Alternative titles; symbols
HGNC Approved Gene Symbol: PTGS2
Cytogenetic location: 1q31.1 Genomic coordinates (GRCh38) : 1:186,671,791-186,680,423 (from NCBI)
A major mechanism for the regulation of prostaglandin synthesis occurs at the level of cyclooxygenase, also known as prostaglandin-endoperoxide synthase (PTGS; EC 1.14.99.1). The first rate-limiting step in the conversion of arachidonic acid to prostaglandins is catalyzed by PTGS. Two isoforms of PTGS have been identified: PTGS1 (COX1; 176805) and a mitogen-inducible form, PTGS2. PTGS1 is involved in production of prostaglandins for cellular housekeeping functions, whereas PTGS2 is associated with biologic events such as injury, inflammation, and proliferation (summary by Hla and Neilson (1992) and Tazawa et al. (1994)).
The antiinflammatory glucocorticoids are potent inhibitors of cyclooxygenase, a key regulator of prostaglandin synthesis. To investigate the mechanism of this inhibition, O'Banion et al. (1991, 1992) cloned a 4.1-kb mouse cDNA that conferred cyclooxygenase activity to transfected cells. The mRNA of this cyclooxygenase, which O'Banion et al. (1991, 1992) called Gripghs, was unique for its long 3-prime untranslated region containing many AUUUA repeats. The 4.1-kb GRIPGHS mRNA was rapidly increased by serum or interleukin-1-beta (IL1B; 147720) in mouse fibroblasts and human monocytes, respectively, and decreased by glucocorticoids, whereas levels of the 2.8-kb cyclooxygenase mRNA did not change. O'Banion et al. (1991, 1992) concluded that the 2.8-kb cyclooxygenase (PGHS1) is constitutive, whereas the 4.1-kb GRIPGHS is regulated and is probably a major mediator of inflammation.
Hla and Neilson (1992) cloned COX2 from a human umbilical vein endothelial cell (HUVEC) cDNA library. The deduced 604-amino acid protein is 61% identical to human COX1 and 88% identical to mouse Cox2. COX2 contains an N-terminal signal sequence, followed by a central transmembrane region, a conserved active-site tyrosine, a conserved aspirin acetylation site, and a C-terminal endoplasmic reticulum retention signal. It also has several N-glycosylation sites, some of which are conserved with COX1. In vitro translation of COX2 resulted in a 70-kD protein. Northern blot analysis detected a 4.5-kb COX2 transcript in HUVECs. RT-PCR analysis revealed expression of COX2 and COX1 in HUVECs, vascular smooth muscle cells, monocytes, and fibroblasts.
Macchia et al. (1997) detected PGHS2 mRNA by Northern blot analysis of term placenta. Western blot analysis using 3 highly specific antibodies also found selective expression of PGHS2 immunoreactive protein in term placenta. No PGHS1 was found in placenta.
Kirschenbaum et al. (2000) studied the immunohistochemical localization of PTGS1 and PTGS2 in the human male fetal and adult reproductive tracts. There was no PTGS1 expression in fetal samples (prostate, seminal vesicles, or ejaculatory ducts), and only minimal expression in adult tissues. There was no expression of PTGS2 in the fetal prostate. In a prepubertal prostate there was some PTGS2 expression that localized exclusively to the smooth muscle cells of the transition zone. In adult hyperplastic prostates, PTGS2 was strongly expressed in smooth muscle cells, with no expression in the luminal epithelial cells. PTGS2 was strongly expressed in epithelial cells of both fetal and adult seminal vesicles and ejaculatory ducts. The PTGS2 staining intensity in the fetal ejaculatory ducts during various times of gestation correlated with previously reported testosterone production rates by the fetal testis. The authors concluded that PTGS2 is the predominant isoform expressed in the fetal male reproductive tract, and its expression may be regulated by androgens.
Hla and Neilson (1992) found that expression of human COX2 in COS-7 cells produced cyclooxygenase activity. COX2 mRNA was preferentially induced by phorbol 12-myristate 13-acetate (PMA) and lipopolysaccharide (LPS) in human endothelial cells and monocytes. This induction could be partially inhibited by pretreatment with dexamethasone. In contrast, COX1 showed minimal induction with LPS and PMA. Hla and Neilson (1992) concluded that high-level induction of COX2 in mesenchymal-derived inflammatory cells suggests a role for COX2 in inflammatory conditions.
Jones et al. (1993) found that stimulation of endothelial cells with TNF (191160), PMA, LPS, or IL1 increased mRNA levels of PHS II, and this change correlated with increased prostacyclin biosynthesis. Cyclohexamide induced PHS II mRNA without a corresponding activity increase, demonstrating that translation is required for enhanced prostacyclin biosynthesis. Jones et al. (1993) concluded that expression of PHS II may have important pathophysiologic effects in vasculature.
Tsujii and DuBois (1995) studied the effects of overexpressing COX2. Rat intestinal epithelial (RIE) cells were stably transfected with a COX2 expression vector oriented in the sense (RIE-S) or antisense (RIE-AS) direction. The RIE-S cells expressed elevated COX2 protein levels and demonstrated increased adhesion to extracellular matrix proteins. E-cadherin (192090) was undetectable in RIE-S cells, but was elevated in parental RIE and RIE-AS cells. RIE-S cells were resistant to butyrate-induced apoptosis, had elevated BCL2 (151430) protein expression, and showed reduced transforming growth factor beta-2 receptor levels. The phenotypic changes involving both increased adhesion to extracellular matrix and inhibition of apoptosis were reversed by sulindac sulfide, a cyclooxygenase inhibitor. These studies demonstrated that overexpression of COX2 leads to phenotypic changes in intestinal epithelial cells that could enhance their tumorigenic potential.
