-s-disease-therapy
#5
Junsang Yoo, Euiyeon Lee, Hee Young Kim, Dong-Ho Youn, Junghyun Jung, Hongwon Kim, Yujung Chang, Wonwoong Lee, Jaein Shin, Soonbong Baek, Wonhee Jang, Won Jun, Soochan Kim, Jongki Hong, Hi-Joon Park, Christopher J Lengner, Sang Hyun Moh, Youngeun Kwon, Jongpil Kim
Electromagnetic fields (EMF) are physical energy fields generated by electrically charged objects, and specific ranges of EMF can influence numerous biological processes, which include the control of cell fate and plasticity. In this study, we show that electromagnetized gold nanoparticles (AuNPs) in the presence of specific EMF conditions facilitate an efficient direct lineage reprogramming to induced dopamine neurons in vitro and in vivo. Remarkably, electromagnetic stimulation leads to a specific activation of the histone acetyltransferase Brd2, which results in histone H3K27 acetylation and a robust activation of neuron-specific genes...
July 17, 2017: Nature Nanotechnology
https://www.readbyqxmd.com/read/28733670/brd3-and-brd4-bet-bromodomain-proteins-differentially-regulate-skeletal-myogenesis
#6
Thomas C Roberts, Usue Etxaniz, Alessandra Dall'Agnese, Shwu-Yuan Wu, Cheng-Ming Chiang, Paul E Brennan, Matthew J A Wood, Pier Lorenzo Puri
Myogenic differentiation proceeds through a highly coordinated cascade of gene activation that necessitates epigenomic changes in chromatin structure. Using a screen of small molecule epigenetic probes we identified three compounds which inhibited myogenic differentiation in C2C12 myoblasts; (+)-JQ1, PFI-1, and Bromosporine. These molecules target Bromodomain and Extra Terminal domain (BET) proteins, which are epigenetic readers of acetylated histone lysine tail residues. BETi-mediated anti-myogenic effects were also observed in a model of MYOD1-mediated myogenic conversion of human fibroblasts, and in primary mouse and human myoblasts...
July 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28710461/bromodomain-factors-of-bet-family-are-new-essential-actors-of-pericentric-heterochromatin-transcriptional-activation-in-response-to-heat-shock
#7
Edwige Col, Neda Hoghoughi, Solenne Dufour, Jessica Penin, Sivan Koskas, Virginie Faure, Maria Ouzounova, Hector Hernandez-Vargash, Nicolas Reynoird, Sylvain Daujat, Eric Folco, Marc Vigneron, Robert Schneider, André Verdel, Saadi Khochbin, Zdenko Herceg, Cécile Caron, Claire Vourc'h
The heat shock response is characterized by the transcriptional activation of both hsp genes and noncoding and repeated satellite III DNA sequences located at pericentric heterochromatin. Both events are under the control of Heat Shock Factor I (HSF1). Here we show that under heat shock, HSF1 recruits major cellular acetyltransferases, GCN5, TIP60 and p300 to pericentric heterochromatin leading to a targeted hyperacetylation of pericentric chromatin. Redistribution of histone acetylation toward pericentric region in turn directs the recruitment of Bromodomain and Extra-Terminal (BET) proteins BRD2, BRD3, BRD4, which are required for satellite III transcription by RNAP II...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28696179/insights-into-the-crystal-structure-of-brd2-bd2-phenanthridinone-complex-and-theoretical-studies-on-phenanthridinone-analogs
#8
Shruti Mathur, Prashant Deshmukh, Shailesh Tripathi, Palaniappan Marimuthu, Balasundaram Padmanbhan
BET (Bromodomain and Extra-terminal) family proteins recognize the acetylated histone code on chromatin and participate in downstream processes like DNA replication, modification, and repair. As part of epigenetic approaches, BRD2 and BRD4 were identified as putative targets, for the management of chronic diseases. We have recently reported the discovery of a new scaffold of the phenanthridinone based inhibitor (L10) of the second bromodomain of BRD2 (BRD2-BD2). Here, we present the crystal structure of the BRD2-BD2, refined to 1...
