Activation of Monocyte Cyclooxygenase-2 Gene Expression by Human Herpesvirus 6

Janelle, Marie‐Ève; Gravel, Annie; Gosselin, Jean; Tremblay, Michel J.; Flamand, Louis

doi:10.1074/jbc.m203041200

Cited by 58 publications

(20 citation statements)

References 98 publications

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“…4). This finding is consistent with previous evidence that AP-1 mediates the induction of COX-2 by a variety of stimuli (10,(21)(22)(23)(24). ChIP analysis indicated that HDAC inhibitors blocked PMA-mediated induction of COX-2 by suppressing the binding of c-Jun to the COX-2 promoter.…”

Section: Discussionsupporting

confidence: 83%

“…Oncogenes, growth factors, cytokines, and tumor promoters stimulate COX-2 transcription via protein kinase C and RAS-mediated signaling (5)(6)(7)(8)(9)(10). Depending on the stimulus and cell type, a variety of transcription factors including activator protein-1 (AP-1) can stimulate COX-2 expression (21)(22)(23). Recently, the histone acetyltransferase activity of the CREB-binding protein/p300 co-activator complex was found to be important for AP-1-mediated induction of COX-2 (24).…”

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confidence: 99%

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Histone Deacetylase Inhibitors Suppress the Induction of c-Jun and Its Target Genes Including COX-2

Yamaguchi

Lantowski

Dannenberg

et al. 2005

Journal of Biological Chemistry

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Cyclooxygenases (COX)2 catalyze the first step in synthesis of prostaglandins (PGs) from arachidonic acid. There are two isoforms of COX. COX-1 is constitutively expressed in most tissues and appears to mediate various physiological functions (1, 2). By contrast, COX-2 is undetectable in most normal tissues but is rapidly induced by both mitogenic and inflammatory stimuli (3-9).COX-2 is widely regarded as a potential pharmacological target for preventing and treating malignancies (10). Tumor formation and growth are reduced in animals that are engineered to be COX-2-deficient or treated with a selective COX-2 inhibitor (11-19). Treatment with a selective COX-2 inhibitor also reduced the number of colorectal polyps in patients with familial adenomatous polyposis (20). Thus far, therapeutic strategies have focused primarily on selective inhibitors of COX-2 activity. Considerably less attention has been given to identifying anticancer agents that suppress the expression of the COX-2 gene.To develop a mechanism-based strategy for suppressing COX-2 expression, it is important to define the signaling pathways and factors that control transcription. Oncogenes, growth factors, cytokines, and tumor promoters stimulate COX-2 transcription via protein kinase C and RAS-mediated signaling (5-10). Depending on the stimulus and cell type, a variety of transcription factors including activator protein-1 (AP-1) can stimulate COX-2 expression (21-23). Recently, the histone acetyltransferase activity of the CREB-binding protein/p300 co-activator complex was found to be important for AP-1-mediated induction of COX-2 (24). This finding raises the possibility that agents that suppress AP-1 binding activity or alter chromatin structure will suppress levels of COX-2. The packaging of DNA into chromatin provides an important point of control for regulation of gene expression. Posttranslational modifications of histones such as acetylation, deacetylation, or phosphorylation can influence chromatin architecture and thereby gene transcription. Acetylation of histones is the best studied of these modifications and depends on net balance between histone acetyltransferase and histone deacetylase (HDAC) activities. HDAC activity is increased in cancer cells and has been linked to carcinogenesis (25). HDAC inhibitors suppress the growth of tumor cells in experimental models and exhibit antitumor activity in clinical trials (26 -29). These beneficial effects can be explained by an accumulation of acetylated proteins that affect diverse cellular processes including gene transcription (30, 31). The mechanism(s) by which HDAC inhibitors modulate gene expression is incompletely understood and remains a subject of intense investigation (32).In this study we investigated whether HDAC inhibitors suppressed the transcriptional activation of COX-2 in human carcinoma cell lines. Trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), two structurally related HDAC inhibitors, inhibited AP-1-mediated induction of COX-2 transcription and PGE 2 biosy...

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Section: Discussionsupporting

confidence: 83%

mentioning

confidence: 99%

Histone Deacetylase Inhibitors Suppress the Induction of c-Jun and Its Target Genes Including COX-2

Yamaguchi

Lantowski

Dannenberg

et al. 2005

Journal of Biological Chemistry

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“…Viral infections often induce the synthesis of elevated levels of inflammatory mediators, including COX-2, that may alter the functions of the infected cells (25). COX-2 is one of the most important inflammation mediators being the target of nonsteroidal anti-inflammatory drugs (48).…”

Section: Discussionmentioning

confidence: 99%

“…One such secreted product released is prostaglandin E 2 (PGE 2 ) that is a strong lipid mediator of inflammation and modulator of the immune response. Recent evidence shows that many viruses have been linked to the regulation of COX-2 expression and the production of prostaglandins (PGs) (25)(26)(27). Viruses that interact with Mo/M efficiently modulate the synthesis of PGE 2 (28,29).…”

mentioning

confidence: 99%

The Viral Protein A238L Inhibits Cyclooxygenase-2 Expression through a Nuclear Factor of Activated T Cell-dependent Transactivation Pathway

