Disease relevance of PTGS2

• Tumor size, histologic grade, presence of primary lymph node metastases, progesterone receptor positivity, or age at diagnosis were not associated with PTGS2 genotypes [1].
• We conclude that the homozygous PTGS2 8473-CC genotype may be associated with breast cancer risk [1].
• PTGS2 seems to be a promising candidate gene for hypertension in men [2].
• Prostaglandin-endoperoxide synthase 2 (PTGS2) gene polymorphisms and risk of biliary tract cancer and gallstones: a population-based study in Shanghai, China [3].
• An association was detected between colorectal cancer and a polymorphism in the untranslated region of exon 10 of PTGS2, with an odds ratio (OR) of 2.49, 95% confidence interval (CI) of 1.17-5.32, P=0.01 [4].
• These data suggest a direct link between COX-2 activity and neoplastic progression in patients with BE and reflux esophagitis [5].
• COX-2 overexpression is associated with worse survival among colon cancer patients [6].
• We conclude that hyaluronan is an important endogenous regulator of colon cancer cell survival properties and that cyclooxygenase-2 is a major mediator of these hyaluronan-induced effects [7].
• Cyclic hypoxia also led to a preferential COX-2 induction in tumor cells and, contrary to continuous hypoxia, fostered a higher metastatic take of prechallenged tumor cells [8].

Psychiatry related information on PTGS2

• Moreover, the neuronal induction of COX-2 has been linked to neuroinflammatory aspects of Alzheimer's disease (AD) [9].
• The proportion of COX-2 positive neurons decreased in subjects with clinical dementia rating (CDR) 5 but not CDR 4, suggesting that this was a late event in the course of the disease [10].
• As COX-2 is up-regulated in colorectal carcinogenesis, this could have important implications for the selective inhibition of cells expressing COX-2 protein over those lacking COX-2 protein expression and for dietary modification to be considered alongside NSAIDs in the prevention, and possibly treatment, of colorectal cancer [11].
• COX-2 expression increases in high renin states and in response to a high-sodium diet or water deprivation [12].
• Selective Cox-2 inhibitors, currently under investigation for cardiovascular risk reduction, may represent a novel therapeutic option for patients with endovascular Cp infection as they target the actuated pathological signal transduction cascade in persistently infected PBMC [13].

High impact information on PTGS2

• We further examine the evidence for independent signaling by PGHS-1 and PGHS-2, and the complex mechanisms for regulation of PGHS-2 gene expression [14].
• PGHS-1 and 2 are of particular interest because they are the major targets of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, ibuprofen, and the new COX-2 inhibitors [14].
• The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis [15].
• CONCLUSIONS: In patients with rheumatoid arthritis, treatment with rofecoxib, a selective inhibitor of cyclooxygenase-2, is associated with significantly fewer clinically important upper gastrointestinal events than treatment with naproxen, a nonselective inhibitor [16].
• METHODS: We studied the effect of celecoxib, a selective cyclooxygenase-2 inhibitor, on colorectal polyps in patients with familial adenomatous polyposis [15].

Chemical compound and disease context of PTGS2

• Polymorphisms in prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/COX2) and risk of colorectal cancer [4].
• Cultured lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize prostaglandin E2 and to express cyclooxygenase-2 [17].
• A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis.Rofecoxib Osteoarthritis Endoscopy Study Group [18].
• The aim of our study was to determine whether selective inhibition of COX-2 by NS-398 would alter the rates of cell growth and apoptosis in human Barrett's-associated esophageal adenocarcinoma cell lines [19].
• In COX-2-positive pancreatic cancer, the nimesulide-induced increase of VEGF production by the cancer cells was offset by a decrease in VEGF production by the nonmalignant cell types leading to reduced tumor angiogenesis and growth [20].

Biological context of PTGS2

• PTGS2 CpG island hypermethylation portended an increased risk of recurrence [21].
• CONCLUSIONS/INTERPRETATION: This study suggests that certain COX2 (PTGS2) inhibitors can alter glucose homeostasis in vivo by stimulating glucose uptake in skeletal muscles that express PTGS2 [22].
• Baseline PGE(2) concentrations, minimum baseline PGE(2) concentrations, and areas under the PGE(2) concentration versus time curve also did not differ between PTGS2 genotypes (P > .28) [23].
• The PTGS inhibitor piroxicam, administered in doses that inhibited PTGS1 but not PTGS2, significantly prolonged gestation [24].
• Analysis of haplotypes confirmed that individuals with these variants were at increased risk of colorectal cancer (OR compared to the most frequent haplotype: 2.17, 95% CI 0.97-4.84, P=0.06) Interactions between PTGS2 genotype and use of nonsteroidal anti-inflammatory drugs and risk of colorectal cancer were also explored [4].

Anatomical context of PTGS2

• In addition, none of the inhibitors modulated the rate of hexose transport in vascular endothelial and smooth muscle cells expressing PTGS2 and SCLC2A1 [22].
• Double immunofluorescent staining showed increased PTGS2 production in pancreatic islets from diabetic mice relative to corresponding controls [25].
• Cyclooxygenase-2 (PTGS2) inhibitors augment the rate of hexose transport in L6 myotubes in an insulin- and AMPKalpha-independent manner [22].
• PTGS2 was expressed in the PYS and the endometrium [24].
• Our results suggest that a common PTGS2 variant increases bile duct cancer risk [3].

