Posttranscriptional and posttranslational determinants of cyclooxygenase expression

  • Mbonye, Uri R. (Department of Molecular Biology and Microbiology, Case Western Reserve University) ;
  • Song, In-Seok (Department of Life Science, University of Seoul)
  • Published : 2009.09.30


Cyclooxygenases (COX-1 and COX-2) are ER-resident proteins that catalyze the committed step in prostanoid synthesis. COX-1 is constitutively expressed in many mammalian cells, whereas COX-2 is usually expressed inducibly and transiently. Abnormal expression of COX-2 has been implicated in the pathogenesis of chronic inflammation and various cancers; therefore, it is subject to tight and complex regulation. Differences in regulation of the COX enzymes at the posttranscriptional and posttranslational levels also contribute significantly to their distinct patterns of expression. Rapid degradation of COX-2 mRNA has been attributed to AU-rich elements (AREs) at its 3’UTR. Recently, microRNAs that can selectively repress COX-2 protein synthesis have been identified. The mature forms of these COX proteins are very similar in structure except that COX-2 has a unique 19-amino acid (19-aa) segment located near the C-terminus. This C-terminal 19-aa cassette plays an important role in mediation of the entry of COX-2 into the ER-associated degradation (ERAD) system, which transports ER proteins to the cytoplasm for degradation by the 26S proteasome. A second pathway for COX-2 protein degradation is initiated after the enzyme undergoes suicide inactivation following cyclooxygenase catalysis. Here, we discuss these molecular determinants of COX-2 expression in detail.


  1. van der Donk, W. A., Tsai, A. L. and Kulmacz, R. J. (2002) The cyclooxygenase reaction mechanism. Biochemistry 41, 15451-15458
  2. MirAfzali, Z., Leipprandt, J. R., McCracken, J. L. and DeWitt, D. L. (2006) Topography of the prostaglandin endoperoxide H2 synthase-2 in membranes. J. Biol. Chem. 281, 28354-28364
  3. Miyamoto, T., Ogino, N., Yamamoto, S. and Hayaishi, O. (1976) Purification of prostaglandin endoperoxide synthetase from bovine vesicular gland microsomes. J. Biol. Chem. 251, 2629-2636
  4. Zaric, J. and Ruegg, C. (2005) Integrin-mediated adhesion and soluble ligand binding stabilize COX-2 protein levels in endothelial cells by inducing expression and preventing degradation. J. Biol. Chem. 280, 1077-1085
  5. Wang, L. H., Hajibeigi, A., Xu, X. M., Loose-Mitchell, D. and Wu, K. K. (1993) Characterization of the promoter of human prostaglandin H synthase-1 gene. Biochem. Biophys. Res. Commun. 190, 406-411
  6. Tanabe, T. and Tohnai, N. (2002) Cyclooxygenase isozymes and their gene structures and expression. Prostaglandins. Other. Lipid. Mediat. 68-69, 95-114
  7. Kang, Y. J., Mbonye, U. R., DeLong, C. J., Wada, M. and Smith, W. L. (2007) Regulation of intracellular cyclooxygenase levels by gene transcription and protein degradation. Prog. Lipid. Res. 46, 108-125
  8. Chen, C. Y. and Shyu, A. B. (1994) Selective degradation of early-response-gene mRNAs: functional analyses of sequence features of the AU-rich elements. Mol. Cell. Biol. 14, 8471-84820
  9. Dixon, D. A., Tolley, N. D., King, P. H., Nabors, L. B., McIntyre, T. M., Zimmerman, G. A. and Prescott, S. M. (2001) Altered expression of the mRNA stability factor HuR promotes cyclooxygenase-2 expression in colon cancer cells. J. Clin. Invest. 108, 1657-1665
