Alternative titles; symbols
HGNC Approved Gene Symbol: PTGES
Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38) : 9:129,738,349-129,753,042 (from NCBI)
DNA damage and/or hyperproliferative signals activate wildtype p53 tumor suppressor protein (TP53; 191170), inducing cell cycle arrest or apoptosis. Mutations that inactivate p53 occur in 50% of all tumors. Polyak et al. (1997) used serial analysis of gene expression (SAGE) to evaluate cellular mRNA levels in a colorectal cancer cell line transfected with p53. Of 7,202 transcripts identified, only 14 were expressed at levels more than 10-fold higher in p53-expressing cells than in control cells. Polyak et al. (1997) termed these genes 'p53-induced genes,' or PIGs, several of which were predicted to encode redox-controlling proteins. They noted that reactive oxygen species (ROS) are potent inducers of apoptosis. Flow cytometric analysis showed that p53 expression induces ROS production, which increases as apoptosis progresses under some conditions. The authors stated that the PIG12 gene encodes a microsomal glutathione S-transferase (see MGST1; 138330).
Jakobsson et al. (1999) identified an EST encoding PIG12, which they called MGST1L1 (microsomal glutathione S-transferase-1-like-1). The authors grouped the MGST1L1 protein with other members of the MAPEG (membrane-associated proteins in eicosanoid and glutathione metabolism) superfamily, which includes MGST2 (601733), MGST3 (604564), LTC4S (246530), and FLAP (ALOX5AP; 603700).
After further characterization of MGST1L1, Jakobsson et al. (1999) redesignated the protein prostaglandin E synthase, or PGES. Western blot analysis showed that the deduced 152-amino acid PGES protein is expressed in membranes as an approximately 16-kD protein. Reverse phase-high performance liquid chromatography (RP-HPLC) analysis determined that synthesis of prostaglandin E2 (PGE2) from prostaglandin H2 in the presence of PGES is time and concentration dependent. The authors found that no other MAPEG substrates constitute PGES substrates. Northern dot blot analysis revealed high expression of PGES in A549 and HeLa cancer cell lines, medium expression in placenta, prostate, testis, mammary gland, and bladder, and lower expression in several other tissues. Northern blot analysis detected a 2-kb PGES transcript in prostate and testis, with lower expression in small intestine and colon. Western blot analysis demonstrated that PGES is associated with the microsomal fraction and is induced by interleukin 1-beta (IL1B; 147720), which is known to induce PGE2 release. Forsberg et al. (2000) showed that induction of PGES by IL1B is blocked by phenobarbital.
By analysis of a genomic clone, Forsberg et al. (2000) determined that the PGES gene contains 3 exons and spans 14.8 kb.
PGE2 synthesis from arachidonic acid involves multiple enzymes, and 2 isoforms of the terminal enzyme of this biosynthetic pathway, PGES, have been identified. Cytosolic PGES (cPGES) is identical to the heat-shock protein-90 (see 140571) chaperone p23 (607061) and is functionally coupled to constitutive prostaglandin-endoperoxide H synthase-1 (176805). Microsomal PGES (mPGES) is inducible by proinflammatory cytokines such as IL1B. Meadows et al. (2003) studied expression and localization of both enzyme isoforms in human fetal membranes either at term or preterm, with or without labor. Western blot analysis of the amnion and choriodecidua showed no differences in amounts of either cPGES or mPGES at term or preterm, with or without labor, in either tissue with advancing gestation. Meadows et al. (2003) concluded that expression of PGES is not the rate-limiting step in PGE2 synthesis in fetal membranes at labor.
Chopra et al. (2019) found that induction of prostaglandin-endoperoxide synthase-2 (PTGS2; 600262) and PTGES 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.
Forsberg et al. (2000) mapped the PGES gene to 9q34.3 by FISH. They noted that all known MAPEGs reside on different chromosomes.
