Bromodomain and Extraterminal (BET) Protein Inhibition Suppresses Human T Cell Leukemia Virus 1 (HTLV-1) Tax Protein-mediated Tumorigenesis by Inhibiting Nuclear Factor κB (NF-κB) Signaling

Wu, Xuewei; Qi, Jun; Bradner, James E.; Xiao, Gutian; Chen, Lin Feng

doi:10.1074/jbc.m113.485029

Cited by 39 publications

(30 citation statements)

References 53 publications

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“…Expression of Tax-1 augments basal p65 acetylation at K310 by an unknown mechanism, which in turn allows binding of Brd4 (bromodomain-containing 4). Knockdown of Brd4 strongly impairs Tax-1-induced NF-κ-driven transcription [150], but it remains to be seen whether Brd4 is a general or stimulus-specific NF-κB coactivator.…”

Section: Molecular Mechanisms Of Tax-1-controlled Nf-κb Activationmentioning

confidence: 99%

The intricate interplay between RNA viruses and NF-κB

Schmitz

Kracht

Saul

2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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RNA viruses have rapidly evolving genomes which often allow cross-species transmission and frequently generate new virus variants with altered pathogenic properties. Therefore infections by RNA viruses are a major threat to human health. The infected host cell detects trace amounts of viral RNA and the last years have revealed common principles in the biochemical mechanisms leading to signal amplification that is required for mounting of a powerful antiviral response. Components of the RNA sensing and signaling machinery such as RIG-I-like proteins, MAVS and the inflammasome inducibly form large oligomers or even fibers that exhibit hallmarks of prions. Following a nucleation event triggered by detection of viral RNA, these energetically favorable and irreversible polymerization events trigger signaling cascades leading to the induction of antiviral and inflammatory responses, mediated by interferon and NF-κB pathways. Viruses have evolved sophisticated strategies to manipulate these host cell signaling pathways in order to ensure their replication. We will discuss at the examples of influenza and HTLV-1 viruses how a fascinating diversity of biochemical mechanisms is employed by viral proteins to control the NF-κB pathway at all levels.

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Section: Molecular Mechanisms Of Tax-1-controlled Nf-κb Activationmentioning

confidence: 99%

The intricate interplay between RNA viruses and NF-κB

Schmitz

Kracht

Saul

2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…BRD4 has been shown to bind acetylated lysine residues on the p65/RelA subunit of NFB, thus driving gene expression. (22,23,33) In endothelial cells, cytokine treatment triggers reorganization of chromatin activators from basal endothelial cell enhancers to inflammatory SEs, triggering inflammatory gene expression via NFB in a BRD4-dependent manner. (34) Importantly, these authors very elegantly demonstrated that NFB activation and SE binding appears to occur upstream of BRD4 as NFB was still bound to SEs in the absence of BRD4.…”

Section: Discussionmentioning

confidence: 99%

“…BRD4, the archetypal BET, is necessary for NFB-mediated inflammatory gene expression in models of atherosclerosis, (20) graft-versus-host disease,(21) and cancer. (22)(23)(24) Thus, we investigated if BETs exert their potent effects on non-myocyte gene expression via NFB. Our extensive RNA-seq studies revealed that NFB signaling was strongly upregulated in PLN R9C hearts and isolated cardiac non-myocytes at all disease stages, and genes activated by NFB were strongly upregulated in cardiac non-myocytes (Figure 7A, B).…”

Section: Bets Interact With Nfb In Cardiac Fibroblastsmentioning

confidence: 99%

BET Bromodomain Proteins Regulate Transcriptional Reprogramming in Genetic Dilated Cardiomyopathy

Antolic

Wakimoto

Jing

et al. 2020

Preprint

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The bromodomain and extraterminal (BET) family of epigenetic reader proteins are key regulators of pathologic gene expression in the heart. Using mice carrying a human mutation in phospholamban (PLN R9C ) that develop progressive dilated cardiomyopathy (DCM), we previously identified the activation of inflammatory gene networks as a key early driver of DCM. We reasoned that BETs control this inflammatory process, representing a key node in the progression of genetic DCM. Using a chemical genetic strategy, PLN R9C or age-matched wild type mice were treated longitudinally with the BET inhibitor JQ1 or vehicle. JQ1 abrogated DCM, reduced cardiac fibrosis, and prolonged survival in PLN R9C mice by inhibiting inflammatory gene network expression at all disease stages. Cardiac fibroblast proliferation was also substantially reduced by JQ1. Interestingly, JQ1 had profound effects on pathologic gene network expression in cardiac fibroblasts, while having little effect on transcription in cardiomyocytes. Using co-immunoprecipitation, we identified BRD4 as a direct and essential regulator of NFB-mediated inflammatory gene transcription in cardiac fibroblasts. In this this model of chronic, heritable DCM, BETs activate inflammatory gene networks in cardiac fibroblasts via an NFB-dependent mechanism, marking them as critical effectors of pathologic gene expression.

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“…In the HIV/AIDS field multiple studies have shown that BET inhibitors (JQ1, I-BET, MS417) can reactivate HIV from latency [92–95]. The same effect has been observed with other viruses [96–99]. Table 2 summarizes the currently published applications of BrD inhibitors.…”

Section: Applications Of Bromodomain Inhibitorsmentioning

confidence: 93%

The bromodomain: From epigenome reader to druggable target

Sánchez

Meslamani

Zhou

2014

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

165

140

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Lysine acetylation is a fundamental post-translational modification that plays an important role in control of gene transcription in chromatin in an ordered fashion. The bromodomain, the conserved structural module present in transcription-associated proteins, functions exclusively to recognize acetyl-lysine on histones and non-histone proteins. The structural analyses of bromodomains’ recognition of lysine-acetylated peptides derived from histones and cellular proteins provide detailed insights into the differences and unifying features of biological ligand binding selectivity by the bromodomains. Newly developed small molecule inhibitors targeting bromodomain proteins further highlight the functional importance of bromodomain/acetyl-lysine binding as a key mechanism in orchestrating molecular interactions and regulation in chromatin biology and gene transcription. These new studies argue that modulating bromodomain/acetyl-lysine interactions with small-molecule chemicals offer new opportunities to control gene expression in a wide array of human diseases including cancer and inflammation.

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Bromodomain and Extraterminal (BET) Protein Inhibition Suppresses Human T Cell Leukemia Virus 1 (HTLV-1) Tax Protein-mediated Tumorigenesis by Inhibiting Nuclear Factor κB (NF-κB) Signaling

Cited by 39 publications

References 53 publications

The intricate interplay between RNA viruses and NF-κB

The intricate interplay between RNA viruses and NF-κB

BET Bromodomain Proteins Regulate Transcriptional Reprogramming in Genetic Dilated Cardiomyopathy

The bromodomain: From epigenome reader to druggable target

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