  10. Jing, Q., Huang, S., Guth, S., Zarubin, T., Motoyama, A., Chen, J., Di Padova, F., Lin, S. C., Gram, H. and Han, J. (2005) Involvement of microRNA in AU-rich elementmediated mRNA instability. Cell. 120, 623-634
  11. Jackson, R. J. and Standart, N. (2007) How do microRNAs regulate gene expression? Sci. STKE. 2007, re1
  12. Sevigny, M. B., Li, C. F., Alas, M. and Hughes-Fulford, M. (2006) Glycosylation regulates turnover of cyclooxygenase-2. FEBS. Lett. 580, 6533-6536
  13. McCracken, A. A. and Brodsky, J. L. (2003) Evolving questions and paradigm shifts in endoplasmic-reticulum- associated degradation (ERAD). Bioessays 25, 868-877
  14. Spear, E. D. and Ng, D. T. (2005) Single, context-specific glycans can target misfolded glycoproteins for ER-associated degradation. J. Cell. Biol. 169, 73-82
  15. Murray, B. P. and Correia, M. A. (2001) Ubiquitin-dependent 26S proteasomal pathway: a role in the degradation of native human liver CYP3A4 expressed in Saccharomyces cerevisiae? Arch. Biochem. Biophys. 393, 106-116
  16. Webster, J. M., Tiwari, S., Weissman, A. M. and Wojcikiewicz, R. J. (2003) Inositol 1,4,5-trisphosphate receptor ubiquitination is mediated by mammalian Ubc7, a component of the endoplasmic reticulum-associated degradation pathway, and is inhibited by chelation of intracellular Zn2+. J. Biol. Chem. 278, 38238-38246
  17. Tokunaga, F., Brostrom, C., Koide, T. and Arvan, P. (2000) Endoplasmic reticulum (ER)-associated degradation of misfolded N-linked glycoproteins is suppressed upon inhibition of ER mannosidase I. J. Biol. Chem. 275, 40757-40764
  18. Hosokawa, N., Tremblay, L. O., You, Z., Herscovics, A., Wada, I. and Nagata, K. (2003) Enhancement of endoplasmic reticulum (ER) degradation of misfolded Null Hong Kong alpha1-antitrypsin by human ER mannosidase I. J. Biol. Chem. 278, 26287-26294
  19. Reddy, S. T. and Herschman, H. R. (1994) Ligand-induced prostaglandin synthesis requires expression of the TIS10/PGS-2 prostaglandin synthase gene in murine fibroblasts and macrophages. J. Biol. Chem. 269, 15473-15480
  20. Kiefer, J. R., Pawlitz, J. L., Moreland, K. T., Stegeman, R. A., Hood, W. F., Gierse, J. K., Stevens, A. M., Goodwin, D. C., Rowlinson, S. W., Marnett, L. J., Stallings, W. C. and Kurumbail, R. G. (2000) Structural insights into the stereochemistry of the cyclooxygenase reaction. Nature 405, 97-101
  21. Xu, X. M., Tang, J. L., Chen, X., Wang, L. H. and Wu, K. K. (1997) Involvement of two Sp1 elements in basal endothelial prostaglandin H synthase-1 promoter activity. J. Biol. Chem. 272, 6943-6950
  22. Okahara, K., Sun, B. and Kambayashi, J. (1998) Upregulation of prostacyclin synthesis-related gene expression by shear stress in vascular endothelial cells. Arterioscler. Thromb. Vasc. Biol. 18, 1922-1926
  23. Kobayashi, T. and Narumiya, S. (2002) Function of prostanoid receptors: studies on knockout mice. Prostaglandins. Other. Lipid. Mediat. 68-69, 557-573
  24. Fagioli, C. and Sitia, R. (2001) Glycoprotein quality control in the endoplasmic reticulum. Mannose trimming by endoplasmic reticulum mannosidase I times the proteasomal degradation of unassembled immunoglobulin subunits. J. Biol. Chem. 276, 12885-12892
  25. Leahy, K. M., Ornberg, R. L., Wang, Y., Zweifel, B. S., Koki, A. T. and Masferrer, J. L. (2002) Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo. Cancer Res. 62, 625-631
