Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An anti-tumor-promoting effect of indomethacin and related nonsteroidal anti-inflammatory drugs (NSAIDs) as well as the ability of the tumor promoter 12-O-tetradecanoylphorbol-13- acetate (TPA) to increase the level of prostaglandins in murine keratinocytes and mouse epidermis in vivo has been repeatedly documented. Here, the expression of prostaglandin H synthase (PGHS) isozymes, which are major targets of NSAIDs, was investigated in different stages of tumor development in mouse skin. Mouse epidermis in vivo constitutively expressed PGHS-1. PGHS-1 steady-state levels remained unchanged upon induction of acute or chronic epidermal hyperplasia by TPA and in papillomas and carcinomas generated by the initiation-promotion procedure, with 7,12-dimethylbenz[a]anthracene as initiator and TPA as promoter. Thus, the elevated prostaglandin level in the acute hyperplastic epidermis was very likely due to PGHS-2 induction. Repeated applications of TPA resulted in stationary hyperplasia and downregulation of PGHS-2 expression and prostaglandin levels, suggesting that the epidermis had adapted to the TPA stimulus. In papillomas and carcinomas, however, constitutive overexpression of PGHS-2 was found, with a large amount of prostaglandin E2 and prostaglandin F2 alpha. Keratinocyte cell lines corresponding to different stages of tumor development also constitutively over-expressed PGHS-2. Considered with inhibitor studies, these data suggest that PGHS-2 has a critical role in skin carcinogenesis. The anti-tumor-promoting effect of the PGHS inhibitor indomethacin is specifically reversed by prostaglandin F2 alpha, indicating that this prostaglandin type has a significant role in tumor development.
Mol Carcinog 1995 Jan
PMID:Differential expression of prostaglandin H synthase isozymes during multistage carcinogenesis in mouse epidermis. 781 63

A mitogen-inducible prostaglandin G/H synthase (PGHS-2 or cyclooxygenase-2) has recently been cloned from chicken and mouse fibroblasts. This protein is distinct from classic prostaglandin G/H synthase (PGHS-1 or cyclooxygenase-1) but has a similar enzymatic activity. Because PGHS-1 is a rate-limiting enzyme in the synthesis of prostaglandins, PGHS-2 may also play an important role in prostaglandin production. To examine whether PGHS-2 is induced by phorbol ester in mast cells, we studied mRNA expression of PGHS-2 and also measured prostaglandin D2 (PGD2) production when canine mastocytoma cells were incubated with phorbol myristate acetate (PMA). PGHS-2 mRNA was induced by PMA, with a maximal induction after 4 h of incubation with 10 nM PMA. There was concentration-dependent production of PGD2 after incubation with PMA. In contrast, PGHS-1 mRNA was expressed in resting cells, and the expression of PGHS-1 mRNA was down-regulated by PMA. Dexamethasone inhibited PMA-induced mRNA expression of PGHS-2 and PGD2 production. Aspirin had no effect on mRNA expression of PGHS-2 but inhibited PGD2 production. In conclusion, PGHS-2 is induced by phorbol ester in canine mast cells. We speculate that PGHS-2 may be important in airway inflammation in which mast cells are activated.
Am J Respir Cell Mol Biol 1993 Nov
PMID:Mitogen-inducible prostaglandin G/H synthase is expressed in canine mastocytoma cells. 821 94

The human amnion may be an important source of prostaglandins involved in the onset of labour. Glucocorticoids are possible regulators of amnion prostaglandin synthesis and have been shown to stimulate the PGE2 output and prostaglandin H2 synthase (PGHS) activity of human amnion cells maintained in primary monolayer culture. There are two known isoforms of PGHS: the constitutively expressed PGHS-1 and the inducible PGHS-2. Recent studies have shown that the latter isoform is induced by glucocorticoids. The amnion consists of a single layer of epithelial cells beneath which lies a mesenchymal layer containing fibroblasts and it is not known which cell types are responding to glucocorticoids in this manner. In the present study, we demonstrate that although both cell types are present in culture, PGHS-2 protein and mRNA levels increase exclusively within the fibroblasts in response to dexamethasone, while PGHS-1 protein and mRNA levels remain unaffected in both cell types. These results suggest that the stimulation of PGE2 in cultured amnion cells by glucocorticoids is due to an upregulation of PGHS-2 gene transcription in fibroblasts, and that these previously overlooked cells may have important roles to play in the synthesis of prostaglandins involved in labour.
Mol Cell Endocrinol 1996 Mar 25
PMID:Glucocorticoids stimulate prostaglandin H synthase type-2 (PGHS-2) in the fibroblast cells in human amnion cultures. 873 73

