Translational Control of Prostaglandin Synthase by Growth Factors and Glucocorticoids

  • J. Martyn Bailey
Part of the GWUMC Department of Biochemistry Annual Spring Symposia book series (GWUN)


The discovery that both glucocorticoids and non-steroidal anti-inflammatory drugs such as aspirin inhibit synthesis of prostaglandins represented a major advance in our understanding of inflammatory processes. Whereas the non-steroidal drugs inhibit the enzyme prostaglandin synthase directly, the molecular basis for the action of the glucocorticoids is incompletely understood. Glucocorticoids have been shown to inhibit prostaglandin production both by inhibiting release of arachidonic acid substrate and by suppressing PG synthase levels directly. In cells with a high degree of glucocorticoid sensitivity, the latter effect predominates.

The principal mechanism in glucocorticoid-treated cells studied in tissue culture is a new type of translational control of the messenger RNA for the PG synthase enzyme. In common with other examples of translational control recently characterized this may involve interaction of glucocorticoid-induced or glucocorticoid activated proteins with a highly conserved 3′ UTR in the PG synthase mRNA, converting the mRNA into a nontranslated cryptic form. The glucocorticoid-linked lipocortin/annexin family of proteins appear to be involved in this process. In sensitive cells, translation of the cryptic form of PG synthase mRNA is activated by EGF. This is accompanied by phosphorylation of endogenous lipocortin by the protein kinase activity of the EGF receptor. The possibility that glucocorticoids induce specific protein phosphatases as suggested by Zor elsewhere in this volume needs further exploration.

A second mechanism by which glucocorticoids suppress prostaglandin synthesis is to inhibit release of arachidonic acid substrate by phospholipase A2. The long-held belief that this is due to a direct inhibitory action of lipocortin on PLA2 has recently been disproved. Instead glucocorticoids inhibit PLA2 in some cells directly by inducing dephosphorylation of the active form of the enzyme. In vascular smooth muscle cells, glucocorticoids inhibit expression of the phospholipase A2 enzyme both at the transcriptional and translational levels by mechanisms that remain to be determined.

These recent findings are important since they indicate that translational control of PG synthase by glucocorticoids may be representative of a more general phenomenon, and may provide a new role for the ubiquitous lipocortin annexin family of proteins. The further implication that growth factors and glucocorticoids differentially influence the phosphorylation status of the annexins could have important consequences for understanding the role of these compounds in cellular homeostasis.


