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  1. Article ; Online: Conditional Human BRD4 Knock-In Transgenic Mouse Genotyping and Protein Isoform Detection.

    Lewis, Michael Paul / Wu, Shwu-Yuan / Chiang, Cheng-Ming

    Bio-protocol

    2022  Volume 12, Issue 7

    Abstract: Bromodomain-containing protein 4 (BRD4) is an acetyl-lysine reader protein and transcriptional regulator implicated in chromatin dynamics and cancer development. Several BRD4 isoforms have been detected in humans with the long isoform (BRD4-L, aa 1-1,362) ...

    Abstract Bromodomain-containing protein 4 (BRD4) is an acetyl-lysine reader protein and transcriptional regulator implicated in chromatin dynamics and cancer development. Several BRD4 isoforms have been detected in humans with the long isoform (BRD4-L, aa 1-1,362) playing a tumor-suppressive role and a major short isoform (BRD4-S, aa 1-722) having oncogenic activity in breast cancer development.
    Language English
    Publishing date 2022-04-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2833269-6
    ISSN 2331-8325 ; 2331-8325
    ISSN (online) 2331-8325
    ISSN 2331-8325
    DOI 10.21769/BioProtoc.4374
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The matrix protein of respiratory syncytial virus suppresses interferon signaling via RACK1 association.

    Cao, Jingjing / Shi, Menghan / Zhu, Lina / Li, Xiangzhi / Li, Aiying / Wu, Shwu-Yuan / Chiang, Cheng-Ming / Zhang, Youming

    Journal of virology

    2023  Volume 97, Issue 10, Page(s) e0074723

    Abstract: Importance: Respiratory syncytial virus (RSV) matrix (M) protein is indispensable for virion assembly and release. It is localized to the nucleus during early infection to perturb host transcription. However, the function of RSV M protein in other ... ...

    Abstract Importance: Respiratory syncytial virus (RSV) matrix (M) protein is indispensable for virion assembly and release. It is localized to the nucleus during early infection to perturb host transcription. However, the function of RSV M protein in other cellular activities remains poorly understood. In this study, several interferon response-associated host factors, including RACK1, were identified by proteomic analysis as RSV M interactors. Knockdown of RACK1 attenuates RSV-restricted IFN signaling leading to enhanced host defense against RSV infection, unraveling a role of M protein in antagonizing IFN response via association with RACK1. Our study uncovers a previously unrecognized mechanism of immune evasion by RSV M protein and identifies RACK1 as a novel host factor recruited by RSV, highlighting RACK1 as a potential new target for RSV therapeutics development.
    MeSH term(s) Humans ; Interferons ; Neoplasm Proteins/genetics ; Proteins ; Proteomics ; Receptors for Activated C Kinase/metabolism ; Respiratory Syncytial Virus Infections/metabolism ; Respiratory Syncytial Virus Infections/virology ; Respiratory Syncytial Virus, Human/genetics ; Viral Matrix Proteins/metabolism
    Chemical Substances Interferons (9008-11-1) ; Neoplasm Proteins ; Proteins ; RACK1 protein, human ; Receptors for Activated C Kinase ; Viral Matrix Proteins
    Language English
    Publishing date 2023-09-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/jvi.00747-23
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: An investigation of the influence of reactive oxygen species produced from riboflavin-5'-phosphate by blue or violet light on the inhibition of WiDr colon cancer cells.

    Chiu, Chi-Ming / Lee, Shwu-Yuan / Chen, Pin-Rong / Zhan, Shao-Qi / Yuann, Jeu-Ming P / Huang, Shiuh-Tsuen / Wu, Ming-Fang / Cheng, Chien-Wei / Chang, Yu-Chung / Liang, Ji-Yuan

    Photodiagnosis and photodynamic therapy

    2023  Volume 44, Page(s) 103810

    Abstract: Riboflavin-5'-phosphate (FMN), an innocuous product of riboflavin (RF) phosphorylation, is vital for humans. FMN is sensitive to light illumination, as indicated by reactive oxygen species (ROS) formation. This investigation was undertaken to evaluate ... ...

