Biochemical Mechanisms of Action of the Phorbol Ester Class of Tumor Promoters

  • Arco Y. Jeng
  • Peter M. Blumberg


The discovery by Driedger and Blumberg1 that the phorbol esters functioned through specific receptors, followed by the finding of Castagna et al.2 that the tumor-promoting phorbol esters activated the Ca2+— and phospholipid-dependent protein kinase (protein kinase C), suggesting its identity with the phorbol ester receptor, has had major impact on the understanding of the molecular mechanisms of tumor promotion. Following the initial convergence of these two previously independent research areas, phorbol ester tumor promotion and protein kinase C, a host of related fields such as signal transduction, phosphatidylinositol turnover, growth factors, and oncogenes have also been found to involve the phorbol ester receptor significantly. Hundreds of publications appearing in the literature yearly demonstrate the emphasis on the interactions among these systems.


Protein Kinase Adenylate Cyclase Phorbol Ester Dependent Protein Kinase Inositol Trisphosphate 
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  1. 1.
    Driedger, P. E., and Blumberg, P. M., 1980, Specific binding of phorbol ester tumor promoters, Proc. Natl. Acad. Sci. USA 77: 567–571.PubMedCrossRefGoogle Scholar
  2. 2.
    Castagna, M., Takai, Y., Kaibuchi, K., Sano, K., Kikkawa, U., and Nishizuka, Y., 1982, Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters, J. Biol. Chem. 257: 7847–7851.PubMedGoogle Scholar
  3. 3.
    Blumberg, P. M., 1980, In vitro studies on the mode of action of the phorbol esters, potent tumor promoters, CRC Crit. Rev. Toxicol. 8: 153–234.Google Scholar
  4. 4.
    Diamond, L., O’Brien, T. G., and Baird, W. M., 1980, Tumor promoters and the mechanism of tumor promotion, Adv. Cancer Res. 32: 1–74.PubMedCrossRefGoogle Scholar
  5. 5.
    Hecker, E., 1978, Structure-activity relationships in diterpene esters irritant and cocarcinogenic to mouse skin, in: Carcinogenesis, Vol. 2 ( T. J. Slaga, A. Sivak, and R. K. Boutwell, eds.), pp. 11–48, Raven, New York.Google Scholar
  6. 6.
    Blumberg, P. M., Dunn, J. A., Jaken, S., Jeng, A. Y., Leach, K. L., Sharkey, N. A., and Yeh, E., 1984, Specific receptors for phorbol ester tumor promoters and their involvement in biological responses, in: Mechanisms of Tumor Promotion, Vol. 3 ( T. J. Slaga, ed.), pp. 143–184, CRC Press, Boca Raton, Florida.Google Scholar
  7. 7.
    Diamond, L., 1984, Tumor promoters and cell transformation, Pharmacol. Ther. 26: 89–145.PubMedCrossRefGoogle Scholar
  8. 8.
    Ashendel, C. L., 1985, The phorbol ester receptor: A phospholipid-regulated protein kinase, Biochim. Biophys. Acta 822: 219–242.PubMedGoogle Scholar
  9. 9.
    Leach, K. L., James, M. L., and Blumberg, P. M., 1983, Characterization of a specific phorbol ester aporeceptor in mouse brain cytosol, Proc. Natl. Acad. Sci. USA 80: 4208–4212.PubMedCrossRefGoogle Scholar
  10. 10.
    Dunn, J. A., and Blumberg, P. M., 1983, Specific binding of [20–3H]I2-deoxyphorbol 13-isobutyrate to phorbol ester receptor subclasses in mouse skin particulate preparations, Cancer Res. 43: 4632–4637.PubMedGoogle Scholar
  11. 11.
    Nishizuka, Y., 1984, The role of protein kinase C in cell surface signal transduction and tumour promotion, Nature (Lord.) 308: 693–698.CrossRefGoogle Scholar
  12. 12.
    Nishizuka, Y., 1986, Studies and perspectives of protein kinase C, Science 233: 305–312.PubMedCrossRefGoogle Scholar
  13. 13.