To explore the role of cyclooxygenase in endothelial cell migration and angiogenesis, Tsujii et al. (1998) used 2 in vitro model systems involving coculture of endothelial cells with colon carcinoma cells. Cells overexpressing COX2 produced prostaglandins and proangiogenic factors, and stimulated both endothelial migration and tube formation, whereas control cells had little activity. The effect was inhibited by antibodies to combinations of angiogenic factors, by NS-398 (a selective COX2 inhibitor), and by aspirin. NS-398 did not inhibit production of angiogenic factors or angiogenesis induced by COX2-negative cells. Tsujii et al. (1998) also found that COX2 can modulate production of angiogenic factors by colon cancer cells.
Zhou et al. (1999) found that culturing cells with highly purified human chorionic gonadotropin (hCG) resulted in a time- and dose-dependent increase in steady state levels of COX2 mRNA and protein and the secretion of prostaglandin E2 (PGE2). Although human luteinizing hormone (LH; see 152780) could mimic hCG, follicle-stimulating hormone (see 136530), thyroid-stimulating hormone (see 188540), and the alpha (CGA; 118850) and beta (CGB; 118860) subunits of hCG had no effect on COX2 protein levels. The authors concluded that hCG and LH treatment can increase expression of COX2 in human endometrial gland epithelial cells; the effect is time and dose dependent, hormone specific, and mediated by the cAMP/type I protein kinase A signaling pathway; the hCG actions require a normal complement of its receptors in cells; and these hCG and LH effects may be another action of these hormones in human endometrium that is important for implantation of the blastocyst and continuation of pregnancy.
In a randomized control study comparing the effect of COX2 inhibitors with nonselective NSAIDS upon the renal function of elderly subjects, Swan et al. (2000) found that both agents cause a significant decrease in the glomerular filtration rate. They concluded that COX2 therefore seems to play an important role in human renal function.
Erkinheimo et al. (2000) investigated the expression of COX2 in human myometrium. Myometrial samples collected from women in labor during lower segment cesarean section expressed 15-fold higher levels of COX2 mRNA compared to myometrial specimens collected from women not in labor, as detected by Northern blot analysis. Immunohistochemical detection of COX2 protein showed cytoplasmic staining in the smooth muscle cells of the myometrium. Cultured myometrial cells expressed low levels of COX2 mRNA under baseline conditions, but IL1-beta caused a 17-fold induction of expression of the PTGS2 transcript after incubation for 6 hours. IL1-beta also induced expression of biologically active COX2 protein, as detected by immunofluorescence, Western blot analysis, and measuring the conversion of arachidonic acid to prostanoids in the presence and absence of a COX2-selective inhibitor, NS-398. PGE2 receptor subtype EP2 (176804) mRNA was expressed in cultured myometrial smooth muscle cells, whereas transcripts for EP1 (176802), EP3 (176806), EP4 (601586), FP (601204), and IP (600022) were low or below the detection limit as measured by Northern blot analysis. However, IL1-beta stimulated expression of EP4 receptor mRNA. The authors concluded that expression of COX2 transcript is elevated at the onset of labor in myometrial smooth muscle cells. This increase in expression may depend on cytokines. As, in addition to COX2, the expression of prostanoid receptors is regulated, not only the production of prostanoids, but also responsiveness to them, may be modulated.
Inflammation causes the induction of COX2, leading to the release of prostanoids, which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity. Peripheral inflammation also generates pain hypersensitivity in neighboring uninjured tissue, because of the increased neuronal excitability in the spinal cord, and a syndrome comprising diffuse muscle and joint pain, fever, lethargy, and anorexia. Samad et al. (2001) showed that COX2 may be involved in central nervous system (CNS) responses, by finding a widespread induction of COX2 expression in spinal cord neurons and in other regions of the CNS, elevating prostaglandin E2 (PGE2) levels in the cerebrospinal fluid. The major inducer of central COX2 upregulation is IL1-beta in the CNS, and as basal phospholipase A2 (see 600522) activity in the CNS does not change with peripheral inflammation, COX2 levels must regulate central prostanoid production. In the rat, intraspinal administration of an interleukin-converting enzyme or COX2 inhibitor decreased inflammation-induced central PGE2 levels and mechanical hyperalgesia. Thus, Samad et al. (2001) concluded that preventing central prostanoid production by inhibiting the IL1-beta-mediated induction of COX2 in neurons or by inhibiting central COX2 activity reduces centrally generated inflammatory pain hypersensitivity.