Granja

Nogal

Hurtado

et al. 2004

Journal of Biological Chemistry

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Cyclooxygenase-2 is transiently induced upon cell activation or viral infections, resulting in inflammation and modulation of the immune response. Here we report that A238L, an African swine fever virus protein, efficiently inhibits cyclooxygenase-2 gene expression in Jurkat T cells and in virus-infected Vero cells. Transfection of Jurkat cells stably expressing A238L with cyclooxygenase-2 promoter-luciferase constructs containing 5 -terminal deletions or mutations in distal or proximal nuclear factor of activated T cell (NFAT) response elements revealed that these sequences are involved in the inhibition induced by A238L. Overexpression of a constitutively active version of the calciumdependent phosphatase calcineurin or NFAT reversed the inhibition mediated by A238L on cyclooxygenase-2 promoter activation, whereas overexpression of p65 NF B had no effect. A238L does not modify the nuclear localization of NFAT after phorbol 12-myristate 13-acetate/calcium ionophore stimulation. Moreover, we show that the mechanism by which the viral protein downregulates cyclooxygenase-2 activity does not involve inhibition of the binding between NFAT and its specific DNA sequences into the cyclooxygenase-2 promoter. Strikingly, A238L dramatically inhibited the transactivation mediated by a GAL4-NFAT fusion protein containing the N-terminal transactivation domain of NFAT1. Taken together, these data indicate that A238L down-regulates cyclooxygenase-2 transcription through the NFAT response elements, being NFAT-dependent transactivation implicated in this down-regulation.Viruses have been known for a long time to use a variety of strategies not only to alter the host metabolism via their signaling proteins but also to hijack cellular signaling pathways and transcription factors to control them to their own advantage. Both the nuclear factor-B (NF B) 1 and the nuclear factor of activated T cells (NFAT) pathways appear to be attractive targets for common viral pathogens, probably due to their ability to promote the expression of numerous proteins involved in adaptative and innate immunity (1, 2). Several viruses, including hepatitis C virus (3), immunodeficiency virus (4), herpes viruses (5), and African swine fever virus (ASFV) (6 -8) have been shown to modulate the activation of NFAT or NF B.NF B is a collective term referring to a class of dimeric transcription factors belonging to the rel family. In resting cells, NF B exists in the cytoplasm as an inactive complex bound to inhibitory proteins of the I B family (9, 10). In response to a variety of stimuli, I B proteins undergo phosphorylation of Ser 32 and Ser 36 (11, 12), followed by ubiquitination and degradation in the proteasome, thus unmasking the nuclear localization sequence of the transactivating heterodimers and allowing translocation of active NF B to the nucleus. Recently, there is accumulating evidence suggesting that another level of NF-〉 regulation independent on I B degradation exists. This second level of regulation relies in the activation of the transcription...

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“…In human herpes virus 6 (HHV-6) infected human monocytes/macrophages, COX-2 gene promoter activity increases 22-fold compared to mock-infected cells [49]. HHV-6 encoded IE2, but not HHV-6 IE1 protein, also activates the COX-2 promoter.…”

Section: Introductionmentioning

confidence: 98%

Biological interactions between herpesviruses and cyclooxygenase enzymes

Reynolds

Enquist

2006

Reviews in Medical Virology

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Decades ago, medical researchers noted that non-steroidal anti-inflammatory drugs (NSAIDs), for example aspirin and indomethacin, modulate primary herpesvirus infections and diminish reactivation of latent herpesvirus infections. NSAIDs inhibit cyclooxygenase (COX) enzymes, molecules necessary for generation of prostaglandins. Numerous studies indicate that herpesvirus infections elicit elevated levels of cyclooxygenase 2 (COX-2) with a resultant increase in prostaglandin E(2) levels (PGE(2)). Thus, the biochemical pathway underlying the anti-herpetic mechanism of NSAIDs is linked to the inhibition of COX. The precise roles of COX-2 and PGE(2) in the viral life cycle are unknown. However, among the alphaherpesvirus, betaherpesvirus and gammaherpesvirus subfamilies, evolutionarily conserved mechanisms ensure modulated expression of COX molecules, underscoring their importance in viral replication and virus-host interactions.

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Activation of Monocyte Cyclooxygenase-2 Gene Expression by Human Herpesvirus 6

Cited by 58 publications

References 98 publications

Histone Deacetylase Inhibitors Suppress the Induction of c-Jun and Its Target Genes Including COX-2

Histone Deacetylase Inhibitors Suppress the Induction of c-Jun and Its Target Genes Including COX-2

The Viral Protein A238L Inhibits Cyclooxygenase-2 Expression through a Nuclear Factor of Activated T Cell-dependent Transactivation Pathway

Biological interactions between herpesviruses and cyclooxygenase enzymes

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