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https://www.readbyqxmd.com/read/29149060/epigenetic-regulation-of-viral-biological-processes
#1
REVIEW
Lata Balakrishnan, Barry Milavetz
It is increasingly clear that DNA viruses exploit cellular epigenetic processes to control their life cycles during infection. This review will address epigenetic regulation in members of the polyomaviruses, adenoviruses, human papillomaviruses, hepatitis B, and herpes viruses. For each type of virus, what is known about the roles of DNA methylation, histone modifications, nucleosome positioning, and regulatory RNA in epigenetic regulation of the virus infection will be discussed. The mechanisms used by certain viruses to dysregulate the host cell through manipulation of epigenetic processes and the role of cellular cofactors such as BRD4 that are known to be involved in epigenetic regulation of host cell pathways will also be covered...
November 17, 2017: Viruses
https://www.readbyqxmd.com/read/29139214/a-theoretical-insight-into-selectivity-of-inhibitors-toward-two-domains-of-bromodomain-containing-protein-4-using-molecular-dynamics-simulations
#2
Jing Su, Xinguo Liu, Shaolong Zhang, Fangfang Yan, Qinggang Zhang, Jianzhong Chen
Bromodomains (BRDs) have been an attractive candidate for development of efficient inhibitors toward gene transcription. Molecular dynamics (MD) simulations followed by principal component (PC) analysis were performed to investigate binding selectivity of inhibitors RVX297, BSP, JQ1, SF2523 and CPD2 toward two domains (BD1 and BD2) of bromodomain-containing protein 4 (BRD4). The results show that inhibitor bindings exert different effect on motions of the BC-loops in BD1 and BD2. The rank of binding free energies calculated by using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method agrees with the one determined by experiment...
November 15, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29133261/dual-inhibition-of-brd4-and-pi3k-by-sf2523-suppresses-human-prostate-cancer-cell-growth-in-vitro-and-in-vivo
#3
Gang Shen, Minjun Jiang, Jinxian Pu
Bromodomain-containing protein 4 (BRD4) and phosphatidylinositol 3-kinase (PI3K) are both key oncogenic proteins in human prostate cancer. In the current study, we examined the anti-prostate cancer cell activity by SF2523, a BRD4 and PI3K dual inhibitor. We showed that SF2523 potently inhibited survival and proliferation of the primary human prostate cancer cells. SF2523 induced profound apoptosis activation in prostate cancer cells. The dual inhibitor was yet non-cytotoxic to the prostate epithelial cells...
November 10, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29121538/therapeutic-options-for-leukemic-transformation-in-patients-with-myeloproliferative-neoplasms
#4
REVIEW
Maliha Khan, Rabbia Siddiqi, Naseema Gangat
Approximately 5-10% of patients with Philadelphia chromosome negative myeloproliferative neoplasms (MPN) comprising of essential thrombocythemia, polycythemia vera and primary myelofibrosis) experience transformation to acute myeloid leukemia (AML, ≥20% blasts). Treatment options for post-MPN AML patients are limited, as conventional approaches like standard chemotherapy, fail to offer long-term benefit. Median survival for secondary AML is ∼2.4 months. Post-MPN AML therefore represents an area of urgent clinical need...
October 27, 2017: Leukemia Research
https://www.readbyqxmd.com/read/29113963/gain-of-function-of-asxl1-truncating-protein-in-the-pathogenesis-of-myeloid-malignancies
#5
Hui Yang, Stefan Kurtenbach, Ying Guo, Ines Lohse, Michael A Durante, Jianping Li, Zhaomin Li, Hassan Al-Ali, Lingxiao Li, Zizhen Chen, Matthew G Field, Peng Zhang, Shi Chen, Shohei Yamamoto, Zhuo Li, Yuan Zhou, Stephen D Nimer, J William Harbour, Claes Wahlestedt, Mingjiang Xu, Feng-Chun Yang
Additional Sex Combs-Like 1 (ASXL1) is mutated at a high frequency in all forms of myeloid malignancies associated with poor prognosis. We generated a Vav1 promoter driven Flag-Asxl1(Y588X) transgenic mouse model, Asxl1(Y588X) Tg, to express a truncated FLAG-ASXL1(aa1-587) protein in the hematopoietic system. The Asxl1(Y588X) Tg mice had an enlarged hematopoietic stem cell (HSC) pool, shortened survival, and predisposition to a spectrum of myeloid malignancies, thereby recapitulating the characteristics of myeloid malignancy patients with ASXL1 mutations...