Epithelial tumors may be regulated by COX enzyme products. To determine if COX2 expression and PGE2 synthesis are upregulated in cervical cancers, Sales et al. (2001) used real-time quantitative PCR and Western blot analysis to confirm COX2 RNA and protein expression in squamous cell carcinomas and adenocarcinomas. In contrast, minimal expression of COX2 was detected in histologically normal cervix. Immunohistochemical analyses localized COX2 expression and PGE2 synthesis to neoplastic epithelial cells of all squamous cell carcinomas and adenocarcinomas studied. Immunoreactive COX2 and PGE2 were also colocalized to endothelial cells lining the microvasculature. To establish whether PGE2 has an autocrine/paracrine effect in cervical carcinomas, the authors investigated the expression of 2 subtypes of PGE2 receptors, namely EP2 and EP4 by real-time quantitative PCR. Expression of EP2 and EP4 receptors was significantly higher in carcinoma tissue than in histologically normal cervix. The authors concluded that COX2, EP2, and EP4 expression and PGE2 synthesis are upregulated in cervical cancer tissue and that PGE2 may regulate neoplastic cell function in cervical carcinoma in an autocrine/paracrine manner via the EP2/EP4 receptors.
Lassus et al. (2000) performed COX2 immunohistochemistry on lung tissues from autopsies of fetuses (16 to 32 weeks), preterm infants, term infants, and infants with bronchopulmonary dysplasia (BPD). COX2 staining was found exclusively in the epithelial cells resembling type II pneumocytes in the alveoli, and in ciliated epithelial cells in the bronchi. COX2 staining occurred in a changing pattern: moderate intensity staining in 90 to 100% of cells lining the alveolar epithelium of fetuses; high intensity but scattered staining in cells of preterm infants; less intense and fewer positive cells in term infants; and no staining in alveolar epithelial cells of infants with BPD. COX2 bronchial epithelial staining was found in almost all fetal cells, in approximately half of cells from preterm infants and infants with BPD, and in fewer cells from term infants. The authors suggested that COX2 may play a developmental role in perinatal lung.
COX2 has been associated with carcinogenesis, and it is overexpressed in many human malignancies. Salmenkivi et al. (2001) investigated the expression of COX2 in normal adrenal gland, in 92 primary pheochromocytomas, and in 6 metastases using immunohistochemistry and Northern blot and Western blot analyses. COX2 protein was expressed in the adrenal cortex, whereas the medulla was negative as detected by immunohistochemistry. Interestingly, all 8 malignant pheochromocytomas, regardless of the primary location of the tumor, showed moderate or strong COX2 immunoreactivity, whereas 75% of the 36 benign adrenal tumors showed no or only weak immunopositivity. The authors concluded that normal adrenal medulla does not express COX2 immunohistochemically. However, strong COX2 protein expression was found in malignant pheochromocytomas, whereas most benign tumors expressed COX2 only weakly. These findings suggested that negative or weak COX2 expression in pheochromocytomas favors benign diagnosis.
Yokota et al. (2002) found that brown fat in normal human bone marrow contains adiponectin (605441) and used marrow-derived preadipocyte lines and long-term cultures to explore potential roles of adiponectin in hematopoiesis. Recombinant adiponectin blocked fat cell formation in long-term bone marrow cultures and inhibited the differentiation of cloned stromal preadipocytes. Adiponectin also caused elevated expression of COX2 by these stromal cells and induced release of prostaglandin E2. A COX2 inhibitor prevented the inhibitory action of adiponectin on preadipocyte differentiation, suggesting involvement of stromal cell-derived prostanoids. Furthermore, adiponectin failed to block fat cell generation when bone marrow cells were derived from COX2 heterozygous mice. Yokota et al. (2002) concluded that preadipocytes represent direct targets for adiponectin action, establishing a paracrine negative feedback loop for fat regulation. They also linked adiponectin to the COX2-dependent prostaglandins that are critical in this process.
Estrogen-induced responses in vascular cells have been shown to influence prostaglandins and COX, a key enzyme in the production of prostaglandins that has 2 isoforms, COX1 and COX2. Calkin et al. (2002) investigated the effects of prostaglandins on the acute potentiation by 17-beta-estradiol of acetylcholine (ACh)-mediated vasodilation in the cutaneous vasculature. Acute 17-beta-estradiol administration enhanced the response to ACh after aspirin, diclofenac, and placebo; however, this effect was completely abolished with treatment with celecoxib, a specific COX2 inhibitor (p less than 0.05). The authors concluded that the COX2 pathway plays a specific role in the rapid 17-beta-estradiol-induced potentiation of cholinergic vasodilation in postmenopausal women.
COX2 expression is translationally silenced in epithelial cells undergoing radiation-induced apoptosis. Mukhopadhyay et al. (2003) found that CUGBP2 (602538), a predominantly nuclear protein, is also rapidly induced in response to radiation and translocates to the cytoplasm. Antisense-mediated suppression of CUGBP2 rendered radioprotection through a COX2-dependent prostaglandin pathway, providing an in vivo demonstration of translation inhibition activity for CUGBP2. CUGBP2 bound to 2 sets of AU-rich sequences located within the first 60 nucleotides of the COX2 3-prime untranslated region (UTR). Upon binding, CUGBP2 stabilized a chimeric luciferase-COX2 3-prime UTR mRNA but inhibited its translation. These findings identified a novel paradigm for RNA-binding proteins in facilitating opposing functions of mRNA stability and translation inhibition and revealed a mechanism for inhibiting COX2 expression in cancer cells.