July 11, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28636645/genetic-susceptibility-in-juvenile-myoclonic-epilepsy-systematic-review-of-genetic-association-studies
#9
Bruna Priscila Dos Santos, Chiara Rachel Maciel Marinho, Thalita Ewellyn Batista Sales Marques, Layanne Kelly Gomes Angelo, Maísa Vieira da Silva Malta, Marcelo Duzzioni, Olagide Wagner de Castro, João Pereira Leite, Fabiano Timbó Barbosa, Daniel Leite Góes Gitaí
BACKGROUND: Several genetic association investigations have been performed over the last three decades to identify variants underlying Juvenile Myoclonic Epilepsy (JME). Here, we evaluate the accumulating findings and provide an updated perspective of these studies. METHODOLOGY: A systematic literature search was conducted using the PubMed, Embase, Scopus, Lilacs, epiGAD, Google Scholar and Sigle up to February 12, 2016. The quality of the included studies was assessed by a score and classified as low and high quality...
2017: PloS One
https://www.readbyqxmd.com/read/28591577/androgen-receptor-deregulation-drives-bromodomain-mediated-chromatin-alterations-in-prostate-cancer
#10
Alfonso Urbanucci, Stefan J Barfeld, Ville Kytölä, Harri M Itkonen, Ilsa M Coleman, Daniel Vodák, Liisa Sjöblom, Xia Sheng, Teemu Tolonen, Sarah Minner, Christoph Burdelski, Kati K Kivinummi, Annika Kohvakka, Steven Kregel, Mandeep Takhar, Mohammed Alshalalfa, Elai Davicioni, Nicholas Erho, Paul Lloyd, R Jeffrey Karnes, Ashley E Ross, Edward M Schaeffer, Donald J Vander Griend, Stefan Knapp, Eva Corey, Felix Y Feng, Peter S Nelson, Fahri Saatcioglu, Karen E Knudsen, Teuvo L J Tammela, Guido Sauter, Thorsten Schlomm, Matti Nykter, Tapio Visakorpi, Ian G Mills
Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect...
June 6, 2017: Cell Reports
https://www.readbyqxmd.com/read/28588073/brd4-brd2-isoform-switching-coordinates-pluripotent-exit-and-smad2-dependent-lineage-specification
#11
Rosalia Fernandez-Alonso, Lindsay Davidson, Jens Hukelmann, Michael Zengerle, Alan R Prescott, Angus Lamond, Alessio Ciulli, Gopal P Sapkota, Greg M Findlay
Pluripotent stem cells (PSCs) hold great clinical potential, as they possess the capacity to differentiate into fully specialised tissues such as pancreas, liver, neurons and cardiac muscle. However, the molecular mechanisms that coordinate pluripotent exit with lineage specification remain poorly understood. To address this question, we perform a small molecule screen to systematically identify novel regulators of the Smad2 signalling network, a key determinant of PSC fate. We reveal an essential function for BET family bromodomain proteins in Smad2 activation, distinct from the role of Brd4 in pluripotency maintenance...
July 2017: EMBO Reports
https://www.readbyqxmd.com/read/28549975/knockdown-of-epigenetic-transcriptional-co-regulator-brd2a-disrupts-apoptosis-and-proper-formation-of-hindbrain-and-midbrain-hindbrain-boundary-mhb-region-in-zebrafish
#12
Tami Murphy, Heather Melville, Eliza Fradkin, Giana Bistany, Gregory Branigan, Kelly Olsen, Catharine R Comstock, Hayley Hanby, Ellie Garbade, Angela J DiBenedetto
Brd2 is a member of the bromodomain-extraterminal domain (BET) family of proteins and functions as an acetyl-histone-directed transcriptional co-regulator and recruitment scaffold in chromatin modification complexes affecting signal-dependent transcription. While Brd2 acts as a protooncogene in mammalian blood, developmental studies link it to regulation of neuronal apoptosis and epilepsy, and complete knockout of the gene is invariably embryonic lethal. In Drosophila, the Brd2 homolog acts as a maternal effect factor necessary for segment formation and identity and proper expression of homeotic loci, including Ultrabithorax and engrailed...