    Abstract Riboflavin-5'-phosphate (FMN), an innocuous product of riboflavin (RF) phosphorylation, is vital for humans. FMN is sensitive to light illumination, as indicated by reactive oxygen species (ROS) formation. This investigation was undertaken to evaluate the influence of blue light illumination (BLI) and violet light illumination (VLI) upon FMN to develop a method to inhibit WiDr colon cancer cells by FMN photolysis. When FMN is subjected to BLI and VLI, it inhibits WiDr colon cancer cells by generating superoxide radical anions (O
    MeSH term(s) Humans ; Reactive Oxygen Species/metabolism ; Light ; Photochemotherapy/methods ; Photosensitizing Agents/pharmacology ; Riboflavin/pharmacology ; Colonic Neoplasms/drug therapy ; Phosphates
    Chemical Substances Reactive Oxygen Species ; Photosensitizing Agents ; Riboflavin (TLM2976OFR) ; Phosphates
    Language English
    Publishing date 2023-09-23
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2149918-4
    ISSN 1873-1597 ; 1572-1000
    ISSN (online) 1873-1597
    ISSN 1572-1000
    DOI 10.1016/j.pdpdt.2023.103810
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Direct interaction with the BRD4 carboxyl-terminal motif (CTM) and TopBP1 is required for human papillomavirus 16 E2 association with mitotic chromatin and plasmid segregation function.

    Prabhakar, Apurva T / James, Claire D / Fontan, Christian T / Otoa, Raymonde / Wang, Xu / Bristol, Molly L / Yeager, Calvin / Hill, Ronald D / Dubey, Aanchal / Wu, Shwu-Yuan / Chiang, Cheng-Ming / Morgan, Iain M

    Journal of virology

    2023  Volume 97, Issue 10, Page(s) e0078223

    Abstract: Importance: Human papillomavirus 16 (HPV16) is a causative agent in around 3%-4% of all human cancers, and currently, there are no anti-viral therapeutics available for combating this disease burden. In order to identify new therapeutic targets, we must ...

    Abstract Importance: Human papillomavirus 16 (HPV16) is a causative agent in around 3%-4% of all human cancers, and currently, there are no anti-viral therapeutics available for combating this disease burden. In order to identify new therapeutic targets, we must increase our understanding of the HPV16 life cycle. Previously, we demonstrated that an interaction between E2 and the cellular protein TopBP1 mediates the plasmid segregation function of E2, allowing distribution of viral genomes into daughter nuclei following cell division. Here, we demonstrate that E2 interaction with an additional host protein, BRD4, is also essential for E2 segregation function, and that BRD4 exists in a complex with TopBP1. Overall, these results enhance our understanding of a critical part of the HPV16 life cycle and presents several therapeutic targets for disruption of the viral life cycle.
    MeSH term(s) Humans ; Bromodomain Containing Proteins ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Chromatin/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Human papillomavirus 16/genetics ; Human papillomavirus 16/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Oncogene Proteins, Viral/genetics ; Oncogene Proteins, Viral/metabolism ; Plasmids/genetics ; Transcription Factors/genetics ; Transcription Factors/metabolism
    Chemical Substances BRD4 protein, human ; Bromodomain Containing Proteins ; Cell Cycle Proteins ; Chromatin ; DNA-Binding Proteins ; Nuclear Proteins ; Oncogene Proteins, Viral ; Transcription Factors ; E2 protein, Human papillomavirus type 16 ; TOPBP1 protein, human
    Language English
    Publishing date 2023-09-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/jvi.00782-23
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Direct interaction with the BRD4 carboxyl-terminal motif (CTM) and TopBP1 is required for human papillomavirus 16 E2 association with mitotic chromatin and plasmid segregation function.

    Prabhakar, Apurva T / James, Claire D / Fontan, Christian T / Otoa, Raymonde / Wang, Xu / Bristol, Molly L / Hill, Ronald D / Dubey, Aanchal / Wu, Shwu-Yuan / Chiang, Cheng-Ming / Morgan, Iain M

    bioRxiv : the preprint server for biology

    2023  

    Abstract: During the human papillomavirus 16 life cycle, the E2 protein binds simultaneously to the viral genome and host chromatin throughout mitosis, ensuring viral genomes reside in daughter cell nuclei following cell division. Previously, we demonstrated that ... ...