  26. Cao, C., Matsumura, K., Yamagata, K. and Watanabe, Y. (1998) Cyclooxygenase-2 is induced in brain blood vessels during fever evoked by peripheral or central administration of tumor necrosis factor. Brain. Res. Mol. Brain. Res. 56, 45-56
  27. Sinicrope, F. A. (2006) Targeting cyclooxygenase-2 for prevention and therapy of colorectal cancer. Mol. Carcinog. 45, 447-454
  28. Otto, J. C. and Smith, W. L. (1994) The orientation of prostaglandin endoperoxide synthases-1 and -2 in the endoplasmic reticulum. J. Biol. Chem. 269, 19868-19875
  29. Xu, X. M., Tang, J. L., Hajibeigi, A., Loose-Mitchell, D. S. and Wu, K. K. (1996) Transcriptional regulation of endothelial constitutive PGHS-1 expression by phorbol ester. Am. J. Physiol. 270, C259-264
  30. Spiro, R. G. (2004) Role of N-linked polymannose oligosaccharides in targeting glycoproteins for endoplasmic reticulum- associated degradation. Cell. Mol. Life. Sci. 61, 1025-1041
  31. Kitzmuller, C., Caprini, A., Moore, S. E., Frenoy, J. P., Schwaiger, E., Kellermann, O., Ivessa, N. E. and Ermonval, M. (2003) Processing of N-linked glycans during endoplasmic-reticulum-associated degradation of a short-lived variant of ribophorin I. Biochem. J. 376, 687-696
  32. Schildknecht, S., Bachschmid, M., Baumann, A. and Ullrich, V. (2004) COX-2 inhibitors selectively block prostacyclin synthesis in endotoxin-exposed vascular smooth muscle cells. Faseb. J. 18, 757-759
  33. Lasa, M., Mahtani, K. R., Finch, A., Brewer, G., Saklatvala, J. and Clark, A. R. (2000) Regulation of cyclooxygenase 2 mRNA stability by the mitogen-activated protein kinase p38 signaling cascade. Mol. Cell. Biol. 20, 4265-4274
  34. Ravid, T., Doolman, R., Avner, R., Harats, D. and Roitelman, J. (2000) The ubiquitin-proteasome pathway mediates the regulated degradation of mammalian 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J. Biol. Chem. 275, 35840-35847
  35. Perkins, D. J. and Kniss, D. A. (1997) Rapid and transient induction of cyclo-oxygenase 2 by epidermal growth factor in human amnion-derived WISH cells. Biochem. J. 321 (Pt 3), 677-681
  36. Kang, Y. J., Wingerd, B. A., Arakawa, T. and Smith, W. L. (2006) Cyclooxygenase-2 gene transcription in a macrophage model of inflammation. J. Immunol. 177, 8111-8122
  37. Otto, J. C., DeWitt, D. L. and Smith, W. L. (1993) N-glycosylation of prostaglandin endoperoxide synthases-1 and -2 and their orientations in the endoplasmic reticulum. J. Biol. Chem. 268, 18234-18242
  38. Zhang, Y., Shaffer, A., Portanova, J., Seibert, K. and Isakson, P. C. (1997) Inhibition of cyclooxygenase-2 rapidly reverses inflammatory hyperalgesia and prostaglandin E2 production. J. Pharmacol. Exp. Ther. 283, 1069-1075
  39. Liou, J. Y., Shyue, S. K., Tsai, M. J., Chung, C. L., Chu, K. Y. and Wu, K. K. (2000) Colocalization of prostacyclin synthase with prostaglandin H synthase-1 (PGHS-1) but not phorbol ester-induced PGHS-2 in cultured endothelial cells. J. Biol. Chem. 275, 15314-15320
  40. Bustos, M., Coffman, T. M., Saadi, S. and Platt, J. L. (1997) Modulation of eicosanoid metabolism in endothelial cells in a xenograft model. Role of cyclooxygenase-2. J. Clin. Invest. 100, 1150-1158
  41. Lasa, M., Brook, M., Saklatvala, J., and Clark, A. R. (2001) Dexamethasone destabilizes cyclooxygenase 2 mRNA by inhibiting mitogen-activated protein kinase p38. Mol. Cell. Biol. 21, 771-780