November 7, 2017: Blood
https://www.readbyqxmd.com/read/29108467/spop-mediated-degradation-of-brd4-dictates-cellular-sensitivity-to-bet-inhibitors
#6
Xiangpeng Dai, Zhiwei Wang, Wenyi Wei
Bromodomain and extra-terminal (BET) proteins are frequently overexpressed in various human cancers, therefore have been clinically pursed as attractive therapeutic anti-cancer targets. However, relatively little is known about the mechanism(s) underlying aberrant BET overexpression in human cancers. Recently, we reported that prostate cancer-derived SPOP mutants fail to interact with and promote BRD4 degradation, leading to accumulation of BRD4 in prostate cancer cells. As a result, prostate cancer cells harboring SPOP mutations are more resistant to BET inhibitors...
November 6, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29103140/synthesis-and-biological-evaluation-of-indazole-4-7-dione-derivatives-as-novel-brd4-inhibitors
#7
Minjin Yoo, Miyoun Yoo, Ji Eun Kim, Heung Kyoung Lee, Chong Ock Lee, Chi Hoon Park, Kwan-Young Jung
Bromodomain-containing protein 4 (BRD4) is known to regulate the expression of c-Myc to control the proliferation of cancer cells. Therefore, development of small-molecule inhibitors targeting the bromodomain has been widely studied. However, some clinical trials on BRD4 inhibitors have shown its drawbacks such as toxicity including the loss of organ weight. Here, we report the development of the novel and promising scaffold, 1H-indazol-4,7-dione, as a bromodomain inhibitor and synthesized derivatives for the inhibition of binding of bromodomain to acetylated histone peptide...
November 4, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/29083896/filling-blank-spots-on-the-map-identification-of-ligand-binding-modes-and-interacting-water-molecules-for-brd4-bd1-by-waterlogsy-titrations
#8
Ann-Christin Pöppler
Fragment-based drug discovery and continuous improvement of existing protein inhibitors rely on the knowledge of exactly how and how strongly a range of small molecules bind to their respective protein targets. By increasing the (perdeuterated) protein concentration, WaterLOGSY titration experiments give access to ligand binding modes even in the case of weak binders as well as to the location of protein-bound water in the surroundings of the ligand. On the basis of these findings, specific chemical modifications of the ligand could be shown to yield significantly enhanced binding affinities...
October 30, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29082752/chemical-constituents-of-the-fermentative-extracts-of-marine-fungi-phoma-sp-czd-f11-and-aspergillus-sp-czd-f18-from-zhoushan-archipelago-china
#9
Xiaomei Wu, Zhe Chen, Wanjing Ding, Yu Liu, Zhongjun Ma
A new diphenyl ether (1) as well as 20 other compounds were identified from the fermentative extracts of marine-derived fungi Phoma sp. CZD-F11 (Compounds 1-8) and Aspergillus sp. CZD-F18(Compounds 9-21). Their structures were elucidated on the basis of extensive spectroscopic analysis. The broth extracts of the fungi exhibited very good anticancer activity against H1975 cells with 5.62 and 25.8% viability at concentration of 10 μg/mL for Phoma sp. CZD-F11 and Aspergillus sp. CZD-F18, respectively. The inhibitory activity of all compounds against PC-3 cell lines, BRD4 and aromatase were evaluated...
October 29, 2017: Natural Product Research
https://www.readbyqxmd.com/read/29082287/flow-cytometric-analysis-of-hiv-1-transcriptional-activity-in-response-to-shrna-knockdown-in-a2-and-a72-j-lat-cell-lines
#10
Daniela Boehm, Melanie Ott
The main obstacle to eradicating HIV-1 from patients is post-integration latency (Finzi et al., 1999). Antiretroviral treatments target only actively replicating virus, while latent infections that have low or no transcriptional activity remain untreated (Sedaghat et al., 2007). To eliminate viral reservoirs, one strategy focuses on reversing HIV-1 latency via 'shock and kill' (Deeks, 2012). The basis of this strategy is to overcome the molecular mechanisms of HIV-1 latency by therapeutically inducing viral gene and protein expression under antiretroviral therapy and to cause selective cell death via the lytic properties of the virus, or the immune system now recognizing the infected cells...
June 5, 2017: Bio-protocol
https://www.readbyqxmd.com/read/29079177/sinonasal-nut-carcinoma-clinicopathological-and-cytogenetic-analysis-with-autopsy-findings
#11
Hiroshi Minato, Eriko Kobayashi, Satoko Nakada, Nozomu Kurose, Mio Tanaka, Yukichi Tanaka, Shioto Suzuki, Fumihiko Tanioka, Yutaka Saikawa, Takaki Miwa, Takayuki Nojima
Nuclear protein in testis (NUT) carcinoma is a rare malignant neoplasm with an undifferentiated morphology. Its diagnosis is often difficult, especially as the sinonasal tract gives rise to many tumors with undifferentiated morphologies. Not many cases of sinonasal NUT carcinomas have been reported, and its clinicopathological features have not been sufficiently clarified. In this study, we performed a clinicopathological study of 4 patients with sinonasal NUT carcinoma, including wide-ranging immunohistochemical tests and cytogenetic analyses using fluorescence in situ hybridization and DNA sequencing...