Qin et al. (2003) found that expression of COX1 or COX2 in hamster and human cells exogenously and endogenously expressing human amyloid precursor protein (APP; 104760) induced production of the amyloid peptides A-beta(1-40) and A-beta(1-42), as well as the gamma-secretase-generated C-terminal fragment of APP. Peptide production was coincident with the secretion of prostaglandin-E2 into the culture medium. Treatment of APP-overexpressing cells with ibuprofen or with a specific gamma-secretase inhibitor significantly attenuated COX1- and COX2-mediated APP peptide production.
In rat hippocampal slices, Kim and Alger (2004) found evidence suggesting that COX2 limits endocannabinoid action and signaling between neurons.
Xu et al. (2004) demonstrated that activated T cells of patients with systemic lupus erythematosus (SLE; 152700) resisted anergy and apoptosis by markedly upregulating and sustaining COX2 expression. Inhibition of COX2 caused apoptosis of the anergy-resistant lupus T cells by augmenting FAS (134637) signaling and markedly decreasing the survival molecule FLIP (603599), and this mechanism was found to involve anergy-resistant lupus T cells selectively. Xu et al. (2004) noted that the COX2 gene is located in a lupus susceptibility region on chromosome 1. They also found that only some COX2 inhibitors were able to suppress the production of pathogenic autoantibodies to DNA by causing autoimmune T-cell apoptosis, an effect that was independent of PGE2.
Egan et al. (2004) reported that estrogen acts on estrogen receptor subtype alpha (133430) to upregulate the production of atheroprotective prostacyclin (PGI2) by activation of COX2. This mechanism restrained both oxidant stress and platelet activation that contribute to atherogenesis in female mice. Deletion of the Pgi2 receptor removed the atheroprotective effect of estrogen in ovariectomized female mice. Egan et al. (2004) concluded that this suggested that chronic treatment of patients with selective inhibitors of COX2 could undermine protection from cardiovascular disease in premenopausal females.
Kothapalli et al. (2004) investigated the antimitogenic effect of high density lipoprotein (HDL) on the inhibition of S-phase entry of murine aortic smooth muscle cells, which they found to be mediated by apolipoprotein E (APOE; 107741). They also demonstrated that specific inhibition of Cox2 blocks the antimitogenic effects of HDL and Apoe, that both HDL and Apoe induce Cox2 gene expression, and that the prostacyclin receptor IP (600022) is required for the antimitogenic effects of HDL and Apoe. Kothapalli et al. (2004) concluded that the COX2 gene is a target of APOE signaling, linking HDL and APOE to IP action, and suggested that this mechanism may contribute to the cardioprotective effect of HDL and APOE.
By in vivo selection, transcriptomic analysis, functional verification, and clinical validation, Minn et al. (2005) identified a set of genes that marks and mediates breast cancer metastasis to the lungs. Some of these genes serve dual functions, providing growth advantages both in the primary tumor and in the lung microenvironment. Others contribute to aggressive growth selectivity in the lung. Among the lung metastasis signature genes identified, several, including PTGS2, were functionally validated. Those subjects expressing the lung metastasis signature had a significantly poorer lung metastasis-free survival, but not bone metastasis-free survival, compared to subjects without the signature.
Liu et al. (2004) found that nitric oxide (NO) induced COX2 expression in a human colorectal cell line and in nontransformed mouse colon epithelial cells. NO-induced induction was due to PEA3 (ETV4; 600711)-p300 (EP300; 602700)-mediated activation of an ETS site and an NFIL6 (CEBPB; 189965)-binding site in the COX2 promoter.
Kim et al. (2005) showed that inducible NO synthase (iNOS; 163730) specifically binds to COX2 and S-nitrosylates it, enhancing COX2 catalytic activity. Selectively disrupting iNOS-COX2 binding prevented NO-mediated activation of COX2. Kim et al. (2005) suggested that the molecular synergism between iNOS and COX2 may represent a major mechanism of inflammatory responses.
Metastasis entails numerous biologic functions that collectively enable cancerous cells from a primary site to disseminate and overtake distant organs. Using genetic and pharmacologic approaches, Gupta et al. (2007) showed that the epidermal growth factor receptor ligand epiregulin (602061), the cyclooxygenase COX2, and the matrix metalloproteinases MMP1 (120353) and MMP2 (120360), when expressed in human breast cancer cells, collectively facilitate the assembly of new tumor blood vessels, the release of tumor cells into the circulation, and the breaching of lung capillaries by circulating tumor cells to seed pulmonary metastasis. Gupta et al. (2007) concluded that their findings revealed how aggressive primary tumorigenic functions can be mechanistically coupled to greater lung metastatic potential, and how such biologic activities can be therapeutically targeted with specific drug combinations.
To identify new modulators of hematopoietic stem cell formation and homeostasis, North et al. (2007) screened a panel of biologically active compounds for effects on stem cell induction in the zebrafish aorta-gonad-mesonephros region. The authors showed that chemicals that enhance prostaglandin E2 synthesis increased hematopoietic stem cell numbers, and those that blocked prostaglandin synthesis decreased stem cell numbers. The cyclooxygenases responsible for PGE2 synthesis were required for hematopoietic stem cell formation. A stable derivative of PGE2 improved kidney marrow recovery following irradiation injury in adult zebrafish. In murine embryonic stem cell differentiation assays, PGE2 caused amplification of multipotent progenitors. Furthermore, in vivo exposure to stabilized PGE2 enhanced spleen colony-forming units at day 12 post transplant and increased the frequency of long-term repopulating hematopoietic stem cells present in murine bone marrow after limiting dilution competitive transplantation. The conserved role for PGE2 in the regulation of vertebrate hematopoietic stem cell homeostasis indicates that modulation of the prostaglandin pathway may facilitate expansion of hematopoietic stem cell number for therapeutic purposes.
