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Ptgs2  -  prostaglandin-endoperoxide synthase 2

Mus musculus

 
 
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Disease relevance of Ptgs2

  • A Ptgs2 null mutation reduced the number and size of the intestinal polyps dramatically [1].
  • Furthermore, Ptgs2-deficient mice showed minimal histologic evidence of pancreatitis, a marked attenuation in the severity of lung injury, and a significant reduction in myeloperoxidase activity [2].
  • Furthermore, treating Apc delta716 mice with a novel COX-2 inhibitor reduced the polyp number more significantly than with sulindac, which inhibits both isoenzymes [1].
  • Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2) [1].
  • Therefore, COX-1-selective inhibitors may provide effective treatment to delay preterm labor with fewer adverse effects on fetal or neonatal health than nonselective or COX-2-selective inhibitors [3].
  • We engineered mice with conditional deletion of Cox2 in neurons and glial cells to determine the relative contribution of peripheral and central COX2 to inflammatory pain hypersensitivity [4].
 

Psychiatry related information on Ptgs2

  • Recent studies demonstrated that COX-2 expression was up-regulated in the brain of patients with Alzheimer's disease [5].
  • The results of the present study suggest strongly the possible role of cyclooxygenases, particularly COX-2 inhibitors, on ethanol-induced withdrawal symptoms and the potential use of COX-2 inhibitors in their prevention and treatment [6].
  • Starting at 4 weeks of age, the treated group (T group) were given a diet containing JTE-522, a selective COX-2 inhibitor, and the control group (C group) were given a control diet [7].
  • The broad-spectrum MMP inhibitor (A-177430; MMPI) and the selective COX-2 inhibitor (A-285969; COX-2I) both showed dose-dependent inhibition of the number of adenomas in Min mice [8].
  • The results showed that chronic treatment with flavonoids reverses cognitive deficits in aged and LPS-intoxicated mice which suggests that modulation of cyclooxygenase-2 and inducible nitric synthase by flavonoids may be important in the prevention of memory deficits, one of the symptoms related to AD [9].
 

High impact information on Ptgs2

  • The effect is inhibited by antibodies to combinations of angiogenic factors, by NS-398 (a selective COX-2 inhibitor), and by aspirin [10].
  • We demonstrate herein that the targeted disruption of COX-2, but not COX-1, in mice produces multiple failures in female reproductive processes that include ovulation, fertilization, implantation, and decidualization [11].
  • Using multiple approaches, we conclude that these defects are the direct result of target organ-specific COX-2 deficiency but are not the result of deficiency of pituitary gonadotropins or ovarian steroid hormones, or reduced responsiveness of the target organs to their respective hormones [11].
  • Two cyclooxygenase isozymes catalyze conversion of arachidonic acid to prostaglandin H2: constitutive COX-1 and inducible COX-2 [1].
  • The prostaglandin endoperoxide H synthase isoform 2, cyclooxygenase 2 (COX-2), is induced at high levels in migratory and other responding cells by pro-inflammatory stimuli [12].
 

Chemical compound and disease context of Ptgs2

 

Biological context of Ptgs2

  • We provide evidence that this improved fertility in CD1 Ptgs2 null mice is the result of a compensatory up-regulation of Ptgs1 which does not occur in C57BL/6J/129 mice missing Ptgs2 [17].
  • Here we show that Ptgs2 null mice on a CD1 background have dramatically improved female fertility including ovulation, fertilization, and implantation, giving rise to live births [17].
  • Here, we developed a new genetic mouse model of selective COX2 inhibition using a gene-targeted point mutation, resulting in a Y385F substitution [18].
  • Chronic inhibition of COX-2 during pregnancy (gestation days 15-18) significantly increased neonatal mortality by preventing closure of the DA after birth, whereas acute COX-2 inhibition near the end of term (gestation day 18) constricted the fetal DA [3].
  • Finally, the effects of these agents were additive, indicating that COX-2 is involved in maximal induction of osteogenesis [19].
 

Anatomical context of Ptgs2

 

Associations of Ptgs2 with chemical compounds

  • Results also reveal that PGE2, but not PGI2, is the major PG at implantation sites where Ptgs2 and microsomal type PGE synthases but not PGI synthases are co-expressed [21].
  • It is known that Ptgs2 expression and Ptgs2-derived prostacyclin (PGI2) synthesis at implantation sites are needed for implantation in the mouse (a rodent that needs ovarian estrogen for implantation) [21].
  • Mice lacking COX-2 have normal inflammatory responses to treatments with tetradecanoyl phorbol acetate or with arachidonic acid [12].
  • Here we report the structures of unliganded murine COX-2 and complexes with flurbiprofen, indomethacin and SC-558, a selective COX-2 inhibitor, determined at 3.0 to 2.5 A resolution [22].
  • BMMCs stimulated by KL + IL-10 for 10 h exhibited a delayed phase of PGD2 generation, which was dependent on de novo induction of PGHS-2 [23].
  • Taken together with a recent crystal structure of a lumiracoxib-COX-2 complex, the kinetic analyses presented herein of the inhibition of mutant COX-2s by lumiracoxib allows the definition of the molecular basis of COX-2 inhibition [24].
 