Associations of PTGS2 with chemical compounds

• Thus the results indicate the need for further investigation toward PTGS2 pharmacogenetics-based prescription of celecoxib [23].
• Although the mechanisms by which NSAIDs lower cancer risk remain unclear, NSAIDs reduce prostaglandin production by blocking prostaglandin-endoperoxide synthase 2 (PTGS2, commonly known as COX-2), an enzyme induced by proinflammatory stimuli that is often overexpressed in malignant tissue [3].
• These findings indicate that genetic variants in PTGS2 may play a role in mediating susceptibility to T2DM in Pima Indians and are consistent with the hypothesis that chronic inflammation may contribute to the development of T2DM in some individuals [26].
• CONCLUSION(S): Monkey OSE expresses mRNA for PTGS1, PTGS2, and all PGE synthases and produces PGE(2) both before and 36 hours after hCG [27].
• Our data indicate that F-IPF have a striking defect in their capacity to synthesize the antiinflammatory and antifibrogenic molecule PGE2, apparently because of a diminished induction of COX-2 protein [17].
• GS-HCl (5 mM) also facilitated degradation of the higher molecular species of COX-2 in IL-1beta-treated A549 cells that was retarded by MG132 [28].
• Inhibition of Cn activity by the immunosuppressive drug cyclosporin A impaired NFAT activation and diminished Cox-2 expression in BBS-stimulated cells [29].

Physical interactions of PTGS2

• Here we describe two heterodimers in which a native subunit of human PGHS-2 has been coupled to a subunit having a defect within the COX active site at some distance from the dimer interface [30].
• Transcriptional regulation of cyclooxygenase-2 in response to proteasome inhibitors involves reactive oxygen species-mediated signaling pathway and recruitment of CCAAT/enhancer-binding protein delta and CREB-binding protein [31].
• Recent evidence suggests that cyclooxygenase-2 (COX-2) modulates angiogenesis by interacting with the VEGF system [32].
• Cyclooxygenase-2 interacts with p53 and interferes with p53-dependent transcription and apoptosis [33].
• The ability of PPARgamma ligands to inhibit COX-2 appears to be mediated predominantly through inhibition of AP-1 protein binding to the CRE site in the COX-2 promoter [34].

Enzymatic interactions of PTGS2

• The ability of the PGHS-2 proteins to catalyze two-electron hydroperoxide reduction correlated with the activation of cyclooxygenase activity [35].

Co-localisations of PTGS2

• Nitrotyrosine was found in the same distribution as that of iNOS and was colocalized with Cox-2 in macrophages [36].

Regulatory relationships of PTGS2

• Cyclooxygenase-2 inhibitor (SC-236) suppresses activator protein-1 through c-Jun NH2-terminal kinase [37].
• The side chain structures of Asn-382 and Thr-383 in PGHS-2 thus selectively influence two important aspects of cyclooxygenase catalytic regulation: activation by peroxide and self-inactivation [38].
• The adenomatous polyposis coli tumor suppressor gene regulates expression of cyclooxygenase-2 by a mechanism that involves retinoic acid [39].
• Cyclooxygenase 2 (COX-2) was also induced by OSM [40].
• In the present study, we tested the hypothesis that progesterone/PR inhibits uterine contractility by blocking nuclear factor kappaB (NF-kappaB) activation and induction of cyclooxygenase-2 (COX-2), a contractile gene that is up-regulated in labor [41].

Other interactions of PTGS2

• The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression [42].
• Also, a selective Cox-2 inhibitor, NS-398, significantly enhanced genotoxic stress-induced apoptosis in several types of p53+/+ normal human cells, through a caspase-dependent pathway [43].
• Regulation of cyclooxygenase 2 mRNA stability by the mitogen-activated protein kinase p38 signaling cascade [44].
• Constitutively active MAPKAPK-2 was also able to stabilize chimeric beta-globin-Cox-2 transcripts [44].
• Retinoids and carnosol suppress cyclooxygenase-2 transcription by CREB-binding protein/p300-dependent and -independent mechanisms [45].

Analytical, diagnostic and therapeutic context of PTGS2

• Islet PTGS2 production in animal models was assessed by immunofluorescence [25].
• In a Minnesota-based case-control study of cases with adenomatous (n = 494) or hyperplastic polyps (n = 186) versus polyp-free controls (n = 584), we investigated the role of the PTGS2 -765G > C promoter polymorphism [46].
• Immediately following oocyte retrieval, the cumulus was stripped from the oocyte, and cumulus gene expression for PTGS2, HAS2 and GREM1 was assessed using a one-step real-time quantitative RT-PCR assay [47].
• A fluorescence in situ hybridization study showed that the human genes coding for prostaglandin-endoperoxide synthase 1 (PTGS1) and prostaglandin-endoperoxidase synthase 2 (PTGS2) were mapped to distinct chromosomes 9q32-q33.3 and 1q25.2-q25.3, respectively, indicating that these genes are not genetically linked [48].
• MAIN OUTCOME MEASURE(S): Ovarian surface epithelium expression of prostaglandin-endoperoxide synthase 1 (PTGS1) and PTGS2 proteins was determined by immunocytochemistry [27].

References