Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of cyclooxygenase-2 (COX-2) has been observed in human colorectal cancer. COX-2 expression in human tumors can be induced by growth factors, cytokines, oncogenes, and other factors. The mechanisms regulating COX-2 expression in human colon cancer have not been completely elucidated. We hypothesized that the proinflammatory cytokine interleukin-1 beta (IL-1 beta) mediates COX-2 expression in HT-29 human colon cancer cells. Treatment of HT-29 cells with IL-1 beta induced expression of COX-2 mRNA and protein in a time- and dose-dependent manner. Inhibitors of the extracellular signal-regulated kinase 1/2, c-Jun NH(2)-terminal kinase, P38 mitogen-activated protein kinase, and nuclear factor-kappa B (NF-kappa B) signaling pathways blocked the ability of IL-1 beta to induce COX-2 mRNA. In contrast, Wortmannin, a phosphoinositide 3-kinase inhibitor upstream of protein kinase B/Akt, led to a slight increase in COX-2 mRNA expression after IL-1 beta treatment. Electrophoretic mobility shift assay on nuclear extracts demonstrated that IL-1 beta induced NF-kappa B DNA binding activity in HT-29 cells, and the activated NF-kappa B complex was eliminated after treatment with an inhibitor of NF-kappa B. Supershift assay indicated that the two NF-kappa B subunits, p65 and p50, were involved in activation of NF-kappa B complex by IL-1 beta stimulation. The stability of COX-2 mRNA was not altered by IL-1 beta treatment. These data demonstrate that IL-1 beta induces COX-2 expression in HT-29 cells through multiple signaling pathways and NF-kappa B.
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PMID:Cyclooxygenase-2 is up-regulated by interleukin-1 beta in human colorectal cancer cells via multiple signaling pathways. 1283 52

Bryostatin-1 (bryostatin) is a macrocyclic lactone derived from Bugula neritina, a marine bryozoan. On the basis of the strength of in vitro and animal studies, bryostatin is being investigated as a possible treatment for a variety of human malignancies. Severe myalgias are a common dose-limiting side effect. Because cyclooxygenase-2 (COX-2)-derived prostaglandins can cause pain, we investigated whether bryostatin induced COX-2. Bryostatin (1-10 nM) induced COX-2 mRNA, COX-2 protein, and prostaglandin biosynthesis. These effects were observed in macrophages as well as in a series of human cancer cell lines. Transient transfections localized the stimulatory effects of bryostatin to the cyclic AMP response element of the COX-2 promoter. Electrophoretic mobility shift assays and supershift experiments revealed a marked increase in the binding of activator protein-1 (AP-1)(c-Jun/c-Fos) to the cyclic AMP response element of the COX-2 promoter. Pharmacological and transient transfection studies indicated that bryostatin stimulated COX-2 transcription via the protein kinase C-->mitogen-activated protein kinase-->AP-1 pathway. All-trans-retinoic acid, a prototypic AP-1 antagonist, blocked bryostatin-mediated induction of COX-2. Taken together, these results suggest that bryostatin-mediated induction of COX-2 can help to explain the myalgias that are commonly associated with treatment. Moreover, it will be worthwhile to evaluate whether the addition of a selective COX-2 inhibitor can increase the antitumor activity of bryostatin.
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PMID:Bryostatin-1 stimulates the transcription of cyclooxygenase-2: evidence for an activator protein-1-dependent mechanism. 1458 79

