Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclooxygenase-2 is the rate-limiting enzyme in synthesis of prostaglandins and other eicosanoids. Prior reports have shown that inhibition of cyclooxygenase-2 activity, either by selective inhibitors or by antisense oligonucleotide, results in suppression of growth of squamous cell carcinoma cell lines which express high cyclooxygenase-2 levels, such as NA, a cell line established from a squamous cell carcinoma of the tongue. To investigate the mechanisms by which cyclooxygenase-2 inhibitors suppressed growth of these cells, the effects of NS-398, the selective cyclooxygenase-2 inhibitor, on cell-cycle distribution were examined. NS-398 induced G0/G1 cell-cycle arrest in NA cells which expressed cyclooxygenase-2. G0/G1 arrest induced by NS-398 was accompanied by up-regulation of cyclin-dependent kinase inhibitor p21, but not by up-regulation of the other cyclin-dependent kinase inhibitors. Transfection with p21 antisense oligonucleotide inhibited cell-cycle arrest induced by NS-398. Accumulation in G0/G1 was also observed in NA cells transfected with cyclooxygenase-2 antisense oligonucleotide. On the other hand, NS-398-treated NA cells showed a loss of plasma membrane asymmetry, a marker of early events in apoptosis. However, NS-398 did not induce other morphological and biochemical changes related to apoptotic cell death. These results suggest that cyclooxygenase-2 inhibitor induces G0/G1 cell-cycle arrest in NA cells by up-regulation of p21. Our results also suggest that NS-398 is not sufficient to complete the whole process of apoptosis in NA cells, although it induces an early event in apoptosis.
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PMID:Inhibitor of cyclooxygenase-2 induces cell-cycle arrest in the epithelial cancer cell line via up-regulation of cyclin dependent kinase inhibitor p21. 1195 64

This study was designed to elucidate the molecular mechanism(s) mediating cyclooxygenase-2 (Cox-2) regulation during differentiation of the granulosa cell. The 5' flanking sequence of the Cox-2 gene was linked to a vector with a luciferase reporter gene, and this vector was transfected into freshly isolated bovine granulosa cells or granulosa cells after culture with or without forskolin to induce luteinization in vitro. The Cox-2 promoter was inducible by 8-bromo cAMP but not by phorbol esters in fresh granulosa cells, and maximal expression by cAMP was delayed until 48 h after treatment. In contrast, after luteinization of granulosa cells by 8-day treatment with forskolin, the Cox-2 promoter was immediately inducible by phorbol esters but not by cAMP. In granulosa cells cultured for 8 days without forskolin, the Cox-2 promoter continued to be inducible only by cAMP and not by phorbol esters. Unexpectedly, no delay was observed in the induction of Cox-2 by cAMP in granulosa cells that were cultured without forskolin, compared with an approximately 1 day delay in Cox-2 induction by cAMP in fresh granulosa cells. Myristoylated protein kinase (PK) A and PKC inhibitory peptides were utilized to further confirm the PKA- or PKC-dependence of Cox-2 induction. Time-course experiments showed that only 2 days of forskolin treatment could induce PKC-responsiveness of the Cox-2 promoter, although maximal responsiveness was not observed until 10 days of luteinization. Promoter activity was also analyzed in a series of deletion mutants as well as site-directed mutants of C/EBP, CRE, and E-box. A 282-base pair sequence in the Cox-2 5' flanking region maintained full inducibility by PKA in granulosa cells and by PKC in luteinized granulosa cells. The E-box element was found to be the critical regulatory element for Cox-2 induction by either PKA in granulosa cells or by PKC in luteinized granulosa cells. Electrophoretic mobility shift assays were performed on nuclear extracts from fresh or luteinized granulosa cells. Upstream stimulatory factor (USF)-1 and USF-2 bound to the E-box of the Cox-2 gene, and binding was similar for nuclear extracts from fresh, cultured, or luteinized granulosa cells. Thus, although luteinization changes transcriptional regulation of Cox-2 from PKA- to PKC-dependence, the crucial role of the E-box element in this transcriptional activation is conserved.
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PMID:Transcriptional regulation of the cyclooxygenase-2 gene changes from protein kinase (PK) A- to PKC-dependence after luteinization of granulosa cells. 1196 17