    Abstract During the human papillomavirus 16 life cycle, the E2 protein binds simultaneously to the viral genome and host chromatin throughout mitosis, ensuring viral genomes reside in daughter cell nuclei following cell division. Previously, we demonstrated that CK2 phosphorylation of E2 on serine 23 promotes interaction with TopBP1, and that this interaction is required for optimum E2 mitotic chromatin association and plasmid segregation function. Others have implicated BRD4 in mediating the plasmid segregation function of E2 and we have demonstrated that there is a TopBP1-BRD4 complex in the cell. We therefore further investigated the role of the E2-BRD4 interaction in mediating E2 association with mitotic chromatin and plasmid segregation function. Using a combination of immunofluorescence and our novel plasmid segregation assay in U2OS and N/Tert-1 cells stably expressing a variety of E2 mutants, we report that direct interaction with the BRD4 carboxyl-terminal motif (CTM) and TopBP1 is required for E2 association with mitotic chromatin and plasmid segregation. We also identify a novel TopBP1 mediated interaction between E2 and the BRD4 extra-terminal (ET) domain
    Importance: HPV16 is a causative agent in around 3-4% of all human cancers and currently there are no anti-viral therapeutics available for combating this disease burden. In order to identify new therapeutic targets, we must increase our understanding of the HPV16 life cycle. Previously, we demonstrated that an interaction between E2 and the cellular protein TopBP1 mediates the plasmid segregation function of E2, allowing distribution of viral genomes into daughter nuclei following cell division. Here, we demonstrate that E2 interaction with an additional host protein, BRD4, is also essential for E2 segregation function, and that BRD4 exists in a complex with TopBP1. Overall, these results enhance our understanding of a critical part of the HPV16 life cycle and presents several therapeutic targets for disruption of the viral life cycle.
    Language English
    Publishing date 2023-05-26
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.05.25.542291
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: IDR-targeting compounds suppress HPV genome replication via disruption of phospho-BRD4 association with DNA damage response factors.

    Wu, Shwu-Yuan / Lai, Hsien-Tsung / Sanjib Banerjee, N / Ma, Zonghui / Santana, Juan F / Wei, Shuguang / Liu, Xisheng / Zhang, Meirong / Zhan, Jian / Chen, Haiying / Posner, Bruce / Chen, Yadong / Price, David H / Chow, Louise T / Zhou, Jia / Chiang, Cheng-Ming

    Molecular cell

    2023  Volume 84, Issue 2, Page(s) 202–220.e15

    Abstract: Compounds binding to the bromodomains of bromodomain and extra-terminal (BET) family proteins, particularly BRD4, are promising anticancer agents. Nevertheless, side effects and drug resistance pose significant obstacles in BET-based therapeutics ... ...

    Abstract Compounds binding to the bromodomains of bromodomain and extra-terminal (BET) family proteins, particularly BRD4, are promising anticancer agents. Nevertheless, side effects and drug resistance pose significant obstacles in BET-based therapeutics development. Using high-throughput screening of a 200,000-compound library, we identified small molecules targeting a phosphorylated intrinsically disordered region (IDR) of BRD4 that inhibit phospho-BRD4 (pBRD4)-dependent human papillomavirus (HPV) genome replication in HPV-containing keratinocytes. Proteomic profiling identified two DNA damage response factors-53BP1 and BARD1-crucial for differentiation-associated HPV genome amplification. pBRD4-mediated recruitment of 53BP1 and BARD1 to the HPV origin of replication occurs in a spatiotemporal and BRD4 long (BRD4-L) and short (BRD4-S) isoform-specific manner. This recruitment is disrupted by phospho-IDR-targeting compounds with little perturbation of the global transcriptome and BRD4 chromatin landscape. The discovery of these protein-protein interaction inhibitors (PPIi) not only demonstrates the feasibility of developing PPIi against phospho-IDRs but also uncovers antiviral agents targeting an epigenetic regulator essential for virus-host interaction and cancer development.
    MeSH term(s) Humans ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Human Papillomavirus Viruses ; Papillomavirus Infections/drug therapy ; Papillomavirus Infections/genetics ; Proteomics ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Papillomaviridae/genetics ; Papillomaviridae/metabolism ; Viral Proteins/genetics ; Virus Replication/physiology ; DNA Repair ; Bromodomain Containing Proteins
    Chemical Substances Transcription Factors ; Nuclear Proteins ; Cell Cycle Proteins ; Viral Proteins ; BRD4 protein, human ; Bromodomain Containing Proteins
    Language English
    Publishing date 2023-12-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2023.11.022
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Discovery, X-ray Crystallography, and Anti-inflammatory Activity of Bromodomain-containing Protein 4 (BRD4) BD1 Inhibitors Targeting a Distinct New Binding Site.