Physical interactions of Ptgs2

  • Enhancement of LPS-inducible COX-2 expression and C/EBP DNA binding by C2 was abrogated in dominant-negative mutant of JNK1 [JNK1(-)] cells [25].
  • Luciferase reporter constructs with alterations in presumptive cis-acting transcriptional regulatory elements demonstrate that the cyclic AMP-response element and two nuclear factor interleukin-6 (CCAAT/enhancer-binding protein (C/EBP)) sites of the COX-2 promoter are required for optimal endotoxin-dependent induction [26].
  • NF-kappaB DNA binding activity was selectively affected in the COX-2-/- mice compared to the wild type as there was no significant change in NFATc DNA binding activity [27].
  • Conversely, IL-1 beta stabilized the COX-2 protein without affecting its mRNA level [28].
  • Double mutation of the AhR and CREB-binding sites showed synergy in repressing COX-2 promoter activity as did mutation of all three sites [29].
 

Enzymatic interactions of Ptgs2

  • A number of 1,5-diarylimidazoles has been synthesized and evaluated for their inhibitory activities of COX-2 catalyzed PGE2 production [30].
 

Regulatory relationships of Ptgs2

 

Other interactions of Ptgs2

  • Cox-1 is thought to be a constitutively expressed enzyme, and the expression of Cox-2 is inducible by cytokines or other stimuli in a variety of cell types [34].
  • JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease [35].
  • Genetic disruption of Ptgs-1, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice [36].
  • Our results raise the possibility that deprivation of COX-2 of its substrate by the suppression of cPLA2 mRNA expression is an additional mechanism used by NSAIDs to inhibit tumorigenesis [37].
  • Transcriptional roles of nuclear factor kappa B and nuclear factor-interleukin-6 in the tumor necrosis factor alpha-dependent induction of cyclooxygenase-2 in MC3T3-E1 cells [38].
 