  42. Narumiya, S. and FitzGerald, G. A. (2001) Genetic and pharmacological analysis of prostanoid receptor function. J. Clin. Invest. 108, 25-30
  43. Funk, C. D. (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294, 1871-1875
  44. DeWitt, D. L., Day, J. S., Sonnenburg, W. K. and Smith, W. L. (1983) Concentrations of prostaglandin endoperoxide synthase and prostaglandin I2 synthase in the endothelium and smooth muscle of bovine aorta. J. Clin. Invest. 72, 1882-1888
  45. Mukhopadhyay, D., Houchen, C. W., Kennedy, S., Dieckgraefe, B. K. and Anant, S. (2003) Coupled mRNA stabilization and translational silencing of cyclooxygenase-2 by a novel RNA binding protein, CUGBP2. Mol. Cell. 11, 113-126
  46. Rockwell, P., Yuan, H., Magnusson, R. and Figueiredo-Pereira, M. E. (2000) Proteasome inhibition in neuronal cells induces a proinflammatory response manifested by upregulation of cyclooxygenase-2, its accumulation as ubiquitin conjugates, and production of the prostaglandin PGE(2). Arch. Biochem. Biophys. 374, 325-333
  47. DeWitt, D. L. and Meade, E. A. (1993) Serum and glucocorticoid regulation of gene transcription and expression of the prostaglandin H synthase-1 and prostaglandin H synthase-2 isozymes. Arch. Biochem. Biophys. 306, 94-102
  48. Langenbach, R., Morham, S. G., Tiano, H. F., Loftin, C. D., Ghanayem, B. I., Chulada, P. C., Mahler, J. F., Lee, C. A., Goulding, E. H., Kluckman, K. D., Kim, H. S. and Smithies, O. (1995) Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell. 83, 483-492
  49. Chen, C. Y., Chen, T. M. and Shyu, A. B. (1994) Interplay of two functionally and structurally distinct domains of the c-fos AU-rich element specifies its mRNA-destabilizing function. Mol. Cell. Biol. 14, 416-426
  50. Song, I., Ball, T. M. and Smith, W. L. (2001) Different suicide inactivation processes for the peroxidase and cyclooxygenase activities of prostaglandin endoperoxide H synthase-1. Biochem. Biophys. Res. Commun. 289, 869-875
  51. Yuan, C., Rieke, C. J., Rimon, G., Wingerd, B. A. and Smith, W. L. (2006) Partnering between monomers of cyclooxygenase-2 homodimers. Proc. Natl. Acad. Sci. U.S.A. 103, 6142-6147
  52. 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. and Stallings, W. C. (1996) Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature 384, 644-648
  53. Rich, G., Yoder, E. J., and Moore, S. A. (1998) Regulation of prostaglandin H synthase-2 expression in cerebromicrovascular smooth muscle by serum and epidermal growth factor. J. Cell. Physiol. 176, 495-505<495::AID-JCP6>3.0.CO;2-J
  54. Caughey, G. E., Cleland, L. G., Penglis, P. S., Gamble, J. R. and James, M. J. (2001) Roles of cyclooxygenase (COX)-1 and COX-2 in prostanoid production by human endothelial cells: selective up-regulation of prostacyclin synthesis by COX-2. J. Immunol. 167, 2831-2838
  55. Smith, W. L., DeWitt, D. L. and Garavito, R. M. (2000) Cyclooxygenases: structural, cellular, and molecular biology. Annu. Rev. Biochem. 69, 145-182
  56. Smith, W. L. (2008) Nutritionally essential fatty acids and biologically indispensable cyclooxygenases. Trends. Biochem. Sci. 33, 27-37
  57. Spencer, A. G., Thuresson, E., Otto, J. C., Song, I., Smith, T., DeWitt, D. L., Garavito, R. M. and Smith, W. L. (1999) The membrane binding domains of prostaglandin endoperoxide H synthases 1 and 2. Peptide mapping and mutational analysis. J. Biol. Chem. 274, 32936-32942