    Liu, Zhiqing / Li, Yi / Chen, Haiying / Lai, Hsien-Tsung / Wang, Pingyuan / Wu, Shwu-Yuan / Wold, Eric A / Leonard, Paul G / Joseph, Sarah / Hu, Haitao / Chiang, Cheng-Ming / Brasier, Allan R / Tian, Bing / Zhou, Jia

    Journal of medicinal chemistry

    2022  Volume 65, Issue 3, Page(s) 2388–2408

    Abstract: Bromodomain-containing protein 4 (BRD4) is an emerging epigenetic drug target for intractable inflammatory disorders. The lack of highly selective inhibitors among BRD4 family members has stalled the collective understanding of this critical system and ... ...

    Abstract Bromodomain-containing protein 4 (BRD4) is an emerging epigenetic drug target for intractable inflammatory disorders. The lack of highly selective inhibitors among BRD4 family members has stalled the collective understanding of this critical system and the progress toward clinical development of effective therapeutics. Here we report the discovery of a potent BRD4 bromodomain 1 (BD1)-selective inhibitor ZL0590 (
    MeSH term(s) Animals ; Anti-Inflammatory Agents/chemical synthesis ; Anti-Inflammatory Agents/metabolism ; Anti-Inflammatory Agents/pharmacokinetics ; Anti-Inflammatory Agents/pharmacology ; Binding Sites ; Cell Cycle Proteins/antagonists & inhibitors ; Cell Cycle Proteins/metabolism ; Cell Line ; Crystallography, X-Ray ; Gene Expression/drug effects ; Humans ; Interleukin-6/genetics ; Interleukin-6/metabolism ; Male ; Mice, Inbred C57BL ; Nuclear Proteins/antagonists & inhibitors ; Oxidoreductases Acting on CH-CH Group Donors/genetics ; Oxidoreductases Acting on CH-CH Group Donors/metabolism ; Phenylurea Compounds/chemical synthesis ; Phenylurea Compounds/metabolism ; Phenylurea Compounds/pharmacokinetics ; Phenylurea Compounds/pharmacology ; Protein Binding ; Protein Domains ; Rats ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/metabolism ; Mice
    Chemical Substances Anti-Inflammatory Agents ; BRD4 protein, human ; Brd4 protein, mouse ; Cell Cycle Proteins ; IL6 protein, human ; Interleukin-6 ; Nuclear Proteins ; Phenylurea Compounds ; Transcription Factors ; Oxidoreductases Acting on CH-CH Group Donors (EC 1.3.-) ; RSAD2 protein, human (EC 1.3.-)
    Language English
    Publishing date 2022-01-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.1c01851
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: The Influence of the Degradation of Tetracycline by Free Radicals from Riboflavin-5'-Phosphate Photolysis on Microbial Viability.

    Huang, Shiuh-Tsuen / Lee, Shwu-Yuan / Wang, Song-Hua / Wu, Chun-Yi / Yuann, Jeu-Ming P / He, Sin / Cheng, Chien-Wei / Liang, Ji-Yuan

    Microorganisms

    2019  Volume 7, Issue 11

    Abstract: Tetracycline (TC) is a broad-spectrum antibiotic compound. Wastewater with TC may have an adverse effect on ecosystems. Riboflavin-5'-phosphate (FMN or flavin mononucleotide) is a non-toxic product of the phosphorylation of vitamin ... ...