Prostaglandin H synthase (PGHS) is the rate-limiting enzyme responsible for the formation of the prostaglandins from arachidonic acid. Prostaglandins (and other metabolites) elicit signals for inflammation, which is thought to be required for tumor promotion in the mouse skin carcinogenesis model. This study was designed to examine the effect of protein kinase C (PKC)-activating tumor promoters (4 beta-12-O-tetradecanoylphorbol-13-acetate (TPA)), non-PKC-type promoters (anthralin, benzoyl peroxide, okadaic acid), and mitogens (epidermal growth factor (EGF)) on the levels of the constitutive (PGHS-1) and inducible (PGHS-2) forms of PGHS in murine keratinocytes. Northern analysis of mRNA isolated from cultures treated with TPA (1 microgram/mL) showed that a single treatment of TPA produced a sevenfold increase in PGHS-2 mRNA by 1 h that decreased by 6 h after treatment. PGHS-2 protein levels were elevated threefold by 3 h and remained elevated through 9 h. Downregulation of PKC with a second TPA treatment 15 h after the first resulted in diminished induction of PGHS-2 expression. Of the other promoters examined, anthralin (5 microM), benzoyl peroxide (10 microM), and okadaic acid (1 microM) induced PGHS-2 mRNA with different kinetics and to different extents. Additionally, the non-tumor-promoting phorbol ester analogue 4 alpha-12-O-tetradecanoylphorbol-13-acetate induced PGHS-2 mRNA significantly by 1 h, and this response remained elevated up to 6 h after treatment. Elevated PGHS-2 expression was also observed by 3 h in response to EGF (10 ng/mL) treatment. Collectively, these observations indicate that there are several different signaling pathways by which PGHS-2 can be upregulated in murine keratinocytes.
Mol Carcinog 1996 Dec
PMID:Multifactor regulation of prostaglandin H synthase-2 in murine keratinocytes. 898 14

Cyclo-oxygenase (COX) is a rate-limiting enzyme that converts arachidonic acid to prostaglandins (PGs) and exists in two isoforms, COX-1 and COX-2. In the rodent, increased uterine vascular permeability at sites of blastocyst apposition is one of the earliest prerequisite events in the implantation process. This event is preceded by generalized uterine edema and luminal closure, and coincides with the initial attachment reaction between the trophectoderm and luminal epithelium. Vasoactive PGs are implicated in these processes. Here we demonstrate that COX genes are differentially regulated in the peri-implantation mouse uterus. During the preimplantation period (days 1-4), the COX-1 gene was expressed in the uterine epithelium mainly on day 4 until the initiation of attachment reaction in the evening after which the expression was downregulated. This COX-1 expression coincides with the generalized uterine edema required for luminal closure. In contrast, the COX-2 gene was expressed in the luminal epithelium and subepithelial stromal cells at the anti-mesometrial pole exclusively surrounding the blastocyst at the time of attachment reaction on day 4 and persisted through the morning of day 5. This uterine gene was not expressed at the sites of blastocyst apposition during progesterone (P(4))-treated delayed implantation, but was readily induced in the uterus surrounding the activated blastocysts after termination of the delay by estradiol-17beta (E(2)). The results suggest that PG synthesis catalyzed by COX-2 is important for localized increased uterine vascular permeability and attachment reaction. The COX-1 gene that was downregulated from the time of attachment reaction on day 4 was again expressed in the mesometrial and anti-mesometrial secondary decidual beds on days 7 and 8. These results suggest that PGs generated by COX-1 are involved in decidualization and/or continued localized endometrial vascular permeability observed during this period. In contrast, the COX-2 gene, expressed at the anti-mesometrial pole on days 4 and 5, switched its expression to the mesometrial pole from day 6 onward. These results suggest that PGs produced at this site by COX-2 are involved in angiogenesis for the establishment of placenta. In the ovariectomized mice, the COX-1 gene was induced in the epithelium by a combined treatment with P(4) and E(2). However, P(4) and/or E(2) treatments failed to influence the uterine COX-2 gene. Overall, the results suggest that the uterine COX-1 gene is influenced by ovarian steroids, while the COX-2 gene is regulated by the implanting blastocyst during early pregnancy.
J Mol Endocrinol 1996 Apr
PMID:Developmental expression of the cyclo-oxygenase-1 and cyclo-oxygenase-2 genes in the peri-implantation mouse uterus and their differential regulation by the blastocyst and ovarian steroids. 915 14