Using RT-PCR, Pan et al. (2008) showed that both COX2 and CCR7 (600242) were upregulated in a significant number of breast tumor samples compared with adjacent normal tissue, and that this upregulation was associated with enhanced lymph node metastasis. Overexpression and knockdown studies in human breast cancer cell lines revealed that COX2 acted via the prostaglandin receptors EP2 (PTGER2; 176804) and EP4 (PTGER4; 601586), resulting in increased intracellular cAMP and activation of the PKA (see 188830)-AKT (see 164730) signaling pathway, which led to induction of CCR7 expression. Elevated CCR7 enhanced the migration of breast cancer cells toward lymphatic endothelial cells, suggesting that CCR7 upregulation ultimately mediates COX2-associated lymph node metastasis.
Bos et al. (2009) isolated cells that preferentially infiltrate the brain from patients with advanced breast cancer. Gene expression analysis of these cells and of clinical samples, coupled with functional analysis, identified the cyclooxygenase COX2, the epidermal growth factor receptor (EGFR; 131550) ligand HBEGF (126150), and the alpha-2,6-sialyltransferase ST6GALNAC5 (610134) as mediators of cancer cell passage through the blood-brain barrier. EGFR ligands and COX2 had been linked to breast cancer infiltration of the lungs, but not the bones or liver, suggesting a sharing of these mediators in cerebral and pulmonary metastases. In contrast, ST6GALNAC5 specifically mediates brain metastasis. Normally restricted to the brain, the expression of ST6GALNAC5 in breast cancer cells enhances their adhesion to brain endothelial cells and their passage through the blood-brain barrier. This co-option of a brain sialyltransferase highlights the role of cell surface glycosylation in organ-specific metastatic interactions. Bos et al. (2009) demonstrated that breast cancer metastasis to the brain involves mediators of extravasation through nonfenestrated capillaries, complemented by specific enhancers of blood-brain barrier crossing and brain colonization.
The acetylation of COX2 by aspirin enables the biosynthesis of R-containing precursors of endogenous antiinflammatory mediators termed resolvins (Serhan et al., 2002). Spite et al. (2009) established the complete stereochemistry of endogenous resolvin-D2 and its potent stereoselective actions facilitating resolution of inflammatory sepsis.
Coward et al. (2009) found that expression of COX2 mRNA and protein and production of PGE2 was induced by TGF-beta-1 (TGFB1; 190180) and IL1B in cultured normal lung fibroblasts, but not in fibroblasts cultured from lung tissue of patients with idiopathic pulmonary fibrosis (IPF; 178500). They showed that defective histone acetylation was responsible for diminished COX2 transcription in IPF.
Using mouse models, Vegiopoulos et al. (2010) showed that COX2, a rate-limiting enzyme in prostaglandin synthesis, is a downstream effector of beta-adrenergic signaling in white adipose tissue and is required for the induction of brown adipose tissue in white adipose tissue depots. Prostaglandin shifted the differentiation of defined mesenchymal progenitors toward a brown adipocyte phenotype. Overexpression of COX2 in white adipose tissue induced de novo brown adipose tissue recruitment in white adipose tissue, increased systemic energy expenditure, and protected mice against high fat diet-induced obesity. Thus, Vegiopoulos et al. (2010) concluded that COX2 appears integral to de novo brown adipose tissue recruitment, which suggests that the prostaglandin pathway regulates systemic energy homeostasis.
Using real-time PCR, Park et al. (2013) detected significantly reduced expression of miRNA-558 (MIR558; 616473) in osteoarthritic (OA) cartilage compared with normal cartilage. In both normal and OA cartilage, MIR558 targeted COX2 and reduced its catabolic effects. MIR558 expression was reduced following stimulation with IL1-beta, permitting elevated COX2 expression. A MIR558 antagomir also elevated COX2 expression. Overexpression of MIR558 in primary human chondrocytes and an SW1353 chondrogenic cell line markedly reduced IL1B-induced PGE2 production. Park et al. (2013) concluded that MIR558 directly targets COX2 and regulates IL1-beta-stimulated catabolic effects in human chondrocytes.
By chromatin immunoprecipitation experiments with primary human mammary epithelial cells, followed by quantitative RT-PCR and RACE, Krawcyzk and Emerson (2014) identified PACER (PACERR; 617650), an expressed antisense long noncoding RNA (lncRNA) originating from the upstream promoter region of the COX2 gene. Expression of PACER and COX2 was reduced following small interfering RNA (siRNA)-mediated knockdown of CTCF (604167) in human mammary epithelial cells, suggesting that CTCF establishes an open chromatin domain to permit expression of the locus. Knockdown of PACER via siRNA decreased COX2 expression levels but did not alter CTCF binding at the COX2 promoter, indicating that PACER itself regulates COX2 mRNA expression. PACER knockdown significantly reduced histone H3 (see 602810) and H4 (see 602822) acetylation upstream of the COX2 gene. Binding of p300 to the COX2 promoter was also significantly reduced by PACER knockdown, suggesting that promotion of histone acetylation by PACER is mediated by p300 recruitment. PACER knockdown also reduced RNA polymerase II (pol II; see 180660) complex association with the COX2 promoter. RNA immunoprecipitation revealed that PACER interacted directly with p50 (164011), the small subunit of NF-kappa-B, and PACER knockdown resulted in increased levels of bound p50 within the COX2 promoter. Krawcyzk and Emerson (2014) proposed that PACER regulates COX2 expression by restricting p50 binding at the COX2 promoter, thereby facilitating recruitment of p300, induction of histone acetylation, and assembly of pol II complexes to allow for transcriptional activation.