    Abstract Tetracycline (TC) is a broad-spectrum antibiotic compound. Wastewater with TC may have an adverse effect on ecosystems. Riboflavin-5'-phosphate (FMN or flavin mononucleotide) is a non-toxic product of the phosphorylation of vitamin B
    Language English
    Publishing date 2019-10-28
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2720891-6
    ISSN 2076-2607
    ISSN 2076-2607
    DOI 10.3390/microorganisms7110500
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Involvement of Brd4 in different steps of the papillomavirus life cycle.

    Iftner, Thomas / Haedicke-Jarboui, Juliane / Wu, Shwu-Yuan / Chiang, Cheng-Ming

    Virus research

    2017  Volume 231, Page(s) 76–82

    Abstract: 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 ... ...

    Abstract 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. Phosphorylation of Brd4, regulated by casein kinase II (CK2) and protein phosphatase 2A (PP2A), is critical for viral gene transcription as well as E1- and E2-dependent origin replication. Thus, pharmacological agents regulating Brd4 phosphorylation and inhibitors blocking phospho-Brd4 functions are promising candidates for therapeutic intervention in treating human papillomavirus (HPV) infections as well as associated disease.
    Language English
    Publishing date 2017-03-02
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 605780-9
    ISSN 1872-7492 ; 0168-1702
    ISSN (online) 1872-7492
    ISSN 0168-1702
    DOI 10.1016/j.virusres.2016.12.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination

    Hyunkyung Jung / Jinjing Chen / Xiangming Hu / Hao Sun / Shwu-Yuan Wu / Cheng-Ming Chiang / Byron Kemper / Lin-Feng Chen / Jongsook Kim Kemper

    JCI Insight, Vol 6, Iss

    2021  Volume 1

    Abstract: Activation of farnesoid X receptor (FXR) by obeticholic acid (OCA) reduces hepatic inflammation and fibrosis in patients with primary biliary cholangitis (PBC), a life-threatening cholestatic liver failure. Inhibition of bromodomain-containing protein 4 ( ...

    Abstract Activation of farnesoid X receptor (FXR) by obeticholic acid (OCA) reduces hepatic inflammation and fibrosis in patients with primary biliary cholangitis (PBC), a life-threatening cholestatic liver failure. Inhibition of bromodomain-containing protein 4 (BRD4) also has antiinflammatory, antifibrotic effects in mice. We determined the role of BRD4 in FXR function in bile acid (BA) regulation and examined whether the known beneficial effects of OCA are enhanced by inhibiting BRD4 in cholestatic mice. Liver-specific downregulation of BRD4 disrupted BA homeostasis in mice, and FXR-mediated regulation of BA-related genes, including small heterodimer partner and cholesterol 7 alpha-hydroxylase, was BRD4 dependent. In cholestatic mice, JQ1 or OCA treatment ameliorated hepatotoxicity, inflammation, and fibrosis, but surprisingly, was antagonistic in combination. Mechanistically, OCA increased binding of FXR, and the corepressor silencing mediator of retinoid and thyroid hormone receptor (SMRT) decreased NF-κB binding at inflammatory genes and repressed the genes in a BRD4-dependent manner. In patients with PBC, hepatic expression of FXR and BRD4 was significantly reduced. In conclusion, BRD4 is a potentially novel cofactor of FXR for maintaining BA homeostasis and hepatoprotection. Although BRD4 promotes hepatic inflammation and fibrosis in cholestasis, paradoxically, BRD4 is required for the antiinflammatory, antifibrotic actions of OCA-activated FXR. Cotreatment with OCA and JQ1, individually beneficial, may be antagonistic in treatment of liver disease patients with inflammation and fibrosis complications.
    Keywords Hepatology ; Inflammation ; Medicine ; R
    Subject code 570
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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