Expression of transcription factor NF-KAPPA B/P65 and cyclooxygenase-2 (COX-2) in testicular damage induced by Red Bull energy drink in rat

ABSTRACT Treatment of AZ-521 cells with Helicobacter pylori VacA increased cyclooxygenase 2 (COX-2) mRNA in a time- and dose-dependent manner. A p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, blocked elevation of COX-2 mRNA levels, whereas PD98059, which blocks the Erk1/2 cascade, partially suppressed the increase. Consistent with involvement of p38 MAPK, VacA-induced accumulation of COX-2 mRNA was reduced in AZ-521 cells overexpressing a dominant-negative p38 MAPK (DN-p38). Phosphatidylinositol-specific phospholipase C, which inhibits VacA-induced p38 MAPK activation, blocked VacA-induced COX-2 expression. In parallel with COX-2 expression, VacA increased prostaglandin E2 (PGE2) production, which was inhibited by SB203580 and NS-398, a COX-2 inhibitor. VacA-induced PGE2 production was markedly attenuated in AZ-521 cells stably expressing DN-p38. VacA increased transcription of a COX-2 promoter reporter gene and activated a COX-2 promoter containing mutated NF-κB or NF-interleukin-6 sites but not a mutated cis-acting replication element (CRE) site, suggesting direct involvement of the activating transcription factor 2 (ATF-2)/CREB-binding region in VacA-induced COX-2 promoter activation. The reduction of ATF-2 expression in AZ-521 cells transformed with ATF-2-small interfering RNA duplexes resulted in suppression of COX-2 expression. Thus, VacA enhances PGE2 production by AZ-521 cells through induction of COX-2 expression via the p38 MAPK/ATF-2 cascade, leading to activation of the CRE site in the COX-2 promoter.

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Defective Histone Acetylation Is Responsible for the Diminished Expression of Cyclooxygenase 2 in Idiopathic Pulmonary Fibrosis

Molecular and Cellular Biology ◽

10.1128/mcb.01776-08 ◽

2009 ◽

Vol 29 (15) ◽

pp. 4325-4339 ◽

Cited By ~ 122

Author(s):

William R. Coward ◽

Keiria Watts ◽

Carol A. Feghali-Bostwick ◽

Alan Knox ◽

Linhua Pang

Keyword(s):

Transcription Factor ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Hdac Inhibitors ◽

Histone H3 ◽

Cyclooxygenase 2 ◽

Prostaglandin E ◽

Mrna Levels ◽

Gene Assay ◽

Cox 2

ABSTRACT Diminished cyclooxygenase 2 (COX-2) expression in fibroblasts, with a resultant defect in the production of the antifibrotic mediator prostaglandin E2, plays a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we have characterized the molecular mechanism. We found that COX-2 mRNA levels in fibroblasts from patients with IPF (F-IPF) were significantly lower than those in fibroblasts from nonfibrotic lungs (F-NL) after transforming growth factor β1 and interleukin-1β treatment but that COX-2 mRNA degradation rates were similar, suggesting defective transcription. A reporter gene assay showed that there were no clear differences between F-IPF and F-NL in transcription factor involvement and activation in COX-2 gene transcription. However, a chromatin immunoprecipitation assay revealed that transcription factor binding to the COX-2 promoter in F-IPF was reduced compared to that in F-NL, an effect that was dynamically linked to reduced histone H3 and H4 acetylation due to decreased recruitment of histone acetyltransferases (HATs) and increased recruitment of transcriptional corepressor complexes to the COX-2 promoter. The treatment of F-IPF with histone deacetylase (HDAC) inhibitors together with cytokines increased histone H3 and H4 acetylation. Both HDAC inhibitors and the overexpression of HATs restored cytokine-induced COX-2 mRNA and protein expression in F-IPF. The results demonstrate that epigenetic abnormality in the form of histone hypoacetylation is responsible for diminished COX-2 expression in IPF.

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Cyclooxygenase-2-Mediated Up-Regulation of Mitochondrial Transcription Factor A Mitigates the Radio-Sensitivity of Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20051218 ◽

2019 ◽

Vol 20 (5) ◽

pp. 1218 ◽

Cited By ~ 7

Author(s):

Fan Tang ◽

Rui Zhang ◽

Jun Wang

Keyword(s):

Transcription Factor ◽

Cancer Cells ◽

Tumor Cells ◽

Cyclooxygenase 2 ◽

Mitochondrial Fragmentation ◽

Mitochondrial Transcription ◽

Mitochondrial Transcription Factor ◽

Radiation Induced ◽

Mitochondrial Transcription Factor A ◽

Cox 2

Mitochondrial transcription factor A (TFAM) regulates mitochondrial biogenesis, and it is a candidate target for sensitizing tumor during therapy. Previous studies identified that increased TFAM expression conferred tumor cells resistance to ionizing radiation. However, the mechanisms on how TFAM are regulated in irradiated tumor cells remain to be explored. In this research, we demonstrated the contribution of cyclooxygenase-2 (COX-2) to enhancing TFAM expression in irradiated tumor cells. Our results showed TFAM was concomitantly up-regulated with COX-2 in irradiated tumor cells. Inhibition of COX-2 by NS-398 blocked radiation-induced expression of TFAM, and prostaglandin E2 (PGE2) treatment stimulated TFAM expression. We next provided evidence that DRP1-mediated mitochondrial fragmentation was a reason for TFAM up-regulation in irradiated cells, by using small interfering RNA (siRNA) and selective inhibitor-targeted DRP1. Furthermore, we proved that p38-MAPK-connected COX-2, and DRP1-mediated TFAM up-regulation. Enhanced phosphorylation of p38 in irradiated tumor cells promoted DRP1 expression, mitochondrial fragmentation, and TFAM expression. NS-398 treatment inhibited radiation-induced p38 phosphorylation, while PGE2 stimulated the activation of p38. The results put forward a mechanism where COX-2 stimulates TFAM expression via p38-mediated DRP1/mitochondrial fragmentation signaling in irradiated tumor cells, which may be of value in understanding how to sensitize cancer cells during radiotherapy.