Septic shock is the most common cause of death in intensive care units, and no effective treatment is available at present. Lipopolysaccharide (LPS) is the primary mediator of Gram-negative sepsis by inducing the production of macrophage-derived proinflammatory cytokines, in which activation of nuclear factor-kappaB (NF-kappaB) plays an important role. PC-SPES is an eight-herb mixture active against a variety of malignancies, including prostate cancer and leukemia. In this study, we demonstrated that PC-SPES inhibited the LPS-induced NF-kappaB reporter activity in RAW264.7 macrophages. Electrophoretic mobility shift assay showed that PC-SPES inhibited the binding of NF-kappaB to specific DNA sequences; however, it did not affect either degradation of inhibitory kappaBalpha or nuclear translocation of NF-kappaB. Also, we explored the effect of PCSPES on LPS-induced mitogen-activated protein (MAP) kinase signaling; PC-SPES did not affect LPS-induced phosphorylation of MAP kinases, including c-Jun NH2-terminal kinase, p38, and extracellular signal-regulated kinase 1/2. Moreover, PC-SPES decreased the production of proinflammatory cytokines and inducible enzymes, such as tumor necrosis factor (TNF) alpha, interleukin (IL)-1beta, IL-6, cyclooxygenase-2, as well as inducible nitric-oxide synthase in RAW264.7 macrophages and peritoneal macrophages from C57BL/6 mice after the cells were stimulated by either LPS or LPS and interferon-gamma. Furthermore, PC-SPES rescued C57BL/6 mice from death caused by LPS-induced septic shock in conjunction with decreased serum levels of TNFalpha and IL-1beta. Together, PC-SPES is a potent inhibitor of NF-kappaB and might be useful for the treatment of sepsis and inflammatory diseases.
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PMID:PC-SPES: a potent inhibitor of nuclear factor-kappa B rescues mice from lipopolysaccharide-induced septic shock. 1464 83

We reported previously that cadmium, an oxidative stressor, induced cyclooxygenase-2 (COX-2) upregulation in mouse neuronal cells that culminated in cell death. Herein, we show that cadmium induces reactive oxygen species (ROS) that activate c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) and their substrates, activating transcription factor 2 (ATF-2), CRE-binding protein (CREB) and c-Jun. This response is accompanied by induction of heme-oxygenase-1 (HO-1), poly(ADP-ribose) polymerase cleavage and a caspase-independent cell death. Inhibition of p38 MAPK, but not JNK, suppressed COX-2 protein expression and the cytotoxic response induced by cadmium. Selective inhibitors of phosphatidylinositol-3-kinase (PI3-K), LY294002, and flavoproteins, dipheneylene iodonium chloride (DPI), attenuated cadmium-induced ROS and stress kinase activation, suggesting that ROS can signal the COX-2 upregulation and neuronal cell death mediated by p38 MAPK. Collectively, these findings implicate PI3-K, a flavoprotein, p38 MAPK and COX-2 in a neuronal redox-regulated pathway that mediates cadmium-induced oxidative stress.
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PMID:Redox regulates COX-2 upregulation and cell death in the neuronal response to cadmium. 1468 64

Celecoxib, the first US FDA-approved selective cyclooxygenase-2 (COX-2) inhibitor initially developed for the treatment of adult rheumatoid arthritis and osteoarthritis, was reported to reduce the polyp burden in patients with familial adenomatous polyposis. This specific COX-2 inhibitor also protects against experimentally induced carcinogenesis, but molecular mechanisms underlying its chemopreventive activities remain largely unresolved. In the present work, we found that celecoxib inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced expression of COX-2 in female ICR mouse skin when applied topically 30 min prior to TPA as determined by both immunoblot and immunohistochemical analyses. In another study, celecoxib attenuated the DNA binding activity of activator protein 1 (AP-1) through suppression of c-Jun and c-Fos expression in TPA-treated mouse skin. In addition, celecoxib inhibited both the catalytic activity and phosphorylation of p38 mitogen-activated protein (MAP) kinase. In the same animal model, TPA treatment resulted in rapid activation via phosphorylation of extracellular signal-regulated protein kinase (ERK)1/2 and p38 MAP kinase, which are upstream of AP-1 in mouse skin. In order to clarify the roles of p38 and ERK in TPA-induced AP-1 activation, we utilized the pharmacologic inhibitors of these enzymes. The p38 inhibitor SB203580 blocked TPA-mediated AP-1 activation, while the MEK1/2 inhibitor U0126 was not inhibitory despite suppression of c-Fos expression in mouse skin. Furthermore, SB203580 markedly inhibited COX-2 expression induced by TPA. Taken together, these findings suggest that celecoxib down-regulates COX-2 by blocking activation of p38 MAP kinase and AP-1, which may represent molecular mechanisms underlying antitumor promoting effects of this drug on mouse skin tumorigenesis.
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PMID:Celecoxib inhibits phorbol ester-induced expression of COX-2 and activation of AP-1 and p38 MAP kinase in mouse skin. 1472 83