Epidermal Growth Factor Receptor Epidermal Growth Factor Creatine Kinase Vascular Smooth Muscle Cell Prostaglandin Synthesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Vane, J.R. 1971. Nature New Biol. 231: 232–235 (1971).PubMedGoogle Scholar
  2. 2.
    Roth, G.J., Standford, N., and Majerus, P.W. 1975.Proc. Natl. Acad. Sci. USA. 72: 3073–3076 (1975).Google Scholar
  3. 3.
    Lewis, G.P. and Piper, P.J. Nature (London). 254: 308–311 (1975).CrossRefGoogle Scholar
  4. 4.
    Blackwell, G.J., Carnuccio, R., DiRosa, M., Flower, R.J., Parente, L., Dersico, P. Nature 237: 147–149 (1980).CrossRefGoogle Scholar
  5. 5.
    Hirata, F., Schiffmann, E., Venkatasubramanian, K., Salomon, D. and Axelrod, J. Proc. Natl. Acad. Sci. USA 77: 2533–2536 (1980).CrossRefGoogle Scholar
  6. 6.
    Crumpton, M.J., Dedman, J R Nature. 345: 212 (190).Google Scholar
  7. 7.
    Davidson, F.F., Dennis, E.A. Powell, M., Glenney, J.R. J. Biol. Chem. 262: 1698–1705 (1987).Google Scholar
  8. 8.
    Schlaepfer, D.D., Haigler, H.T. J. Biol. Chem. 262: 6931–6937 (1987).Google Scholar
  9. 9.
    Carnuccio, R., DiRosa, M. and Persico, P. Br. J. Pharmacol. 68: 14–16 (1980).Google Scholar
  10. 10.
    Feinmark, S.J., Bailey, J.M. J. Biol. Chem. 257: 2816–2821 (1982).Google Scholar
  11. 11.
    Hong, S.C. and Levine,L. Proc. Natl. Acad. Sci. U.S.A. 73: 1730–1734 (1976).CrossRefGoogle Scholar
  12. 12.
    Casey, M.L., MacDonald, P.C., Mitchell, M.D. J. Clinic. Invest. 75: 1852–1857 (1985).CrossRefGoogle Scholar
  13. 13.
    Axelrod, L., Lancet. 8330: 804–6 (1983).Google Scholar
  14. 14.
    Bailey, J.M., Miuza, B., Hla, T., Salata, K. J. Lipid Res. 26: 54–61 (1986).Google Scholar
  15. 15.
    Crutchley, D.J., Ryan, U.S., Ryan, J.W. J. Pharmacol. Exp. Ther. 233: 650–655 (1985).Google Scholar
  16. 16.
    Caterina, R. and Weksler, B.B. Thrombosis and Hemotasis. 55: 369–374 (1988).Google Scholar
  17. 17.
    Goppelt-Strube, M., Wolter, D., Resch, K. Br. J. Pharmacol. 98: 1287–1295 (1989).Google Scholar
  18. 18.
    Pash, J.M., Bailey, J.M. Faseb. J. 2: 2613–2618 (1988).PubMedGoogle Scholar
  19. 19.
    Raz, A., Wyche, A., Needleman, P Proc. Natl. Acad. Sci. 86: 1657–1661 (1989).CrossRefGoogle Scholar
  20. 20.
    Cirino, G., Peers, S.H., Flower, R.J., Browning, J.L., Pepinsky,R.B. Proc. Natl. Acad. Sci. 86: 3428–3432 (1989).CrossRefGoogle Scholar
  21. 21.
    Bailey, J.M., Makheja, A.N., Verma, M. FASEB J. 4: 4984 (1990).Google Scholar
  22. 22.
    Theile, B.J., Andree, H., Hohne, M., Rapoport, S.M. Europ. J. Biochem. 129: 133–141 (1982).CrossRefGoogle Scholar
  23. 23.
    Ch’ng, J., Lai, C., Shoemaker, D.L., Schimmer, P., Holmes, E.L. Science 248: 10031005 (1990).Google Scholar
  24. 24.
    Bailey, J.M., Makheja, A.N. Pash, J., Verma, M. Biochem. Biophys. Res. Commn. 157: 1159–1163 (1988).CrossRefGoogle Scholar
  25. 25.
    Rapoport, S.M., Schewe, T., Wiesner, R., Halang, K.W., Ludwig, P., Janicke-Hohne, M., Tannert, C., Hiebsch, C., and Klatt, D. Eur. J. Biochem. 96: 563–569 (1979).PubMedCrossRefGoogle Scholar
  26. 26.
    Daouk, G.H., Daouk, K.R., Putney, S., Kingston, R., Schimmel, P. J. Biol. Chem. 263: 2442 (1988).PubMedGoogle Scholar