  58. Lim, H., Paria, B. C., Das, S. K., Dinchuk, J. E., Langenbach, R., Trzaskos, J. M. and Dey, S. K. (1997) Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell. 91, 197-208
  59. Hosokawa, N., Wada, I., Hasegawa, K., Yorihuzi, T., Tremblay, L. O., Herscovics, A. and Nagata, K. (2001) A novel ER alpha-mannosidase-like protein accelerates ER-associated degradation. EMBO. Rep. 2, 415-422
  60. Rouzer, C. A. and Marnett, L. J. (2009) Cyclooxygenases: structural and functional insights. J. Lipid. Res. 50(Suppl), S29-34
  61. Samad, T. A., Moore, K. A., Sapirstein, A., Billet, S., Allchorne, A., Poole, S., Bonventre, J. V. and Woolf, C. J. (2001) Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410, 471-475
  62. Xiao, G., Chen, W. and Kulmacz, R. J. (1998) Comparison of structural stabilities of prostaglandin H synthase-1 and -2. J. Biol. Chem. 273, 6801-6811
  63. Spencer, A. G., Woods, J. W., Arakawa, T., Singer, I. I. and Smith, W. L. (1998) Subcellular localization of prostaglandin endoperoxide H synthases-1 and -2 by immunoelectron microscopy. J. Biol. Chem. 273, 9886-9893
  64. Meusser, B., Hirsch, C., Jarosch, E. and Sommer, T. (2005) ERAD: the long road to destruction. Nat. Cell. Biol. 7, 766-772
  65. Duquette, M. and Laneuville, O. (2002) Translational regulation of prostaglandin endoperoxide H synthase-1 mRNA in megakaryocytic MEG-01 cells. Specific protein binding to a conserved 20-nucleotide CIS element in the 3'-untranslated region. J. Biol. Chem. 277, 44631-44637
  66. Hampton, R. Y. (2002) ER-associated degradation in protein quality control and cellular regulation. Curr. Opin. Cell. Biol. 14, 476-482
  67. Smith, W. L. and Song, I. (2002) The enzymology of prostaglandin endoperoxide H synthases-1 and -2. Prostaglandins. Other. Lipid. Mediat. 68-69, 115-128
  68. Murmu, N., Jung, J., Mukhopadhyay, D., Houchen, C. W., Riehl, T. E., Stenson, W. F., Morrison, A. R., Arumugam, T., Dieckgraefe, B. K. and Anant, S. (2004) Dynamic antagonism between RNA-binding protein CUGBP2 and cyclooxygenase-2-mediated prostaglandin E2 in radiation damage. Proc. Natl. Acad. Sci. U.S.A. 101, 13873-13878
  69. Wu, Y., Swulius, M. T., Moremen, K. W. and Sifers, R. N. (2003) Elucidation of the molecular logic by which misfolded alpha 1-antitrypsin is preferentially selected for degradation. Proc. Natl. Acad. Sci. U.S.A. 100, 8229-8234
  70. Moncada, S. and Vane, J. R. (1979) The role of prostacyclin in vascular tissue. Fed. Proc. 38, 66-71
  71. Murakami, M., Shimbara, S., Kambe, T., Kuwata, H., Winstead, M. V., Tischfield, J. A. and Kudo, I. (1998) The functions of five distinct mammalian phospholipase A2S in regulating arachidonic acid release. Type IIa and type V secretory phospholipase A2S are functionally redundant and act in concert with cytosolic phospholipase A2. J. Biol. Chem. 273, 14411-14423
  72. Mbonye, U. R., Wada, M., Rieke, C. J., Tang, H. Y., Dewitt, D. L. and Smith, W. L. (2006) The 19-amino acid cassette of cyclooxygenase-2 mediates entry of the protein into the endoplasmic reticulum-associated degradation system. J. Biol. Chem. 281, 35770-35778
  73. Chakrabarty, A., Tranguch, S., Daikoku, T., Jensen, K., Furneaux, H. and Dey, S. K. (2007) MicroRNA regulation of cyclooxygenase-2 during embryo implantation. Proc. Natl. Acad. Sci. U. S. A. 104, 15144-15149
  74. Picot, D., Loll, P. J. and Garavito, R. M. (1994) The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature 367, 243-249