Development, growth and function of the ovary are controlled by endocrine and paracrine signals. These may also influence the development of ovarian cancer. The aim of this study was to identify the key molecular markers of the unregulated growth and hormone synthesis seen in ovarian tumours, particularly in granulosa cell tumours (GCT). Genes used in this study were chosen on the basis of our understanding of growth and differentiation in the normal ovary. We sought to define the patterns of gene expression in a panel of epithelial and stromal ovarian tumours. Expression was determined by RT-PCR using gene-specific primers for the FSH receptor (FSHR); the FSH early response genes: regulatory subunit of protein kinase A (RII-beta), cyclin D2 (cycD2) and sgk; and late response markers: cyclooxygenase-2 (COX-2) and the LH receptor (LHR). The GCT had high expression of FSHR compared with normal ovaries and the other tumours. cycD2 and RII-beta and COX-2 genes were also highly expressed in the GCT. sgk and LHR expression was lower in all of the tumours than in normal ovaries. Serous cystadenocarcinomas also had an unexpectedly high expression of COX-2. Comparison of the gene expression profiles between each tumour group suggests a molecular phenotype for GCT that is similar to that reported for FSH stimulated pre-ovulatory granulosa cells.
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PMID:FSH-regulated gene expression profiles in ovarian tumours and normal ovaries. 1199 39

We investigated the regulation of PG production in human endometrial stromal cells (ESC) by IL-1beta. We found that cyclooxygenase-2 (COX-2) mRNA and protein levels and PGE(2) production in ESC were significantly increased by IL-1beta. COX-2 mRNA, protein, and PGE(2) levels in IL-1beta-treated ESC were decreased by a PKA inhibitor, a nuclear factor (NF-kappaB) inhibitor, and an ERK1/2 inhibitor, but not by a p38 MAPK inhibitor or a PKC inhibitor, suggesting the possible involvement of PKA, NF-kappaB, and/or the ERK1/2 signaling pathway(s) in IL-1beta-mediated COX-2 gene induction in ESC. We then transiently transfected deletion mutants of the COX-2 promoter fused to the luciferase reporter gene and variants of -360/+56 bp promoter construct carrying different site-directed mutations of selected cis-acting elements. We determined that a NF-kappaB site (-222/-213 bp), a nuclear factor for IL-6 expression site (NF-IL6, -132/-124 bp), and a cAMP response element (-59/-52 bp) were essential for the baseline COX-2 gene promoter regulation. The addition of IL-1beta, however, did not affect the activity of these COX-2 promoter constructs. To investigate the potential effects of IL-1beta on COX-2 mRNA stability, ESC were treated with actinomycin D, a general transcription inhibitor, in the absence or presence of IL-1beta. We found that 1) IL-1beta significantly increased COX-2 mRNA stability; 2) continuous transcription was not required to sustain the IL-1beta-induced COX-2 mRNA levels; and 3) COX-2 mRNA was highly unstable in the absence of IL-1beta. Additionally, we found that the ERK1/2 signaling pathway was essential for stabilizing COX-2 mRNA. We conclude that levels of COX-2 mRNA, protein, and enzyme activity in ESC are controlled by various signaling pathways, including PKA, ERK1/2, and NF-kappaB. Moreover, posttranscriptional mRNA stability is an important mechanism for IL-1beta-induced elevation of COX-2 expression in ESC.
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PMID:Interleukin-1beta elevates cyclooxygenase-2 protein level and enzyme activity via increasing its mRNA stability in human endometrial stromal cells: an effect mediated by extracellularly regulated kinases 1 and 2. 1210 35

Cyclooxygenase-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins. The overexpression of cyclooxygenase-2 has been reported in skin cancer cells, and may be involved in carcinogenesis. Prostaglandin E2, the end product of cyclooxygenase-2-induced catalysis, autoamplifies the cyclooxygenase-2 expression. It is suggested that an anti-mycotic drug, ketoconazole may inhibit carcinogenesis. We herein investigated if ketoconazole may inhibit prostaglandin E2-induced cyclooxygenase-2 expression in human epidermoid carcinoma A-431 cells. Ketoconazole suppressed prostaglandin E2-induced cyclooxygenase-2 protein and mRNA expression and promoter activation in A-431; the suppressive effects of ketoconazole were counteracted by cyclic adenosine monophosphate analog. Analyses using deleted or mutated cyclooxygenase-2 promoters revealed that cyclic adenosine monophosphate response element (- 59 to - 53 bp) on the promoter was involved in prostaglandin E2-induced stimulation and ketoconazole-induced inhibition of the promoter activity. Electrophoretic mobility shift assays indicated that cyclic adenosine monophosphate response element binding protein and activating transcription factor-1 may constitutively bind to cyclic adenosine monophosphate response element on cyclooxygenase-2 promoter. Prostaglandin E2 increased the proportion of phosphorylated forms among total bound cyclic adenosine monophosphate response element binding protein/activating transcription factor-1, and the effect was suppressed by ketoconazole. Prostaglandin E2 induced the phosphorylation of cyclic adenosine monophosphate response element binding protein and activating transcription factor-1, and the phosphorylation was suppressed by cyclic adenosine monophosphate-dependent protein kinase (protein kinase A) inhibitor, indicating protein kinase A-mediated phosphorylation. Ketoconazole suppressed the prostaglandin E2-induced phosphorylation of cyclic adenosine monophosphate response element binding protein/activating transcription factor-1. Prostaglandin E2 increased intracellular cyclic adenosine monophosphate level by activating adenylate cyclase in A-431, and the increase was suppressed by ketoconazole. These results suggest that ketoconazole may suppress prostaglandin E2-induced cyclooxygenase-2 expression by inhibiting the cyclic adenosine monophosphate signal in A-431, and stress its anti-cancer effect.
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PMID:Ketoconazole suppresses prostaglandin E(2)-induced cyclooxygenase-2 expression in human epidermoid carcinoma A-431 cells. 1216 41