Qian et al. (2016) found that knockdown of PACER via short hairpin RNA resulted in reduced viability and invasive capability of 134B and MG63 human osteosarcoma cells. PACER knockdown also significantly downregulated COX2 expression. The effects of PACER knockdown on cell proliferation and viability were rescued by COX2 overexpression, suggesting that, in osteosarcoma, PACER function is mediated by COX2. Qian et al. (2016) proposed that PACER-driven COX2 activation may contribute to osteosarcoma cell proliferation and metastasis.
Chopra et al. (2019) found that induction of PTGS2 and prostaglandin E synthase (PTGES; 605172) was compromised in IRE1-alpha (604033)-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors. inducible biosynthesis of prostaglandins, including the proalgesic mediator prostaglandin E2 (PGE2), was decreased in myeloid cells that lack IRE1-alpha or XBP1 (194535) but not other ER stress sensors. Functional XBP1 transactivated the human PTGS2 and PTGES genes to enable optimal PGE2 production. Mice that lacked IRE1a-XBP1 in leukocytes, or that were treated with IRE1-alpha inhibitors, demonstrated reduced pain behaviors in PGE2-dependent models of pain. Thus, Chopra et al. (2019) concluded that IRE1-alpha-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.
Roulis et al. (2020) characterized the heterogeneity of the intestinal mesenchyme using single-cell RNA-sequencing analysis and identified a population of rare pericryptal Ptgs2-expressing fibroblasts that constitutively process arachidonic acid into highly labile PGE2. Specific ablation of Ptgs2 in fibroblasts was sufficient to prevent tumor initiation in 2 different models of sporadic, autochthonous tumorigenesis. Mechanistically, single-cell RNA-sequencing analyses of a mesenchymal niche model showed that fibroblast-derived PGE2 drives the expansion of a population of stem cell antigen-1 (Sca1, also known as Ly6a, present only in mouse)-positive reserve-like stem cells. These express a strong regenerative/tumorigenic program, driven by the Hippo pathway effector Yap (606608). In vivo, Yap is indispensable for Sca1+ cell expansion and early tumor initiation and displays a nuclear localization in both mouse and human adenomas. Using organoid experiments, Roulis et al. (2020) identified a molecular mechanism whereby PGE2 promotes Yap dephosphorylation, nuclear translocation, and transcriptional activity by signaling through the receptor Ptger4 (601586). Epithelial-specific ablation of Ptger4 misdirected the regenerative reprogramming of stem cells and prevented Sca1+ cell expansion and sporadic tumor initiation in mutant mice, thereby demonstrating the robust paracrine control of tumor-initiating stem cells by PGE2-Ptger4. Further analyses of patient-derived organoids established that PGE2-PTGER4 also regulates stem cell function in humans. Roulis et al. (2020) concluded that their study demonstrated that initiation of colorectal cancer is orchestrated by the mesenchymal niche and revealed a mechanism by which rare pericryptal Ptgs2-expressing fibroblasts exert paracrine control over tumor-initiating stem cells via the druggable PGE2-Ptger4-Yap signaling axis.
Tazawa et al. (1994) isolated the entire PGHS2 gene and its 5-prime flanking region and showed that it contains 10 exons and spans 7.5 kb. By comparison, the murine and human PGHS1 genes comprise 11 exons and 10 introns and are approximately 22 kb long (Kraemer et al., 1992).
Kosaka et al. (1994) determined that the PTGS2 gene contains 10 coding exons and spans more than 8.3 kb. The upstream region and intron 1 contain a canonical TATA box and various transcriptional regulatory elements, including a functional cAMP response element.
Jones et al. (1993) and Tazawa et al. (1994) mapped the PTGS2 gene to chromosome 1. By fluorescence in situ hybridization, Tay et al. (1994) mapped the PTGS2 gene to chromosome 1q25. Using FISH, Kosaka et al. (1994) mapped the PTGS2 gene to chromosome 1q25.2-q25.3.
Fritsche et al. (2001) sequenced the COX2 gene from 72 individuals and identified no functionally important polymorphisms. They suggested that there has been selective pressure against such SNPs because of the critical role of COX2 in the maintenance of homeostasis.
Xia et al. (2012) showed that prostaglandin E2 (PGE2) silences certain tumor suppressor and DNA repair genes through DNA methylation to promote tumor growth. Their findings uncovered a theretofore unrecognized role for PGE2 in the promotion of tumor progression, and provided a rationale for considering the development of a combination treatment using PTGS2 inhibitors and demethylating agents for the prevention or treatment of colorectal cancer.