To study the physiologic role of the individual PGE synthases, Trebino et al. (2003) generated by targeted homologous recombination a mouse line deficient in microsomal Ptges (mPtges). The mPtges -/- mice were viable and fertile and developed normally compared with wildtype controls. However, they displayed a marked reduction in inflammatory responses compared with mPtges +/+ mice. Trebino et al. (2003) identified mPtges as the PGE synthase that contributes to the pathogenesis of collagen-induced arthritis, a disease model of human rheumatoid arthritis. They also showed that mPtges is responsible for the production of Pge2 that mediates acute pain during an inflammatory response. These findings suggest that mPTGES provides a target for the treatment of inflammatory diseases and pain associated with inflammatory states.
Engblom et al. (2003) noted that mPTGES is induced in brain endothelial cells upon immune challenge, producing PGE2 that acts on receptors in the median preoptic region of the hypothalamus to produce fever. In mPtges-deficient mice, Engblom et al. (2003) found no fever induction and no central Pge2 synthesis after peripheral injection of bacterial-wall lipopolysaccharide (LPS), whereas wildtype mice had a robust body temperature elevation, an increase in brain Pge2, and a strong induction of the mPtges enzyme. However, the pyretic capacity of the null mice in response to intracerebroventricular injections of Pge2 remained intact. The authors concluded that mPTGES is the central switch during immune-induced pyresis and may be a target for treatment of fever.
Chopra, S., Giovanelli, P., Alvarado-Vazquez, P. A., Alonso, S., Song, M., Sandoval, T. A., Chae, C.-S., Tan, C., Fonseca, M. M., Gutierrez, S., Jimenez, L., Subbaramaiah, K., and 9 others. IRE1-alpha-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain. Science 365: eaau6499, 2019. Note: Electronic Article. [PubMed: 31320508] [Full Text: https://doi.org/10.1126/science.aau6499]
Engblom, D., Saha, S., Engstrom, L., Westman, M., Audoly, L. P., Jakobsson, P.-J., Blomqvist, A. Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis. Nature Neurosci. 6: 1137-1138, 2003. [PubMed: 14566340] [Full Text: https://doi.org/10.1038/nn1137]
Forsberg, L., Leeb, L., Thoren, S., Morgenstern, R., Jakobsson, P.-J. Human glutathione dependent prostaglandin E synthase: gene structure and regulation. FEBS Lett. 471: 78-82, 2000. [PubMed: 10760517] [Full Text: https://doi.org/10.1016/s0014-5793(00)01367-3]
Jakobsson, P.-J., Morgenstern, R., Mancini, J., Ford-Hutchinson, A., Persson, B. Common structural features of MAPEG: a widespread superfamily of membrane associated proteins with highly divergent functions in eicosanoid and glutathione metabolism. Protein Sci. 8: 689-692, 1999. [PubMed: 10091672] [Full Text: https://doi.org/10.1110/ps.8.3.689]
Jakobsson, P.-J., Thoren, S., Morgenstern, R., Samuelsson, B. Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target. Proc. Nat. Acad. Sci. 96: 7220-7225, 1999. [PubMed: 10377395] [Full Text: https://doi.org/10.1073/pnas.96.13.7220]
Meadows, J. W., Eis, A. L. W., Brockman, D. E., Myatt, L. Expression and localization of prostaglandin E synthase isoforms in human fetal membranes in term and preterm labor. J. Clin. Endocr. Metab. 88: 433-439, 2003. [PubMed: 12519887] [Full Text: https://doi.org/10.1210/jc.2002-021061]
Polyak, K., Xia, Y., Zweier, J. L., Kinzler, K. W., Vogelstein, B. A model for p53-induced apoptosis. Nature 389: 300-305, 1997. [PubMed: 9305847] [Full Text: https://doi.org/10.1038/38525]
Trebino, C. E., Stock, J. L., Gibbons, C. P., Naiman, B. M., Wachtmann, T. S., Umland, J. P., Pandher, K., Lapointe, J.-M., Saha, S., Roach, M. L., Carter, D., Thomas, N. A., Durtschi, B. A., McNeish, J. D., Hambor, J. E., Jakobsson, P.-J., Carty, T. J., Perez, J. R., Audoly, L. P. Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proc. Nat. Acad. Sci. 100: 9044-9049, 2003. [PubMed: 12835414] [Full Text: https://doi.org/10.1073/pnas.1332766100]