This study investigated the role of p44/42 and p38 mitogen-activated protein kinase (MAPK) in cyclooxygenase-2 expression caused by lipoteichoic acid in human pulmonary epithelial cell line (A549). Lipoteichoic acid-induced increases in cyclooxygenase activity and cyclooxygenase-2 expression were attenuated by tyrosine kinase inhibitors (genistein and tyrphostin AG126), a MAPK/extracellular signal-regulated protein kinase (MEK) inhibitor [2'-amino-3'-methoxyflavone] (PD 98059) and a p38 MAPK inhibitor [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole] (SB 203580). Lipoteichoic acid-induced p44/42 MAPK activation was inhibited by protein kinase C (PKC) inhibitors [12-(2-cyanoethyl)6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole] (Go 6976) and [3-[1-[3-(amidinothio)propyl-1H-indol-3-yl]-3-(1-methyl-1H-indol-3-yl)maleimide]] (Ro 31-8220), genistein and PD 98059. Lipoteichoic acid-induced increase in p38 MAPK activity was inhibited by Go 6976, Ro 31-8220, genistein and SB 203580. Lipoteichoic acid-mediated formation of nuclear factor-kappa B (NF-kappa B)-specific DNA-protein complex was inhibited by genistein, tyrphostin AG126, PD 98059 and SB 203580. These results suggest that the activations of both p44/42 and p38 MAPK by lipoteichoic acid result in stimulation of NF-kappa B-specific DNA-protein binding and subsequent cyclooxygenase-2 expression in A549 cells. Both events required activation of upstream tyrosine kinase and PKC.
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PMID:Lipoteichoic acid-induced cyclooxygenase-2 expression requires activations of p44/42 and p38 mitogen-activated protein kinase signal pathways. 1217 2

Mechanical loading of bone generates fluid flow within the mineralized matrix which can exert fluid shear stress (FSS) at cell membranes. FSS induces new transcription of cyclooxygenase-2 (COX-2) in MC3T3-E1 osteoblasts, with peak effects at 4-5h. Using MC3T3-E1 cells stably transfected with the COX-2 promoter fused to a luciferase reporter, we examined involvement of the protein kinase A (PKA) and protein kinase C (PKC) signaling pathways in the peak COX-2 mRNA and luciferase responses to FSS (10dyn/cm(2)). Neither inhibition nor down-regulation of the PKC pathway affected the FSS stimulation of COX-2 mRNA or luciferase activity. In contrast, inhibitors of the PKA pathway, used at doses which inhibited forskolin-stimulated luciferase activity by 70-80%, reduced FSS-stimulated COX-2 mRNA expression and luciferase activity by 50-80%. Hence, peak FSS induction of COX-2 expression in MC3T3-E1 osteoblastic cells is largely dependent on the PKA signaling pathway.
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PMID:Fluid flow induces COX-2 expression in MC3T3-E1 osteoblasts via a PKA signaling pathway. 1222 May 6

We examined the inhibitory mechanism of byakangelicol, isolated from Angelica dahurica, on interleukin-1beta (IL-1beta)-induced cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) release in human pulmonary epithelial cell line (A549). Byakangelicol (10-50 microM) concentration-dependently attenuated IL-1beta-induced COX-2 expression and PGE2 release. The selective COX-2 inhibitor, NS-398 (0.01-1 microM), and byakangelicol (10-50 microM) both concentration-dependently inhibited the activity of the COX-2 enzyme. Byakangelicol, at a concentration up to 200 microM, did not affect the activity and expression of COX-1 enzyme. IL-1beta-induced p44/42 mitogen-activated protein kinase (MAPK) activation was inhibited by the MAPK/extracellular signal-regulated protein kinase (MEK) inhibitor, PD 98059 (30 microM), while byakangelicol (50 microM) had no effect. Treatment of cells with byakangelicol (50 microM) or pyrrolidine dithiocarbamate (PDTC; 50 microM) partially inhibited IL-1beta-induced degradation of IkappaB-alpha in the cytosol, translocation of p65 NF-kappaB from the cytosol to the nucleus and the NF-kappaB-specific DNA-protein complex formation. Taken together, we have demonstrated that byakangelicol inhibits IL-1beta-induced PGE2 release in A549 cells; this inhibition may be mediated by suppression of COX-2 expression and the activity of COX-2 enzyme. The inhibitory mechanism of byakangelicol on IL-1beta-induced COX-2 expression may be, at least in part, through suppression of NF-kappaB activity. Therefore, byakangelicol may have therapeutic potential as an anti-inflammatory drug on airway inflammation.
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PMID:Byakangelicol, isolated from Angelica dahurica, inhibits both the activity and induction of cyclooxygenase-2 in human pulmonary epithelial cells. 1235 82