Morham et al. (1995) noted that COX2 is induced at high levels in migratory and other responding cells by proinflammatory stimuli. COX2 is generally considered to be a mediator of inflammation. Its isoform, COX1, is constitutively expressed in most tissues and is thought to mediate housekeeping functions. These 2 enzymes are therapeutic targets of the widely used nonsteroidal antiinflammatory drugs (NSAIDs). To investigate further the different physiologic roles of these isoforms, Morham et al. (1995) used homologous recombination to disrupt the mouse gene encoding Cox2 (Ptgs2). Mice lacking Cox2 were found to have normal inflammatory responses to treatments with tetradecanoyl phorbol acetate or arachidonic acid. However, they developed severe nephropathy and were susceptible to peritonitis.
Oshima et al. (1996) bred mice carrying an APC (611731) mutation (a truncation at residue 716) that causes adenomatous polyposis coli closely mimicking that in the human with mice with a disrupted Ptgs2 gene. All the animals were APC heterozygotes; if homozygous for wildtype Ptgs2, they developed an average of 652 polyps at 10 weeks, while heterozygotes had 224 polyps and homozygously deficient mice had only 93 polyps. This experiment provided definitive genetic evidence that induction of Ptgs2 is an early rate-limiting step for adenoma formation. They showed also that a drug which inhibits the COX2 isoform encoded by Ptgs2, but not COX1, also markedly reduced the number of polyps. Thus, Oshima et al. (1996) concluded that overexpression of COX2 is an early, central event in carcinogenesis.
Lim et al. (1997) generated COX2-deficient mice by gene targeting. These mice showed multiple failures in female reproductive processes that included ovulation, fertilization, implantation, and decidualization. The authors concluded that the defects in these mice were the direct result of target organ-specific COX2 deficiency and not the result of deficiency of pituitary gonadotropins or ovarian steroid hormones, or reduced responsiveness of the target organs to their respective hormones.
The transition to pulmonary respiration following birth requires rapid alterations in the structure of the mammalian cardiovascular system. A dramatic change that occurs is the closure and remodeling of the ductus arteriosus (DA; see 607411), an arterial connection in the fetus that directs blood flow away from the pulmonary circulation. A role of prostaglandins in regulating the closure of this vessel is supported by pharmacologic and genetic studies. The production of prostaglandins is dependent on COX1 and COX2. Loftin et al. (2001) reported that the absence of either or both COX isoforms in mice did not result in premature closure of the DA in utero. However, 35% of COX2 -/- mice died with a patent DA within 48 hours of birth. In contrast, the absence of only the COX1 isoform did not affect closure of the DA. The mortality and patent DA incidence due to absence of COX2 was, however, increased to 79% when one copy of the gene encoding COX1 was also inactivated. Furthermore, 100% of the mice deficient in both isoforms died with a patent DA within 12 hours of birth, indicating that in COX2-deficient mice, the contribution of COX1 to DA closure is gene dosage-dependent. Together, these data established roles for COX1 and especially for COX2 in the transition of the cardiopulmonary circulation at birth.
See also 176805 for the work of Gavett et al. (1999) on allergen-induced pulmonary inflammation and airway hyperresponsiveness in wildtype mice and in Ptgs1 -/- and Ptgs2 -/- mice.
In mice and humans, deregulated expression of COX2, but not of COX1, is characteristic of epithelial tumors, including squamous cell carcinomas of skin. To explore the function of COX2 in epidermis, Neufang et al. (2001) used a keratin-5 (148040) promoter to direct COX2 expression to the basal cells of interfollicular epidermis and the pilosebaceous appendage of transgenic mouse skin. Cox2 overexpression in the expected locations, resulting in increased prostaglandin levels in epidermis and plasma, correlated with a pronounced skin phenotype. Heterozygous transgenic mice exhibited a reduced hair follicle density. Moreover, postnatal hair follicle morphogenesis and thinning of interfollicular dorsal epidermis were delayed. Adult transgenics showed a body site-dependent sparse coat of greasy hair, the latter caused by sebaceous gland hyperplasia and increased epicutaneous sebum levels. In tail skin, hyperplasia of scale epidermis reflecting an increased number of viable and cornified cell layers was observed. Hyperplasia was a result of a disturbed program of epidermal differentiation rather than an increased proliferation rate, as reflected by the strong suppression of keratin-10 (148080), involucrin (147360), and loricrin (152445) expression in suprabasal cells. Further pathologic signs were loss of cell polarity, mainly of basal keratinocytes, epidermal invaginations into the dermis, and formation of horn perls. Invaginating hyperplastic lobes were surrounded by vessels testing positive for CD31, platelet-endothelial cell adhesion molecule-1 (173445).
In a mouse model of retinopathy of prematurity (ROP), Wilkinson-Berka et al. (2003) found that Cox2 was localized to sites associated with retinal blood vessels. The selective Cox2 inhibitor rofecoxib attenuated retinal angiogenesis that accompanied ROP. Normal retinal development indicated that COX2 plays an important role in blood vessel formation in the developing retina.
Brewer et al. (2003) generated healthy mice lacking glucocorticoid receptor (GCCR; 138040) only in T cells and thymus. Gccr was dispensable for T-cell development, but administration of a T-cell stimulus or superantigen to mutant mice, but not control mice, resulted in high mortality that could not be rescued by dexamethasone or anti-Ifng (147570). Microarray and ribonuclease protection analyses suggested that endogenous glucocorticoids are required for transcriptional suppression of Ifng, but not Tnf or Il2 (147680), in T cells. Inhibition of Cox2 protected mice from lethality without affecting Ifng levels. Histologic analysis revealed that T-cell stimulation in mutant mice caused significant damage to the gastrointestinal tract, particularly the cecum, but little or no damage in other tissues. Brewer et al. (2003) concluded that Gccr function in T cells is essential for survival during polyclonal T-cell activation. Furthermore, they suggested that Cox2 inhibition may be useful for treatment of glucocorticoid insufficiency or resistance in patients with toxic shock syndrome (see 607395), graft-versus-host disease (GVHD; see 614395), or other T-cell activating processes.