    Kuo, J. F., Andersson, R. G. G., Wise, B. C., Mackerlova, L., Salomonsson, I., Brackett, N. L., Katoh, N., Shoji, M., and Wrenn, R. W., 1980, Calcium-dependent protein kinase: Widespread occurrence in various tissues and phyla of the animal kingdom and comparison of effects of phospholipid, calmodulin, and trifluoperazine, Proc. Natl. Acad. Sci. USA 77: 7039–7043.PubMedCrossRefGoogle Scholar
  14. 14.
    Nagle, D. S., and Blumberg, P. M., 1983, Regional localization by light microscopic autoradiography of receptors in mouse brain for phorbol ester tumor promoters, Cancer Leu. 18: 35–40.CrossRefGoogle Scholar
  15. 15.
    Worley, P. F., Baraban, J. M., and Snyder, S. H., 1986, Heterogeneous localization of protein kinase C in rat brain: Autoradiographic analysis of phorbol ester receptor binding, J. Neurosci. 6: 199–207.PubMedGoogle Scholar
  16. 16.
    Wood, J. G., Girard, P. R., Mazzei, G. J., and Kuo, J. F., 1986, Immunocytochemical localization of protein kinase C in identified neuronal compartments of rat brain, J. Neurosci. 6: 2571–2577.PubMedGoogle Scholar
  17. 17.
    Turner, R. S., Raynor, R. L., Mazzei, G. J., Girard, P. R., and Kuo, J. F., 1984, Developmental studies of phospholipid-sensitive Cat+-dependent protein kinase and its substrates and of phosphoprotein phosphatases in rat brain, Proc. Natl. Acad. Sci. USA 81: 3143–3147.PubMedCrossRefGoogle Scholar
  18. 18.
    Niedel, J. E., Kuhn, L. J., and Vandenbark, G. R., 1983, Phorbol diester receptor copurifies with protein kinase C, Proc. Natl. Acad. Sci. USA 80: 36–40.PubMedCrossRefGoogle Scholar
  19. 19.
    Kikkawa, U., Takai, Y., Minakuchi, R., Inohara, S., and Nishizuka, Y., 1982, Calcium-activated, phospholipid-dependent protein kinase from rat brain. Subcellular distribution, purification, and properties, J. Biol. Chem. 257: 13341–13348.PubMedGoogle Scholar
  20. 20.
    Le Peuch, C. J., Ballester, R., and Rosen, O. M., 1983, Purified rat brain calcium-and phospholipiddependent protein kinase phosphorylates ribosomal protein S6, Proc. Natl. Acad. Sci. USA 80: 6858–6862.PubMedCrossRefGoogle Scholar
  21. 21.
    Uchida, T., and Filburn, C. R., 1984, Affinity chromatography of protein kinase C-phorbol ester receptor on polyacrylamide-immobilized phosphatidylserine, J. Biol. Chem. 259: 12311–12314.PubMedGoogle Scholar
  22. 22.
    Jeng, A. Y., Sharkey, N. A., and Blumberg, P. M., 1986, Purification of stable protein kinase C from mouse brain cytosol by specific ligand elution using fast protein liquid chromatography, Cancer Res. 46: 1966–1971.PubMedGoogle Scholar
  23. 23.
    Pasti, G., Lacal, J.-C., Warren, B. S., Aaronson, S. A., and Blumberg, P. M., 1986, Loss of mouse fibroblast cell response to phorbol esters restored by microinjected protein kinase C, Nature (Lord.) 324: 375–377.CrossRefGoogle Scholar
  24. 24.
    Mochly-Rosen, D., and Koshland, D. E., Jr., 1987, Domain structure and phosphorylation of protein kinase C, J. Biol. Chem. 262: 2291–2297.PubMedGoogle Scholar
  25. 25.
    Sharkey, N. A., Leach, K. L., and Blumberg, P. M., 1984, Competitive inhibition by diacylglycerol of specific phorbol ester binding, Proc. Natl. Acad. Sci. USA 81: 607–610.PubMedCrossRefGoogle Scholar
  26. 26.
    Blumberg, P. M., Jeng, A. Y., Konig, B., Sharkey, N. A., Leach, K. L., and Jaken, S., 1985, Receptors and endogenous analogues for the phorbol ester tumor promoters, in: Carcinogenesis—A Comprehensive Survey, Vol. 10 ( E. Huberman and S. H. Barr, eds.), pp. 249–262, Raven, New York.Google Scholar
  27. 27.