October 24, 2017: Human Pathology
https://www.readbyqxmd.com/read/29077030/dietary-compound-resveratrol-is-a-pan-bet-bromodomain-inhibitor
#12
Luiz Antonio Dutra, David Heidenreich, Gabriel Dalio Bernardes da Silva, Chung Man Chin, Stefan Knapp, Jean Leandro Dos Santos
The chemopreventive and anticancer effects of resveratrol (RSV) are widely reported in the literature. Specifically, mechanisms involving epigenetic regulation are promising targets to regulate tumor development. Bromodomains act as epigenetic readers by recognizing lysine acetylation on histone tails and boosting gene expression in order to regulate tissue-specific transcription. In this work, we showed that RSV is a pan-BET inhibitor. Using Differential Scanning Fluorimetry (DSF), we showed that RSV at 100 µM increased the melting temperature (∆Tm) of BET bromodomains by around 2...
October 27, 2017: Nutrients
https://www.readbyqxmd.com/read/29075615/pharmacologic-targeting-of-chromatin-modulators-as-therapeutics-of-acute-myeloid-leukemia
#13
REVIEW
Rui Lu, Gang Greg Wang
Acute myeloid leukemia (AML), a common hematological cancer of myeloid lineage cells, generally exhibits poor prognosis in the clinic and demands new treatment options. Recently, direct sequencing of samples from human AMLs and pre-leukemic diseases has unveiled their mutational landscapes and significantly advanced the molecular understanding of AML pathogenesis. The newly identified recurrent mutations frequently "hit" genes encoding epigenetic modulators, a wide range of chromatin-modifying enzymes and regulatory factors involved in gene expression regulation, supporting aberration of chromatin structure and epigenetic modification as a main oncogenic mechanism and cancer-initiating event...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/29070704/bivalent-complexes-of-prc1-with-orthologs-of-brd4-and-moz-morf-target-developmental-genes-in-drosophila
#14
Hyuckjoon Kang, Youngsook L Jung, Kyle A McElroy, Barry M Zee, Heather A Wallace, Jessica L Woolnough, Peter J Park, Mitzi I Kuroda
Regulatory decisions in Drosophila require Polycomb group (PcG) proteins to maintain the silent state and Trithorax group (TrxG) proteins to oppose silencing. Since PcG and TrxG are ubiquitous and lack apparent sequence specificity, a long-standing model is that targeting occurs via protein interactions; for instance, between repressors and PcG proteins. Instead, we found that Pc-repressive complex 1 (PRC1) purifies with coactivators Fs(1)h [female sterile (1) homeotic] and Enok/Br140 during embryogenesis. Fs(1)h is a TrxG member and the ortholog of BRD4, a bromodomain protein that binds to acetylated histones and is a key transcriptional coactivator in mammals...
October 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/29050985/bromodomain-protein-brd4-promotes-cell-proliferation-in-skin-squamous-cell-carcinoma
#15
Tie Xiang, Jin-Yu Bai, Chang She, Dao-Jiang Yu, Xiao-Zhong Zhou, Tian-Lan Zhao
The present study examined the expression and biological functions of bromodomain-containing protein 4 (BRD4) in skin squamous cell carcinoma (SCC) cells. Our results show that BRD4 mRNA and protein expression was upregulated in human skin SCC cells, as compared to its level in the normal skin keratinocytes and fibroblasts. Treatment with BRD4 inhibitors, JQ1 and CPI203, resulted in proliferation inhibition, apoptosis and cell cycle arrest in both established (A431 cell line) and primary skin SCC cells. Furthermore, BRD4 knockdown (by targeted shRNAs) or knockout (by CRISPR/Cas9) largely inhibited A431 cell proliferation...