Liu et al. (2001) generated transgenic mice that overexpressed the human COX2 gene in the mammary glands using the murine mammary tumor virus promoter. The human COX2 mRNA and protein were expressed in mammary glands of female transgenic mice and were strongly induced during pregnancy and lactation. Multiparous but not virgin females exhibited a greatly exaggerated incidence of focal mammary gland hyperplasia, dysplasia, and transformation into metastatic tumors. COX2-induced tumor tissue expressed reduced levels of the pro-apoptotic proteins BAX (600040) and BCLXL (600039) and an increase in the anti-apoptotic protein BCL2, suggesting that decreased apoptosis of mammary epithelial cells contributes to tumorigenesis. Liu et al. (2001) concluded that enhanced COX2 expression is sufficient to induce mammary gland tumorigenesis.
Using Cox1 -/- and Cox2 -/- mice, Zhang et al. (2002) demonstrated that COX2 plays a role in both endochondral and intramembranous bone formation during skeletal repair. Healing of stabilized tibia fractures was significantly delayed in Cox2 -/- mice compared with Cox1 -/- and wildtype mice. Cultured Cox2 -/- bone marrow stromal cells showed a defect in osteogenesis that could be completely rescued by addition of prostaglandin E2. Addition of Bmp2 (112261) enhanced bone formation to a level above that observed with prostaglandin E2 alone in both wildtype and Cox2 -/- cells, indicating the BMP2 is downstream of prostaglandin production. Expression of Cbfa1 (RUNX2; 600211) and osterix (SP7; 606633) was downregulated in Cox2 -/- cells. Addition of prostaglandin E2 rescued this defect, and Bmp2 enhanced Cbfa1 and osterix in Cox2 -/- and wildtype cells. Zhang et al. (2002) concluded that COX2 regulates induction of CBFA1 and osterix to mediate normal skeletal repair.
Zhang et al. (2003) generated a transgenic mouse model overexpressing TGM2 (190196) in cardiomyocytes and found that the mice had an age-dependent left ventricular hypertrophy and cardiac decompensation, characterized by cardiomyocyte apoptosis and fibrosis and a delayed impact on survival. Expression of COX2, thromboxane synthase (274180), and the thromboxane receptor (188070) were increased coincident with the emergence of the cardiac phenotype. The COX2-dependent increase in thromboxane A2 augmented cardiac hypertrophy, whereas formation of PGI2 by the same isozyme, as well as administration of COX2 inhibitors, rescued the cardiac phenotype. Zhang et al. (2003) concluded that TGM2 activation regulates expression of COX2, and that its products may differentially modulate cell death or survival of cardiomyocytes.
Boccaccio et al. (2005) developed a mouse model of sporadic tumorigenesis in which they targeted the activated human MET oncogene (164860) to adult liver. They observed slowly progressive hepatocarcinogenesis, which was preceded and accompanied by a disseminated intravascular coagulation (DIC)-like thrombohemorrhagic syndrome. Genomewide expression profiling of MLP29 cells transduced with the activated MET oncogene revealed prominent upregulation of plasminogen activator inhibitor-1 (PAI1; 173360) and COX2, and in vivo administration of a PAI1 or COX2 inhibitor slowed the evolution towards full-blown DIC. Boccaccio et al. (2005) concluded that this study provided the first direct genetic evidence for the link between oncogene activation and hemostasis.
Brown et al. (2007) found that Myd88 (602170) -/- mice and Ptgs2 -/- mice exhibited a profound inhibition of endothelial proliferation and cellular organization within rectal crypts after injury. The effects of injury in both mutant mouse strains could be rescued by exogenous PGE2, suggesting that Myd88 signaling is upstream of Ptgs2 and PGE2. In wildtype mice, the combination of injury and Myd88 signaling led to repositioning of a subset of Ptgs2-expressing stromal cells from the mesenchyme surrounding the middle and upper crypts to an area surrounding the crypt base adjacent to colonic epithelial progenitor cells. Brown et al. (2007) concluded that the MYD88 and prostaglandin signaling pathways interact to preserve epithelial proliferation during injury, and that proper cellular mobilization within the crypt niche is critical to repair after injury.
Vardeh et al. (2009) observed that mice with conditional deletion of Cox2 in neurons and glial cells, but not in peripheral immune cells, showed no difference in basal nociception to mechanical or thermal pain sensitivity from wildtype mice. There was also no difference in fever induction. However, after induction of peripheral inflammation, mutant mice had loss of Cox2 expression in the spinal cord and showed loss of mechanical hypersensivity. The findings suggested that induction of Cox2 in neural cells in the central nervous system contributes to mechanical pain hypersensitivity after peripheral inflammation, as is seen in postoperative pain and arthritis. Peripheral Cox2 induction appears to regulate thermal hypersensitivity, such as seen in sunburn or other dermatologic conditions.
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