Interferon-induced protein of 10 kDa (IP-10) induces antitumor immunity. Cyclooxygenase-2 and its metabolite prostaglandin E2 (PGE2) are overexpressed in tumor cells, which may suppress antitumor immunity. We examined the in vitro effects of cyclooxygenase-2 inhibitor NS398 on IP-10 production in human epidermoid carcinoma A431. NS398 enhanced interferon-gamma-induced IP-10 secretion, mRNA expression, and promoter activation in A431, and exogenous PGE2 antagonized the enhancement. Interferon-stimulated response element (ISRE) on IP-10 promoter was responsible for the transcriptional regulation by NS398 and PGE2. NS398 enhanced interferon-gamma-induced transcription through ISRE and binding of signal transducer and activator of transcription 1alpha (STAT1alpha to ISRE in A431, and PGE2 antagonized the enhancement. NS398 enhanced interferon-gamma-induced tyrosine phosphorylation of STAT1alpha, Janus tyrosine kinase 1, and Janus tyrosine kinase 2, and PGE2 antagonized the enhancement. PGE2-mediated suppression of IP-10 synthesis was counteracted by adenylate cyclase inhibitor SQ22536 and protein kinase A inhibitor H-89, and PGE2 receptor EP4 antagonist AH23848B. AH23848B, SQ22536, and H-89 counteracted the PGE2-mediated suppression of ISRE-dependent transcription, STAT1alpha binding to ISRE, and tyrosine phosphorylation of STAT1alpha, Janus tyrosine kinase 1, and Janus tyrosine kinase 2. PGE2 increased intracellular cAMP level and protein kinase A activity in A431 pretreated with NS398, and AH23848B blocked the effects of PGE2. These results suggest that A431-derived PGE2 may generate cAMP signal via EP4 in A431, which may activate protein kinase A, and may resultantly inhibit interferon-gamma-induced STAT1alpha activation and IP-10 synthesis. The results also suggest that NS398 may restore IP-10 synthesis by preventing PGE2 production in A431 and thus may be therapeutically useful for skin cancer.
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PMID:Cyclooxygenase-2 inhibitor enhances whereas prostaglandin E2 inhibits the production of interferon-induced protein of 10 kDa in epidermoid carcinoma A431. 1244 96

In this study the regulation of macrophage expression of cyclooxygenase-2 (COX-2) in response to dsRNA and virus infection was examined. Treatment of RAW 264.7 macrophages with dsRNA results in COX-2 mRNA accumulation and protein expression and the production of PGE(2). Similar to dsRNA, encephalomyocarditis virus (EMCV) infection of RAW 264.7 cells stimulates COX-2 expression and PGE(2) accumulation. The dsRNA-dependent protein kinase (PKR), which has been shown to participate in the regulation of gene expression in response to dsRNA and virus infection, does not appear to participate in the regulation of COX-2 expression by macrophages. Expression of dominant negative mutants of PKR in RAW 264.7 cells fails to attenuate dsRNA- and EMCV-induced COX-2 expression or PGE(2) production. Furthermore, dsRNA and EMCV stimulate COX-2 expression and PGE(2) accumulation to similar levels in macrophages isolated from wild-type and PKR-deficient mice. Recently, a novel PKR-independent role for the calcium-independent phospholipase A(2) (iPLA(2)) in the regulation of inducible NO synthase expression by macrophages in response to virus infection has been identified. The selective iPLA(2) suicide substrate inhibitor bromoenol lactone prevents dsRNA- and EMCV-stimulated inducible NO synthase expression; however, bromoenol lactone does not attenuate dsRNA- or EMCV-induced COX-2 expression by macrophages. In contrast, inhibition of NF-kappaB activation prevents dsRNA-stimulated COX-2 expression and PGE(2) accumulation by macrophages. These findings indicate that virus infection and treatment with dsRNA stimulate COX-2 expression by a mechanism that requires the activation of NF-kappaB and that is independent of PKR or iPLA(2) activation.
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PMID:Regulation of cyclooxygenase-2 expression by macrophages in response to double-stranded RNA and viral infection. 1251 75


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