October 16, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/29048129/realgar-nanoparticles-versus-ato-arsenic-compounds-induce-in%C3%A2-vitro-and-in%C3%A2-vivo-activity-against-multiple-myeloma
#16
Danka Cholujova, Zdenka Bujnakova, Erika Dutkova, Teru Hideshima, Richard W Groen, Constantine S Mitsiades, Paul G Richardson, David M Dorfman, Peter Balaz, Kenneth C Anderson, Jana Jakubikova
Multiple myeloma (MM), a B cell malignancy characterized by clonal proliferation of plasma cells in the bone marrow, remains incurable despite the use of novel and conventional therapies. In this study, we demonstrated MM cell cytotoxicity triggered by realgar (REA; As4 S4 ) nanoparticles (NREA) versus Arsenic trioxide (ATO) against MM cell lines and patient cells. Both NREA and ATO showed in vivo anti-MM activity, resulting in significantly decreased tumour burden. The anti-MM activity of NREA and ATO is associated with apoptosis, evidenced by DNA fragmentation, depletion of mitochondrial membrane potential, cleavage of caspases and anti-apoptotic proteins...
October 19, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28991225/super-enhancers-define-a-proliferative-pgc-1%C3%AE-expressing-melanoma-subgroup-sensitive-to-bet-inhibition
#17
K A Gelato, L Schöckel, O Klingbeil, T Rückert, R Lesche, J Toedling, E Kalfon, M Héroult, P Lejeune, U Mönning, A E Fernández-Montalván, S Bäurle, S Siegel, B Haendler
Metabolic changes are linked to epigenetic reprogramming and play important roles in several tumor types. PGC-1α is a transcriptional coactivator controlling mitochondrial biogenesis and is linked to oxidative phosphorylation. We provide evidence that melanoma models with elevated PGC-1α levels are characteristic of the proliferative phenotype and are sensitive to bromodomain and extra-terminal domain (BET) inhibitor treatment. A super-enhancer region highly occupied by the BET family member BRD4 was identified for the PGC-1α gene...
October 9, 2017: Oncogene
https://www.readbyqxmd.com/read/28986391/altered-hydroxymethylation-is-seen-at-regulatory-regions-in-pancreatic-cancer-and-regulates-oncogenic-pathways
#18
Sanchari Bhattacharyya, Kith Pradhan, Nathaniel Campbell, Jozef Mazdo, Aparna Vasantkumar, Shahina Maqbool, Tushar D Bhagat, Sonal Gupta, Masako Suzuki, Yiting Yu, John M Greally, Ulrich Steidl, James Bradner, Meelad Dawlaty, Lucy Godley, Anirban Maitra, Amit Verma
Transcriptional deregulation of oncogenic pathways is a hallmark of cancer and can be due to epigenetic alterations. 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification that has not been studied in pancreatic cancer. Genome-wide analysis of 5-hmC-enriched loci with hmC-seal was conducted in a cohort of low-passage pancreatic cancer cell lines, primary patient-derived xenografts, and pancreatic controls and revealed strikingly altered patterns in neoplastic tissues. Differentially hydroxymethylated regions preferentially affected known regulatory regions of the genome, specifically overlapping with known H3K4me1 enhancers...
November 2017: Genome Research
https://www.readbyqxmd.com/read/28983974/molecular-design-of-stat3-derived-peptide-selectivity-between-bet-proteins-brd2-and-brd4-in-ovarian-cancer
#19
Lixia Zhu, Xi Ding
Stat3 signaling has been recognized as a potential therapeutic target of human ovarian cancer. The signaling is transducted through the peptide-medicated interaction of Stat3 with BET family members Brd2 and Brd4 -- 2 highly homologous proteins involved in differential downstream pathways. Here, we reported a successful design of peptide selectivity between the Brd2 and Brd4. The design resulted in 3 linear peptides SMSLQCXYLGVA, QSKVLTXSYWGA, and RQCNLGXLYMNY with high or moderate selectivity for Brd2 over Brd4 (S = 3...
October 6, 2017: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/28981843/runx2-expression-in-thyroid-and-breast-cancer-requires-the-cooperation-of-three-non-redundant-enhancers-under-the-control-of-brd4-and-c-jun
#20
Valentina Sancisi, Gloria Manzotti, Mila Gugnoni, Teresa Rossi, Greta Gandolfi, Giulia Gobbi, Federica Torricelli, Francesca Catellani, Italo Faria do Valle, Daniel Remondini, Gastone Castellani, Moira Ragazzi, Simonetta Piana, Alessia Ciarrocchi
Aberrant reactivation of embryonic pathways is a common feature of cancer. RUNX2 is a transcription factor crucial during embryogenesis that is aberrantly reactivated in many tumors, including thyroid and breast cancer, where it promotes aggressiveness and metastatic spreading. Currently, the mechanisms driving RUNX2 expression in cancer are still largely unknown. Here we showed that RUNX2 transcription in thyroid and breast cancer requires the cooperation of three distantly located enhancers (ENHs) brought together by chromatin three-dimensional looping...
September 7, 2017: Nucleic Acids Research
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