Acetylsalicylic acid (aspirin) is the drug most commonly self-administered to reduce inflammation, swelling, and pain. The established mechanism of action of aspirin is inhibition of the enzyme cyclo-oxygenase (COX). Once taken, aspirin is rapidly deacetylated to form salicylic acid, which may account, at least in part, for the therapeutic actions of aspirin. However, where tested, salicylic acid has been found to be a relatively inactive inhibitor of COX activity in vitro, despite being an effective inhibitor of prostanoids formed at the site of inflammation in vivo. Recently, the identification of a cytokine-inducible isoform of COX, COX-2, has led to the suggestion that salicylate produces its anti-inflammatory actions by inhibiting COX-2 induction through actions on nuclear factor kappaB (NF-kappaB). We have used interleukin 1beta-induced COX-2 in human A549 cells to investigate the mechanism of action of salicylate on COX-2 activity. Sodium salicylate inhibited prostaglandin E2 release when added together with interleukin 1beta for 24 hr with an IC50 value of 5 microg/ml, an effect that was independent of NF-kappaB activation or COX-2 transcription or translation. Sodium salicylate acutely (30 min) also caused a concentration-dependent inhibition of COX-2 activity measured in the presence of 0, 1, or 10 microM exogenous arachidonic acid. In contrast, when exogenous arachidonic acid was increased to 30 microM, sodium salicylate was a very weak inhibitor of COX-2 activity with an IC50 of >100 microg/ml. Thus, sodium salicylate is an effective inhibitor of COX-2 activity at concentrations far below those required to inhibit NF-kappaB (20 mg/ml) activation and is easily displaced by arachidonic acid.
Mol Pharmacol 1997 Jun
PMID:Sodium salicylate inhibits cyclo-oxygenase-2 activity independently of transcription factor (nuclear factor kappaB) activation: role of arachidonic acid. 918 56

Expression of mRNAs encoding the two prostaglandin endoperoxide synthase (PGHS) isoenzymes (PGHS-1 and -2) was investigated in differentiating clonal Ob1771 mouse preadipocytes and in mouse adipose tissues. Northern analysis revealed that the expression level of PGHS-1 mRNA was reduced by 98+/-0.2% (P <0.01) during differentiation of Ob1771 cells, whereas PGHS-2 mRNA was not detected. By reverse transcriptase-polymerase chain reaction analysis, however, both PGHS-1 and -2 mRNA was detected in Ob1771 preadipose cells. In addition. mRNAs encoding both isoforms were markedly expressed in primary adipose precursor cells with considerably lower expression levels in mature adipocytes (56 75% reduction, P<0.01). Furthermore, exposure to dexamethasone (10 nM) for both 24 h (explants of adipose tissue) and 48 h (Ob1771 adipose cells) resulted in enhanced expression of PGHS-1 mRNA. whereas expression of PGHS-2 mRNA in explants of adipose tissue (24 h incubation) was reduced by 83 +/- 9% (P<0.05). In contrast, exposure to angiotensin II (100 nM) enhanced expression of PGHS-1 mRNA both in mature adipocytes (4 h incubation) and explants of adipose tissue (24 h incubation), and elevated PGHS-2 mRNA expression in mature adipocytes (4 h incubation). In conclusion, this report suggests a differential expression of PGHS mRNAs during adipose cell differentiation, and further suggests that the machinery for prostaglandin synthesis in mature adipocytes may be induced by various hormones.
Mol Cell Endocrinol 1997 Jul 04
PMID:Expression of the two isoforms of prostaglandin endoperoxide synthase (PGHS-1 and PGHS-2) during adipose cell differentiation. 925 65