  75. McCracken, A. A. and Brodsky, J. L. (2005) Recognition and delivery of ERAD substrates to the proteasome and alternative paths for cell survival. Curr. Top. Microbiol. Immunol. 300, 17-40
  76. Mevkh, A. T., Miroshnikov, K. A., Igumnova, N. D. and Varfolomeev, S. D. (1993) Prostaglandin H synthase. Inactivation of the enzyme in the course of catalysis is accompanied by fast and dramatic changes in protein structure. FEBS. Lett. 321, 205-208
  77. Mbonye, U. R., Yuan, C., Harris, C. E., Sidhu, R. S., Song, I., Arakawa, T. and Smith, W. L. (2008) Two distinct pathways for cyclooxygenase-2 protein degradation. J. Biol. Chem. 283, 8611-8623

Cited by

  1. Prostaglandin EP1Receptor Down-regulates Expression of Cyclooxygenase-2 by Facilitating Its Proteasomal Degradation vol.287, pp.21, 2012,
  2. Influenza A viruses suppress cyclooxygenase-2 expression by affecting its mRNA stability vol.6, pp.1, 2016,
  3. Role of cyclooxygenase-2 in Trypanosoma cruzisurvival in the early stages of parasite host-cell interaction vol.110, pp.2, 2015,
  4. Prostaglandin E2and the Pathogenesis of Pulmonary Fibrosis vol.45, pp.3, 2011,
  5. EGF receptor and COX-1/COX-2 enzyme proteins as related to corresponding mRNAs in human per-operative biopsies of colorectal cancer vol.13, pp.1, 2013,
  6. Underwater trauma causes a long-term specific increase in the expression of cyclooxygenase-2 in the ventral CA1 of the hippocampus vol.49, 2014,
  7. Cyclooxygenase 2: its regulation, role and impact in airway inflammation vol.46, pp.3, 2016,
  8. Regulation of Cyclooxygenase-2 Expression by Heat: A Novel Aspect of Heat Shock Factor 1 Function in Human Cells vol.7, pp.2, 2012,
  9. Down-regulation of Cyclooxygenase-2 by the Carboxyl Tail of the Angiotensin II Type 1 Receptor vol.289, pp.45, 2014,
  10. Vanadium Compounds as Pro-Inflammatory Agents: Effects on Cyclooxygenases vol.16, pp.6, 2015,
  11. Distribution of Bioactive Lipid Mediators in Human Skin vol.135, pp.6, 2015,
  12. New insights into pattern recognition receptors and their ligands in gynecologic pathologies vol.72, pp.3, 2011,
  13. β1-Adrenergic receptor downregulates the expression of cyclooxygenase-2 vol.451, pp.2, 2014,
  14. Targeting COX-2 expression by natural compounds: A promising alternative strategy to synthetic COX-2 inhibitors for cancer chemoprevention and therapy vol.80, pp.12, 2010,
  15. FGFR1-Induced Epithelial to Mesenchymal Transition through MAPK/PLCγ/COX-2-Mediated Mechanisms vol.7, pp.6, 2012,
  16. The Effect of Cadmium on COX-1 and COX-2 Gene, Protein Expression, and Enzymatic Activity in THP-1 Macrophages vol.165, pp.2, 2015,
  17. Involvement of interleukin-1 type 1 receptors in lipopolysaccharide-induced sickness responses 2017,
  18. Prostaglandin receptor EP1-mediated differential degradation of cyclooxygenases involves a specific lysine residue vol.443, pp.2, 2014,
  19. RNA-binding protein HuR regulates RGS4 mRNA stability in rabbit colonic smooth muscle cells vol.299, pp.6, 2010,
  20. MiRNA in innate immune responses: novel players in wound inflammation vol.43, pp.10, 2011,
  21. Cyclooxygenase 2: protein-protein interactions and posttranslational modifications vol.49, pp.11, 2017,
  22. Substrate-inactivated cyclooxygenase-2 is disposed of by exosomes through the ER–Golgi pathway vol.475, pp.19, 2018,