Analytical, diagnostic and therapeutic context of Ptgs2

References

  1. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Oshima, M., Dinchuk, J.E., Kargman, S.L., Oshima, H., Hancock, B., Kwong, E., Trzaskos, J.M., Evans, J.F., Taketo, M.M. Cell (1996) [Pubmed]
  2. Cyclooxygenase-2 gene disruption attenuates the severity of acute pancreatitis and pancreatitis-associated lung injury. Ethridge, R.T., Chung, D.H., Slogoff, M., Ehlers, R.A., Hellmich, M.R., Rajaraman, S., Saito, H., Uchida, T., Evers, B.M. Gastroenterology (2002) [Pubmed]
  3. Cyclooxygenase-1-selective inhibition prolongs gestation in mice without adverse effects on the ductus arteriosus. Loftin, C.D., Trivedi, D.B., Langenbach, R. J. Clin. Invest. (2002) [Pubmed]
  4. COX2 in CNS neural cells mediates mechanical inflammatory pain hypersensitivity in mice. Vardeh, D., Wang, D., Costigan, M., Lazarus, M., Saper, C.B., Woolf, C.J., Fitzgerald, G.A., Samad, T.A. J. Clin. Invest. (2009) [Pubmed]
  5. Cyclooxygenase-2 stimulates production of amyloid beta-peptide in neuroblastoma x glioma hybrid NG108-15 cells. Kadoyama, K., Takahashi, Y., Higashida, H., Tanabe, T., Yoshimoto, T. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  6. Protective effect of cyclooxygenase-2 (COX-2) inhibitors but not non-selective cyclooxygenase (COX)-inhibitors on ethanol withdrawal-induced behavioural changes. Dhir, A., Naidu, P.S., Kulkarni, S.K. Addiction biology. (2005) [Pubmed]
  7. The role of cyclooxygenase-2 (COX-2) in two different morphological stages of intestinal polyps in APC(Delta474) knockout mice. Sunayama, K., Konno, H., Nakamura, T., Kashiwabara, H., Shoji, T., Tsuneyoshi, T., Nakamura, S. Carcinogenesis (2002) [Pubmed]
  8. Cooperative effects of matrix metalloproteinase and cyclooxygenase-2 inhibition on intestinal adenoma reduction. Wagenaar-Miller, R.A., Hanley, G., Shattuck-Brandt, R., DuBois, R.N., Bell, R.L., Matrisian, L.M., Morgan, D.W. Br. J. Cancer (2003) [Pubmed]
  9. Protective effect of flavonoids against aging- and lipopolysaccharide-induced cognitive impairment in mice. Patil, C.S., Singh, V.P., Satyanarayan, P.S., Jain, N.K., Singh, A., Kulkarni, S.K. Pharmacology (2003) [Pubmed]
  10. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Tsujii, M., Kawano, S., Tsuji, S., Sawaoka, H., Hori, M., DuBois, R.N. Cell (1998) [Pubmed]
  11. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Lim, H., Paria, B.C., Das, S.K., Dinchuk, J.E., Langenbach, R., Trzaskos, J.M., Dey, S.K. Cell (1997) [Pubmed]
  12. Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. Morham, S.G., Langenbach, R., Loftin, C.D., Tiano, H.F., Vouloumanos, N., Jennette, J.C., Mahler, J.F., Kluckman, K.D., Ledford, A., Lee, C.A., Smithies, O. Cell (1995) [Pubmed]
  13. Preinvasive duct-derived neoplasms in pancreas of keratin 5-promoter cyclooxygenase-2 transgenic mice. Müller-Decker, K., Fürstenberger, G., Annan, N., Kucher, D., Pohl-Arnold, A., Steinbauer, B., Esposito, I., Chiblak, S., Friess, H., Schirmacher, P., Berger, I. Gastroenterology (2006) [Pubmed]
  14. Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Sharma, S., Yang, S.C., Zhu, L., Reckamp, K., Gardner, B., Baratelli, F., Huang, M., Batra, R.K., Dubinett, S.M. Cancer Res. (2005) [Pubmed]
  15. Inhibition of cyclooxygenase-2 by rofecoxib attenuates the growth and metastatic potential of colorectal carcinoma in mice. Yao, M., Kargman, S., Lam, E.C., Kelly, C.R., Zheng, Y., Luk, P., Kwong, E., Evans, J.F., Wolfe, M.M. Cancer Res. (2003) [Pubmed]
  16. Inhibitory effects of mofezolac, a cyclooxygenase-1 selective inhibitor, on intestinal carcinogenesis. Kitamura, T., Kawamori, T., Uchiya, N., Itoh, M., Noda, T., Matsuura, M., Sugimura, T., Wakabayashi, K. Carcinogenesis (2002) [Pubmed]
  17. Rescue of female infertility from the loss of cyclooxygenase-2 by compensatory up-regulation of cyclooxygenase-1 is a function of genetic makeup. Wang, H., Ma, W.G., Tejada, L., Zhang, H., Morrow, J.D., Das, S.K., Dey, S.K. J. Biol. Chem. (2004) [Pubmed]
  18. Genetic model of selective COX2 inhibition reveals novel heterodimer signaling. Yu, Y., Fan, J., Chen, X.S., Wang, D., Klein-Szanto, A.J., Campbell, R.L., FitzGerald, G.A., Funk, C.D. Nat. Med. (2006) [Pubmed]
  19. Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. Zhang, X., Schwarz, E.M., Young, D.A., Puzas, J.E., Rosier, R.N., O'Keefe, R.J. J. Clin. Invest. (2002) [Pubmed]
  20. Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma. Rodriguez, P.C., Hernandez, C.P., Quiceno, D., Dubinett, S.M., Zabaleta, J., Ochoa, J.B., Gilbert, J., Ochoa, A.C. J. Exp. Med. (2005) [Pubmed]
  21. Prostaglandin E2 is a product of induced prostaglandin-endoperoxide synthase 2 and microsomal-type prostaglandin E synthase at the implantation site of the hamster. Wang, X., Su, Y., Deb, K., Raposo, M., Morrow, J.D., Reese, J., Paria, B.C. J. Biol. Chem. (2004) [Pubmed]