Prostaglandins (PGs) are well known for their role in reproductive processes. At the time of pregnancy recognition, PGF2alpha is luteolytic and PGE2 may be antiluteolytic and luteotropic. During the preimplantation period, interferon-tau (IFN-tau) is produced by the conceptus and plays a crucial role in maternal recognition of pregnancy in domestic ruminants. We have demonstrated previously that recombinant bovine and ovine interferon-tau (rbIFN-tau and roIFN-tau) stimulate PGE2 production in epithelial cells, changing the primary PG produced by these cells from F2alpha to E2. In stromal cells, where PGE2 is the major PG produced, roIFN-tau induced an increase of both types of PGs. The aim of this paper is to identify the possible involvement of cyclooxygenases (COXs) in the modulation of PG production by trophoblastic interferons. Epithelial and stromal cells cultured in vitro were isolated from bovine endometrium and stimulated with increasing doses (1, 10 and 20 microg/ml) of roIFN-tau. PG levels in the culture media were measured by enzyme immunoassays (EIA) and total RNA was extracted from the cells. Northern blot analysis was performed to quantify cyclooxygenase COX-1 (constitutive), COX-2 (inducible) and phospholipase A2 (PLA2) messenger RNA (mRNA) production in response to treatment. The results indicate that roIFN-tau treatment did not affect COX-1 and PLA2 mRNA production in either cell type, whereas COX-2 expression was upregulated in both. The up-regulation of COX-2 transcript was greater in stromal than in epithelial cells. The increase in COX-2 mRNA levels was concurrent with increased production of PGE2 and PGF2alpha in stromal cells and principally PGE2 in epithelial cells. Furthermore, addition of indomethacin (1 microM) and a specific COX-2 inhibitor (NS-398, 1 microM) blocked the roIFN-tau-stimulation of PG production in both cell types. The mechanism whereby elevated COX-2 expression results in a selective increase of PGE2 in epithelial cells remains to be elucidated. In stromal cells, an increase in COX-2 mRNA levels may explain increased PG production. The overall effect of roIFN-tau in the two cell types is a net increase in PGE2 output.
Mol Cell Endocrinol 1997 Sep 19
PMID:IFN-tau increases PGE2 production and COX-2 gene expression in the bovine endometrium in vitro. 932 53