Both UVB (280-320 nm) and UVA (320-400 nm) radiation lead to an enhanced expression of cyclooxygenase-2 (COX-2) in epidermal cells in various in-vitro and in-vivo models. It is demonstrated here that the expression of COX-2 is induced in artificial human epidermis exposed to simulated solar light (>290 nm). Employing filters eliminating specified regions from the simulated solar spectrum, the UVB and UVA-2 (320-350 nm) regions are shown to fully account for induction of COX-2 mRNA and protein as well as the enhanced production of prostaglandin E(2) after irradiation. At the protein level, approximately 70% of the total induction by solar light is due to light in the UVA-2 region. UVA-1 (350-400 nm), visible light and IR radiation are practically ineffective. COX-2 induction by simulated solar light is attenuated in the presence of inhibitors of p38(MAPK) or of c-Jun-N-terminal kinases (JNK), whereas COX-2 induction by UVA is blocked only by inhibition of JNK. UV-induced COX-2 expression is not affected by inhibition of the MEK 1,2/ERK 1,2 pathways.
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PMID:Contribution of UVB and UVA to UV-dependent stimulation of cyclooxygenase-2 expression in artificial epidermis. 1499 41

Cyclooxygenase-2 (COX-2) appears to play an important role in inflammation and carcinogenesis, and 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) is a hydrophilic azo compound known to generate free radicals. Because reactive oxygen species (ROS) are known to elevate COX-2 expression, we evaluated the effect of AAPH on the expression of COX-2 in a human keratinocyte cell line, HaCaT. When cells were exposed to AAPH, marked COX-2 induction was observed. To clarify the signaling mechanism involved, we next investigated the effects of AAPH upon three major subfamilies of the mitogen-activated protein kinases (MAPKs). AAPH caused an increase in the phosphorylation of extracellular signal-regulated kinase (ERK), p38 and c-Jun NH(2)-terminal kinase (JNK). Furthermore, we found that PD98059, an ERK pathway inhibitor, and SB203580, a p38 MAPK inhibitor, diminished AAPH-induced COX-2 expression and PGE(2) production, whereas JNK inhibitor did not suppress COX-2 expression or PGE(2) production by AAPH. These findings suggest that the ERK and p38 MAPK pathways, but not the JNK pathway, are involved in AAPH-induced inflammatory progression. In addition, we found that both the water-soluble Vitamin E derivative, Trolox, and the green tea constituent, (-)-epigallocatechin gallate (EGCG), diminished AAPH-induced COX-2 expression and p38 activation.
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PMID:Involvement of ERK AND p38 MAP kinase in AAPH-induced COX-2 expression in HaCaT cells. 1499 26

Interleukin-1 beta (IL-1 beta) is thought to act on the brain to induce fever, neuroendocrine activation, and behavioral changes during disease through induction of prostaglandins at the blood-brain barrier (BBB). However, despite the fact that IL-1 beta induces the prostaglandin-synthesizing enzyme cyclooxygenase-2 (COX-2) in brain vascular cells, no study has established the presence of IL-1 receptor type 1 (IL-1R1) protein in these cells. Furthermore, although COX inhibitors attenuate expression of the activation marker c-Fos in the preoptic and paraventricular hypothalamus after administration of IL-1 beta or bacterial lipopolysaccharide (LPS), they do not alter c-Fos induction in other structures known to express prostaglandin receptors. The present study thus sought to establish whether IL-1R1 protein is present and functional in the rat cerebral vasculature. In addition, the distribution of IL-1R1 protein was compared to IL-1 beta- and LPS-induced COX-2 expression. IL-1R1-immunoreactive perivascular cells were mostly found in choroid plexus and meninges. IL-1R1-immunoreactive vessels were seen throughout the brain, but concentrated in the preoptic area, subfornical organ, supraoptic hypothalamus, and to a lesser extent in the paraventricular hypothalamus, cortex, nucleus of the solitary tract, and ventrolateral medulla. Vascular IL-1R1-ir was associated with an endothelial cell marker, not found in arterioles, and corresponded to the induction patterns of phosphorylated c-Jun and inhibitory-factor kappa B mRNA upon IL-1 beta stimulation, and colocalized with peripheral IL-1 beta- or LPS-induced COX-2 expression. These observations indicate that functional IL-1R1s are expressed in endothelial cells of brain venules and suggest that vascular IL-1R1 distribution is an important factor determining BBB prostaglandin-dependent activation of brain structures during infection.
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PMID:Rat brain vascular distribution of interleukin-1 type-1 receptor immunoreactivity: relationship to patterns of inducible cyclooxygenase expression by peripheral inflammatory stimuli. 1502 56