  27. 27.
    Billadello, J.J., Kelly, D.P., Roman, G.D., Strauss, A.W. Biochem. Biophys. Res. Comm. 138: 397 (1986).CrossRefGoogle Scholar
  28. 28.
    Bailey, J.M., Verma, M. Anal. Biochem. 196: (1991) in press.Google Scholar
  29. 29.
    Bailey, J.M., Verma, M. Prostaglandins. 40: 585–590 (1990).PubMedCrossRefGoogle Scholar
  30. 30.
    DeWitt, D.L., El-Harith, E.A., Kraemer, S.A., Andrews, M.J., Yao, E.F., Armstrong, R.L., Smith, W.L. J.Biol. Chem. 265: 5192–5198 (1990).PubMedGoogle Scholar
  31. 31.
    Bailey, J.M., Makheja, A.N., Pash, J., and Verma, M. New Trends in Lip. Med. Res. 3: 8–16 (1989).Google Scholar
  32. 32.
    Peers, S.H., and Flower, R.J. Am. Rev. Resp. Dis. 147: 518–21 (1990).Google Scholar
  33. 33.
    Carey, F., Forder, R., Edge, M.D., Greene, A.R. Horan, M.A., Stritbos, P.J., Rothwell, N.J. Am. J. Physiol. 259: R266–269 (1990).PubMedGoogle Scholar
  34. 34.
    Wallner, B.D., Mattaliano, R.J., Hession, C., Cate, J.L., Strijbos, P.J., Pepinsky, R.B. Nature 320: 77–81 (1986).PubMedCrossRefGoogle Scholar
  35. 35.
    Floman, N., Zor, U. Invest. Opthamol. Vis. Sci. 16: 69–73 (1990).Google Scholar
  36. 36.
    Bronnegard, M., Anderson, D., Ewall, D., Lund, J., Norstedt, G., Carstedt-Duke. J. Mol. Endocrinol. 8: 732–739 (1988).CrossRefGoogle Scholar
  37. 37.
    Bienkowski, M.J., Petro, M.A., Robinson, L.J. J. Biol. Chem. 264: 6536–6544 (1989).Google Scholar
  38. 38.
    Pepinsky, R.B., Sinclair, L.K. Nature (London). 321: 81–84 (1986).CrossRefGoogle Scholar
  39. 39.
    Goldschmidt-Cleremont, P.J., Won Kim, J., Machesky, L.M., Rhee, S.G., Pollard, T.D. Science. 251: 1231–1235 (1991).CrossRefGoogle Scholar
  40. 40.
    Guan, K., and Dixon, T.E. Science. 249: 553 (1990).PubMedCrossRefGoogle Scholar
  41. 41.
    Pepinsky, R.B. J. Biol. Chem. 263: 10799 (1988).Google Scholar
  42. 42.
    Browning, J.L., Ward, M.P., Wallner, B.P., Pepinsky, R.B. Prog. Clin. Biol. Res. 349: 27–45 (1990).Google Scholar
  43. 43.
    Nakano, R., Ohara, O., Teraksa, H., Arita, H. J. Biol. Chem. 265: 12745–12748 (1990).PubMedGoogle Scholar
  44. 44.
    Beutler, B., Krochin, N., Milsark, S.W., Leudke, C., Cerami, A Science. 232: 977980 (1986).Google Scholar
  45. 45.
    Knudsen, P.J., Dinarello, C.A., Strom, T.B. J. Immunol. 139: 4129–4134 (1987).Google Scholar
  46. 46.
    Hemler, M.E., Lands, W.E.M. J. Biol. Chem. 255: 6253–6251 (1980).PubMedGoogle Scholar
  47. 47.
    Zor, U., Harell, T., Her, E., Fischer, G., Naor, Z., Braques, P., Ferber, E., Reiss, N. Proc. XI Int. Conf. Pros. Leuk. Lipox. Washington, D.C. May (1991) in press.Google Scholar
  48. 48.
    Raz, A., Wyche, A., Fu, J., Seibert, K., Needleman, P., Adv., Pros. Leuk. Res. 20: 2227 (1990).Google Scholar
  49. 49.
    Krishna, P., Kennedy, B.P., Waisman, D.M., Van de Sande, J.H., McGhee, J.D. Proc. Nat. Acad. Sci., USA. 87: 1292–1295 (1990).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1991

Authors and Affiliations

  • J. Martyn Bailey
    • 1
  1. 1.Department of Biochemistry and Molecular BiologyThe George Washington University School of Medicine and Health SciencesUSA

Personalised recommendations