The three-dimensional cocrystal structures of ovine prostaglandin G/H synthase-1 (PGHS-1) with S-flurbiprofen and murine PGHS-2 with S-flurbiprofen and indomethacin reveal that the carboxylate acid groups of these nonsteroidal anti-inflammatory drugs (NSAIDs) form a salt bridge with the guanidinium group of Arg120 in PGHS-1 and Arg106 in PGHS-2. Mutagenesis studies confirmed that the Arg120 residue of PGHS-1 is critical for binding of substrate and inhibitors through ionic interactions of its guanidinium group with the carboxylate moieties of arachidonic acid and certain NSAIDs. We report here that the analogous R106E substitution in human PGHS-2 results in a catalytically active enzyme with a 30-fold higher Km value for arachidonic acid. Comparison of the inhibition of hPGHS-2(R106E) with wild-type hPGHS-2 by 11 structurally diverse selective and nonselective PGHS inhibitors revealed a 0-1000-fold decrease in inhibitory potency on the mutant enzyme. The loss of inhibitory potency of NSAIDs on hPGHS-2(R106E) could not be correlated with the presence or absence of a carboxylate functional group in the inhibitor, as was demonstrated previously for the PGHS-1(R120E) mutant, or with the selective or nonselective nature of the PGHS inhibitor. The decreases in the inhibitory potencies on hPGHS-2(R106E) by the carboxylate-containing NSAIDs flurbiprofen, indomethacin, meclofenamic acid, and diclofenac on hPGHS-2(R106E) were 965-, 48-, 5.5-, and 4.5-fold, respectively. The nonuniversal requirement for interaction of the carboxylate group of certain NSAIDs with the Arg106 residue in hPGHS-2 is supported by the observation that the methyl ester derivative of indomethacin was a more potent inhibitor than indomethacin on both hPGHS-2 and hPGHS-2(R106E). The greatest loss of potency for inhibition of hPGHS-2(R106E) was observed with the hPGHS-2-selective sulfonamide-containing inhibitors NS-398 and flosulide. The PGHS-2-selective inhibitor DuP697 and a desbromo-sulfonamide analogue of DuP697 displayed equivalent potency on hPGHS-2(R106E) and hPGHS-2. The change in inhibitory potency of NS-398 on hPGHS-2(R106E) was due to a difference in the kinetics of inhibition, with NS-398 displaying time-dependent inhibition of hPGHS-2 but time-independent inhibition of PGHS-2(R106E). The time-dependent inhibition of hPGHS-2 by DuP697 was not affected by the presence of the R106E mutation. We conclude that the Arg106 residue of hPGHS-2 is involved in binding arachidonic acid and certain NSAIDs, but interactions with Arg106 are not a universal requirement for inhibition by either carboxylate-containing NSAIDs or PGHS-2-selective inhibitors.
Mol Pharmacol 1997 Nov
PMID:The interaction of arginine 106 of human prostaglandin G/H synthase-2 with inhibitors is not a universal component of inhibition mediated by nonsteroidal anti-inflammatory drugs. 935 74

Treatment with ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDS) has been reported to decrease the incidence as well as slow down the progression of Alzheimer's disease. Understanding the mechanism of this therapeutic effect would provide a target for development of drugs which may be devoid of side effects observed with NSAIDs. In addition to inhibiting cyclooxygenase (COX), the NSAIDs have recently been shown to decrease inducible nitric oxide synthase (iNOS) activity. Ibuprofen and other NSAIDs had no direct effect on catalytic activity of iNOS, but decreased levels of iNOS mRNA. The mechanism of action of ibuprofen on reduction of iNOS activity has been further investigated in the present study using rat primary cerebellar glial cell cultures. In addition, the effect of ibuprofen on COX mRNA expression and prostaglandin formation was also studied. Glial cells treated with E. coli lipopolysaccharide (LPS) and interferony (INFgamma) for 16 h expressed iNOS and COX. Ibuprofen did not directly inhibit iNOS activity. However, when ibuprofen was incubated at the same time with LPS and INFgamma for 16 h, enzyme activity was reduced, with an IC50 of 0.76 mM. Ibuprofen concentration-dependently decreased iNOS mRNA levels, with an IC50 > 2 mM. Thus, there was no correlation between decrease in iNOS activity and reduction in iNOS mRNA levels. Ibuprofen decreased iNOS protein levels, as determined by Western blot, with an IC50 of 0.89 mM. The data suggest that the reduction in iNOS activity by ibuprofen is due to inhibition of post-transcriptional processing of this enzyme. Ibuprofen had no effect on constitutive COX (COX-1) or inducible COX (COX-2) mRNA expression. However, ibuprofen inhibited PGE2 formation with an IC50 of 0.86 mM. The anti-inflammatory actions of ibuprofen have been related to inhibition of COX and, subsequently, reducing prostaglandin formation. Since the potency of ibuprofen for inhibition of PGE2 formation and reduction in iNOS activity are similar, it is suggested that, at therapeutically effective doses, a decrease in iNOS activity may also occur in vivo. Therefore, reduction in iNOS protein levels in the brain may have a role in preserving the integrity of neurons in individuals susceptible to Alzheimer's disease.
Brain Res Mol Brain Res 1997 Oct 15
PMID:Ibuprofen: effect on inducible nitric oxide synthase. 940 24


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