Cyclooxygenase-2 (COX-2) is an inducible enzyme responsible for high-level prostaglandin production during inflammation and carcinogenesis. In this study, the transcriptional regulation of COX-2 expression induced by epidermal growth factor (EGF) in human epidermoid carcinoma A431 cells was studied. EGF treatment induced the expression of COX-2 mRNA, protein, promoter and enzyme activity in a time-dependent manner. EGF-induced COX-2 promoter activity was inhibited by overexpression of the dominant-negative forms of Ras and ERK2. Induction of COX-2 and c-Jun by EGF was completely suppressed by MEK inhibitor combined with JNK inhibitor. Analysis of the COX-2 promoter binding proteins by gel mobility shift assay and DNA affinity precipitation assay revealed that c-Jun and p300 binding to CRE/E-box site were responsible for the EGF-induced COX-2 gene transcription. Overexpression of p300 significantly enhanced COX-2 promoter activity in cells overexpressed of c-Jun or treated with EGF. EGF- and c-Jun-induced transcription of COX-2 promoter was repressed by cotransfection of E1A in a dose-dependent manner. All together, these results indicated that the EGF-induced expression of COX-2 in A431 cells was mediated through the Ras-ERK/JNK signaling pathway, and subsequent induction of c-Jun following MAPK activation, in cooperation with coactivator p300, was required for the EGF response.
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PMID:Essential role of c-Jun induction and coactivator p300 in epidermal growth factor-induced gene expression of cyclooxygenase-2 in human epidermoid carcinoma A431 cells. 1523 18

Polychlorinated biphenyls (PCBs), a group of persistent and widespread environmental pollutants, are considered to be immunotoxic, carcinogenic, and to induce apoptosis. However, the cellular mechanisms underlying the action of PCBs have not been established. Here, we investigated the effects of PCBs on the induction of cyclooxygenase-2 (COX-2). Among the several congeners examined, only 2,2',4,6,6'-pentachlorobiphenyl (PeCB) specifically increased the COX-2 promoter activity, and the levels of COX-2 mRNA and protein, and thereby enhanced prostaglandin E2 (PGE2) synthesis in Rat-1 cells. By conducting mutation analyses of the COX-2 promoter and its transcription factor, we found that the CRE site in COX-2 promoter and c-Jun are important for increased COX-2 promoter activity induced by 2,2',4,6,6'-PeCB. In addition, 2,2',4,6,6'-PeCB-stimulated COX-2 induction was reduced by the specific MAPK kinase (MEK) inhibitor, PD98059, and in p53-deficient cells, implying that COX-2 induction requires the activation of ERK1/2 MAPK and p53. The selective COX-2 inhibitor, NS-398, potentiated the 2,2',4,6,6'-PeCB-induced mitochondrial apoptotic pathway involved in Bcl-xL attenuation, cytochrome c release and the subsequent activation of caspase-3. Furthermore, the cell death was prevented by PGE2 treatment, suggesting that 2,2',4,6,6'-PeCB-induced apoptosis is restricted by prostaglandin upregulation by COX-2. Taken together, these results demonstrate that 2,2',4,6,6'-PeCB-induced COX-2 expression may be an important compensatory mechanism for abating 2,2',4,6,6'-PeCB toxicity.
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PMID:2,2',4,6,6'-Pentachlorobiphenyl-induced apoptosis is limited by cyclooxygenase-2 induction. 1552 91


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