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ROCK and Nuclear Factor-κB–dependent Activation of Cyclooxygenase-2 by Rho GTPases: Effects on Tumor Growth and Therapeutic Consequences

Molecular Biology of the Cell ◽

10.1091/mbc.e03-01-0016 ◽

2003 ◽

Vol 14 (7) ◽

pp. 3041-3054 ◽

Cited By ~ 65

Author(s):

Salvador Aznar Benitah ◽

Pilar F. Valerón ◽

Juan Carlos Lacal

Keyword(s):

Cell Proliferation ◽

Transcription Factor ◽

Epithelial Cells ◽

Tumor Growth ◽

Rho Gtpases ◽

Nuclear Factor Κb ◽

Cyclooxygenase 2 ◽

Human Tumors ◽

Nuclear Factor ◽

Cox 2

Rho GTPases are overexpressed in a variety of human tumors contributing to both tumor proliferation and metastasis. Recently, several studies demonstrate an essential role of transcriptional regulation in Rho GTPases-induced oncogenesis. Herein, we demonstrate that RhoA, Rac1, and Cdc42 promote the expression of cyclooxygenase-2 (COX-2) at the transcriptional level by a mechanism that is dependent on the transcription factor nuclear factor-κB (NF-κB), but not Stat3, a transcription factor required for RhoA-induced tumorigenesis. With respect to RhoA, this effect is dependent on ROCK, but not PKN. Treatment of RhoA-, Rac1-, and Cdc42-transformed epithelial cells with Sulindac and NS-398, two well-characterized nonsteroid antiinflammatory drugs (NSAIDs), results in growth inhibition as determined by cell proliferation assays. Accordingly, tumor growth of RhoA-expressing epithelial cells in syngeneic mice is strongly inhibited by NS-398 treatment. The effect of NSAIDs over RhoA-induced tumor growth is not exclusively dependent on COX-2 because DNA-binding of NF-κB is also abolished upon NSAIDs treatment, resulting in complete loss of COX-2 expression. Finally, treatment of RhoA-transformed cells with Bay11-7083, a specific NF-κB inhibitor, leads to inhibition of cell proliferation. We suggest that treatment of human tumors that overexpress Rho GTPases with NSAIDs and drugs that target NF-κB could constitute a valid antitumoral strategy.

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Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-κB and NFAT transcriptional pathways

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1517642113 ◽

2015 ◽

Vol 113 (2) ◽

pp. 434-439 ◽

Cited By ~ 90

Author(s):

Nicholas S. Kirkby ◽

Melissa V. Chan ◽

Anne K. Zaiss ◽

Eliana Garcia-Vaz ◽

Jing Jiao ◽

...

Keyword(s):

Transcription Factor ◽

Side Effects ◽

Constitutive Expression ◽

Nonsteroidal Antiinflammatory Drugs ◽

Cyclooxygenase 2 ◽

Antiinflammatory Drugs ◽

Activated T Cells ◽

Nfat Activation ◽

Cox 2 ◽

Specific Tissue

Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system.

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Endothelin-1 Induces Cyclooxygenase-2 Expression Via Nuclear Factor of Activated T-Cell Transcription Factor in Glomerular Mesangial Cells

Journal of the American Society of Nephrology ◽

10.1681/asn.v1271359 ◽

2001 ◽

Vol 12 (7) ◽

pp. 1359-1368 ◽

Cited By ~ 1

Author(s):

TOSHIRO SUGIMOTO ◽

MASAKAZU HANEDA ◽

HIROTAKA SAWANO ◽

KEIJI ISSHIKI ◽

SHIRO MAEDA ◽

...

Keyword(s):

Transcription Factor ◽

T Cell ◽

Mesangial Cells ◽

Consensus Sequence ◽

Cyclooxygenase 2 ◽

Nuclear Factor ◽

Glomerular Mesangial Cells ◽

Endothelin 1 ◽

Cell Functions ◽

Cox 2

Abstract. Nuclear factor of activated T cells (NFAT) originally was identified as a T-cell—specific transcription factor whose activity is regulated by calcineurin, one of the serine-threonine phosphatases. Recent studies have shown that NFAT also is expressed in nonlymphoid cells and plays an important role in various cell functions. It is widely known that treatment with cyclosporin A (CsA), which can inhibit calcineurin/NFAT signaling, results in glomerular dysfunction characterized by a decrease of GFR or glomerulosclerosis, suggesting that NFAT might regulate the glomerular function. However, the precise function of NFAT in glomerular cells remains to be clarified. Herein, evidence has been produced that NFAT2/NFATc, one of five known NFAT isoforms, is expressed in glomerular mesangial cells. Stimulation of mesangial cells with endothelin-1 caused translocation of NFAT2 into the nucleus with a concomitant increase in NFAT2 DNA-binding activity, both of which were inhibited by CsA. Furthermore, CsA inhibited endothelin-1—induced cyclooxygenase-2 (COX-2) expression in mesangial cells. NFAT2 bound directly to the GGAAA sequence, which is the minimal consensus sequence for NFAT binding, in a promoter region of ratCOX-2gene, and it enhanced the reporter activity of rat COX-2 promoter in mesangial cells. These findings provide the first evidence that NFAT2 is expressed and regulates COX-2 gene expression in mesangial cells. These results will contribute to evaluation of the precise roles of NFAT in glomerular functions and the CsA-induced nephrotoxicity.

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