  22. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Kurumbail, R.G., Stevens, A.M., Gierse, J.K., McDonald, J.J., Stegeman, R.A., Pak, J.Y., Gildehaus, D., Miyashiro, J.M., Penning, T.D., Seibert, K., Isakson, P.C., Stallings, W.C. Nature (1996) [Pubmed]
  23. Interleukin 4 suppresses c-kit ligand-induced expression of cytosolic phospholipase A2 and prostaglandin endoperoxide synthase 2 and their roles in separate pathways of eicosanoid synthesis in mouse bone marrow-derived mast cells. Murakami, M., Penrose, J.F., Urade, Y., Austen, K.F., Arm, J.P. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  24. Molecular determinants for the selective inhibition of cyclooxygenase-2 by lumiracoxib. Blobaum, A.L., Marnett, L.J. J. Biol. Chem. (2007) [Pubmed]
  25. Potentiation of lipopolysaccharide-inducible cyclooxygenase 2 expression by C2-ceramide via c-Jun N-terminal kinase-mediated activation of CCAAT/enhancer binding protein beta in macrophages. Cho, Y.H., Lee, C.H., Kim, S.G. Mol. Pharmacol. (2003) [Pubmed]
  26. Transcriptional activation of the cyclooxygenase-2 gene in endotoxin-treated RAW 264.7 macrophages. Wadleigh, D.J., Reddy, S.T., Kopp, E., Ghosh, S., Herschman, H.R. J. Biol. Chem. (2000) [Pubmed]
  27. Down-regulation of brain nuclear factor-kappa B pathway in the cyclooxygenase-2 knockout mouse. Rao, J.S., Langenbach, R., Bosetti, F. Brain Res. Mol. Brain Res. (2005) [Pubmed]
  28. Cross-linking of the high-affinity IgE receptor induces the expression of cyclo-oxygenase 2 and attendant prostaglandin generation requiring interleukin 10 and interleukin 1 beta in mouse cultured mast cells. Ashraf, M., Murakami, M., Kudo, I. Biochem. J. (1996) [Pubmed]
  29. Transcriptional regulation of cyclooxygenase-2 gene in pancreatic beta-cells. Yang, F., Bleich, D. J. Biol. Chem. (2004) [Pubmed]
  30. Synthesis and antiinflammatory activity of 1,5-diarylimidazoles. Tuyen, T.N., Sin, K.S., Kim, H.P., Park, H. Arch. Pharm. Res. (2005) [Pubmed]
  31. Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals. Eliopoulos, A.G., Dumitru, C.D., Wang, C.C., Cho, J., Tsichlis, P.N. EMBO J. (2002) [Pubmed]
  32. Tumor necrosis factor-alpha inversely regulates prostaglandin D2 and prostaglandin E2 production in murine macrophages. Synergistic action of cyclic AMP on cyclooxygenase-2 expression and prostaglandin E2 synthesis. Fournier, T., Fadok, V., Henson, P.M. J. Biol. Chem. (1997) [Pubmed]
  33. MAPK mediation of hypertonicity-stimulated cyclooxygenase-2 expression in renal medullary collecting duct cells. Yang, T., Huang, Y., Heasley, L.E., Berl, T., Schnermann, J.B., Briggs, J.P. J. Biol. Chem. (2000) [Pubmed]
  34. Crypt stem cell survival in the mouse intestinal epithelium is regulated by prostaglandins synthesized through cyclooxygenase-1. Cohn, S.M., Schloemann, S., Tessner, T., Seibert, K., Stenson, W.F. J. Clin. Invest. (1997) [Pubmed]
  35. JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease. Hunot, S., Vila, M., Teismann, P., Davis, R.J., Hirsch, E.C., Przedborski, S., Rakic, P., Flavell, R.A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  36. Genetic disruption of Ptgs-1, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice. Chulada, P.C., Thompson, M.B., Mahler, J.F., Doyle, C.M., Gaul, B.W., Lee, C., Tiano, H.F., Morham, S.G., Smithies, O., Langenbach, R. Cancer Res. (2000) [Pubmed]
  37. Transcriptional regulation of cyclooxygenase-2 gene expression: novel effects of nonsteroidal anti-inflammatory drugs. Yuan, C.J., Mandal, A.K., Zhang, Z., Mukherjee, A.B. Cancer Res. (2000) [Pubmed]
  38. Transcriptional roles of nuclear factor kappa B and nuclear factor-interleukin-6 in the tumor necrosis factor alpha-dependent induction of cyclooxygenase-2 in MC3T3-E1 cells. Yamamoto, K., Arakawa, T., Ueda, N., Yamamoto, S. J. Biol. Chem. (1995) [Pubmed]
  39. Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Dinchuk, J.E., Car, B.D., Focht, R.J., Johnston, J.J., Jaffee, B.D., Covington, M.B., Contel, N.R., Eng, V.M., Collins, R.J., Czerniak, P.M. Nature (1995) [Pubmed]
  40. Elevated cyclooxygenase-2 levels in Min mouse adenomas. Williams, C.S., Luongo, C., Radhika, A., Zhang, T., Lamps, L.W., Nanney, L.B., Beauchamp, R.D., DuBois, R.N. Gastroenterology (1996) [Pubmed]
  41. Constitutive expression and function of cyclooxygenase-2 in murine gastric muscles. Porcher, C., Horowitz, B., Bayguinov, O., Ward, S.M., Sanders, K.M. Gastroenterology (2002) [Pubmed]
  42. Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Vane, J.R., Mitchell, J.A., Appleton, I., Tomlinson, A., Bishop-Bailey, D., Croxtall, J., Willoughby, D.A. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
 
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