August 2017: Mechanisms of Development
https://www.readbyqxmd.com/read/28490802/transcriptome-analysis-of-dominant-negative-brd4-mutants-identifies-brd4-specific-target-genes-of-small-molecule-inhibitor-jq1
#13
Tim-Michael Decker, Michael Kluge, Stefan Krebs, Nilay Shah, Helmut Blum, Caroline C Friedel, Dirk Eick
The bromodomain protein Brd4 is an epigenetic reader and plays a critical role in the development and maintenance of leukemia. Brd4 binds to acetylated histone tails and activates transcription by recruiting the positive elongation factor P-TEFb. Small molecule inhibitor JQ1 competitively binds the bromodomains of Brd4 and displaces the protein from acetylated histones. However, it remains unclear whether genes targeted by JQ1 are mainly regulated by Brd4 or by other bromodomain proteins such as Brd2 and Brd3...
May 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28388437/the-bet-protein-brd2-cooperates-with-ctcf-to-enforce-transcriptional-and-architectural-boundaries
#14
Sarah C Hsu, Thomas G Gilgenast, Caroline R Bartman, Christopher R Edwards, Aaron J Stonestrom, Peng Huang, Daniel J Emerson, Perry Evans, Michael T Werner, Cheryl A Keller, Belinda Giardine, Ross C Hardison, Arjun Raj, Jennifer E Phillips-Cremins, Gerd A Blobel
Bromodomain and extraterminal motif (BET) proteins are pharmacologic targets for the treatment of diverse diseases, yet the roles of individual BET family members remain unclear. We find that BRD2, but not BRD4, co-localizes with the architectural/insulator protein CCCTC-binding factor (CTCF) genome-wide. CTCF recruits BRD2 to co-bound sites whereas BRD2 is dispensable for CTCF occupancy. Disruption of a CTCF/BRD2-occupied element positioned between two unrelated genes enables regulatory influence to spread from one gene to another, suggesting that CTCF and BRD2 form a transcriptional boundary...
April 6, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28339196/discovery-of-a-small-molecule-degrader-of-bromodomain-and-extra-terminal-bet-proteins-with-picomolar-cellular-potencies-and-capable-of-achieving-tumor-regression
#15
Bing Zhou, Jiantao Hu, Fuming Xu, Zhuo Chen, Longchuan Bai, Ester Fernandez-Salas, Mei Lin, Liu Liu, Chao-Yie Yang, Yujun Zhao, Donna McEachern, Sally Przybranowski, Bo Wen, Duxin Sun, Shaomeng Wang
The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic "readers" and play a key role in the regulation of gene transcription. BET proteins are considered to be attractive therapeutic targets for cancer and other human diseases. Recently, heterobifunctional small-molecule BET degraders have been designed based upon the proteolysis targeting chimera (PROTAC) concept to induce BET protein degradation. Herein, we present our design, synthesis, and evaluation of a new class of PROTAC BET degraders...
March 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28262505/distinct-roles-of-brd2-and-brd4-in-potentiating-the-transcriptional-program-for-th17-cell-differentiation
#16
Ka Lung Cheung, Fan Zhang, Anbalagan Jaganathan, Rajal Sharma, Qiang Zhang, Tsuyoshi Konuma, Tong Shen, June-Yong Lee, Chunyan Ren, Chih-Hung Chen, Geming Lu, Matthew R Olson, Weijia Zhang, Mark H Kaplan, Dan R Littman, Martin J Walsh, Huabao Xiong, Lei Zeng, Ming-Ming Zhou
The BET proteins are major transcriptional regulators and have emerged as new drug targets, but their functional distinction has remained elusive. In this study, we report that the BET family members Brd2 and Brd4 exert distinct genomic functions at genes whose transcription they co-regulate during mouse T helper 17 (Th17) cell differentiation. Brd2 is associated with the chromatin insulator CTCF and the cohesin complex to support cis-regulatory enhancer assembly for gene transcriptional activation. In this context, Brd2 binds the transcription factor Stat3 in an acetylation-sensitive manner and facilitates Stat3 recruitment to active enhancers occupied with transcription factors Irf4 and Batf...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28248992/altered-regulation-and-expression-of-genes-by-bet-family-of-proteins-in-copd-patients
#17
Rajneesh Malhotra, Nisha Kurian, Xiao-Hong Zhou, Fanyi Jiang, Susan Monkley, Amy DeMicco, Ib G Clausen, Göran Delgren, Goran Edenro, Miika J Ahdesmäki, Maryam Clausen, Lisa Öberg, Elisabeth Israelsson, Graham Belfield, Outi Vaarala
BACKGROUND: BET proteins (BRD2, BRD3, BRDT and BRD4) belong to the family of bromodomain containing proteins, which form a class of transcriptional co-regulators. BET proteins bind to acetylated lysine residues in the histones of nucleosomal chromatin and function either as co-activators or co-repressors of gene expression. An imbalance between HAT and HDAC activities resulting in hyperacetylation of histones has been identified in COPD. We hypothesized that pan-BET inhibitor (JQ1) treatment of BET protein interactions with hyperacetylated sites in the chromatin will regulate excessive activation of pro-inflammatory genes in key inflammatory drivers of alveolar macrophages (AM) in COPD...
2017: PloS One
https://www.readbyqxmd.com/read/28211522/structure-and-polymorphisms-of-the-major-histocompatibility-complex-in-the-oriental-stork-ciconia-boyciana
#18
Hiroki Tsuji, Yukio Taniguchi, Shintaro Ishizuka, Hirokazu Matsuda, Takahisa Yamada, Kazuaki Naito, Hiroaki Iwaisaki
The major histocompatibility complex (MHC) is highly polymorphic and plays a central role in the vertebrate immune system. Despite its functional consistency, the MHC genomic structure differs substantially among organisms. In birds, the MHCs of Galliformes and the Japanese crested ibis (Pelecaniformes) are well-characterized, but information about other avian MHCs remains scarce. The Oriental stork (Ciconia boyciana, order Ciconiiformes) is a large endangered migrant. The current Japanese population of this bird originates from a few founders; thus, understanding the genetic diversity among them is critical for effective population management...
February 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28194432/bet-inhibitors-block-pancreatic-stellate-cell-collagen-i-production-and-attenuate-fibrosis-in-vivo
#19
Krishan Kumar, Brian T DeCant, Paul J Grippo, Rosa F Hwang, David J Bentrem, Kazumi Ebine, Hidayatullah G Munshi
The fibrotic reaction, which can account for over 70%-80% of the tumor mass, is a characteristic feature of human pancreatic ductal adenocarcinoma (PDAC) tumors. It is associated with activation and proliferation of pancreatic stellate cells (PSCs), which are key regulators of collagen I production and fibrosis in vivo. In this report, we show that members of the bromodomain and extraterminal (BET) family of proteins are expressed in primary PSCs isolated from human PDAC tumors, with BRD4 positively regulating, and BRD2 and BRD3 negatively regulating, collagen I expression in primary cancer-associated PSCs...
February 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28173625/bet-proteins-an-approach-to-future-therapies-in-transplantation
#20
B Suarez-Alvarez, R M Rodriguez, M Ruiz-Ortega, C Lopez-Larrea
In order to develop new efficient therapies for organ transplantation, it is essential to acquire a comprehensive knowledge of the molecular mechanisms and processes, such as immune activation, chronic inflammation, and fibrosis, which lead to rejection and long-term graft loss. Recent efforts have shed some light on the epigenetic regulation associated with these processes. In this context, the bromo and extraterminal (BET) family of bromodomain proteins (BRD2, BRD3, BRD4, and BRDT) have emerged as major epigenetic players, connecting chromatin structure with gene expression changes...
February 7, 2017: American Journal of Transplantation
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