    Rando, R. R., and Young, N., 1984, The stereospecific activation of protein kinase C, Biochem. Biophys. Res. Commun. 122: 818–823.PubMedCrossRefGoogle Scholar
  28. 28.
    Hannun, Y. A., and Bell, R. M., 1986, Phorbol ester binding and activation of protein kinase C on Triton X-100 mixed micelles containing phosphatidylserine, J. Biol. Chem. 261: 9341–9347.PubMedGoogle Scholar
  29. 29.
    Ganong, B. R., Loomis, C. R., Hannun, Y. A., and Bell, R. M., 1986, Specificity and mechanism of protein kinase C activation by sn-1,2-diacylglycerols, Proc. Natl. Acad. Sci. USA 83: 1184–1188.PubMedCrossRefGoogle Scholar
  30. 30.
    Kishimoto, A., Kajikawa, N., Shiota, M., and Nishizuka, Y., 1983, Proteolytic activation of calcium-activated, phospholipid-dependent protein kinase by calcium-dependent neutral protease, J. Biol. Chem. 258: 1156–1164.PubMedGoogle Scholar
  31. 31.
    Huang, K.-P., and Huang, F. L., 1986, Immunochemical characterization of rat brain protein kinase C, J. Biol. Chem. 261: 14781–14787.PubMedGoogle Scholar
  32. 32.
    Lee, M.-H., and Bell, R. M., 1986, The lipid binding, regulatory domain of protein kinase C, J. Biol. Chem. 261: 14867–14870.PubMedGoogle Scholar
  33. 33.
    Nakadate, T., Jeng, A. Y., and Blumberg, P. M., 1987, Effect of phospholipid on substrate phosphorylation by a catalytic fragment of protein kinase C, J. Biol. Chem. 262: 11507–11513.PubMedGoogle Scholar
  34. 34.
    Parker, P. J., Coussens, L., Totty, N., Rhee, L., Young, S., Chen, E., Stabel, S., Waterfield, M. D., and Ullrich, A., 1986, The complete primary structure of protein kinase C—the major phorbol ester receptor, Science 233: 853–859.PubMedCrossRefGoogle Scholar
  35. 35.
    Slaga, T. J., Fischer, S. M., Nelson, K., and Gleason, G. L., 1980, Studies on the mechanism of skin tumor promotion: Evidence for several stages in promotion, Proc. Natl. Acad. Sci. USA 77: 3659–3663.PubMedCrossRefGoogle Scholar
  36. 36.
    Schmidt, R., and Hecker, E., 1982, Simple phorbol esters as inhibitors of tumor promotion by TPA in mouse skin, in: Cocarcinogenesis and Biological Effects of Tumor Promoters ( E. Hecker, N. E. Fusenig, W. Kunz, F. Marks, and H. W. Thielmann, eds.), pp. 57–63, Raven, New York.Google Scholar
  37. 37.
    Kikkawa, U., Go, M., Koumoto, J., and Nishizuka, Y., 1986, Rapid purification of protein kinase C by high performance liquid chromatography, Biochem. Biophys. Res. Commun. 135: 636–643.PubMedCrossRefGoogle Scholar
  38. 38.
    Huang, K.-P., Nakabayashi, H., and Huang, F. L., 1986, Isozymic forms of rat brain Caz+-activated and phospholipid-dependent protein kinase, Proc. Natl. Acad. Sci. USA 83: 8535–8539.PubMedCrossRefGoogle Scholar
  39. 39.
    Coussens, L., Parker, P. J., Rhee, L., Yang-Feng, T. L., Chen, E., Waterfield, M. D., Francke, U., and Ullrich, A., 1986, Multiple, distinct forms of bovine and human protein kinase C suggest diversity in cellular signaling pathways, Science 233: 859–866.PubMedCrossRefGoogle Scholar
  40. 40.
    Ohno, S., Kawasaki, H., Imajoh, S., and Suzuki, K., 1987, Tissue-specific expression of three distinct types of rabbit protein kinase C, Nature (Gond.) 325: 161–166.CrossRefGoogle Scholar
  41. 41.
    Knopf, J. L., Lee, M.-H., Sultzman, L. A., Kriz, R. W., Loomis, C. R., Hewick, R. M., and Bell, R. M., 1986, Cloning and expression of multiple protein kinase C cDNAs, Cell 46: 491–502.PubMedCrossRefGoogle Scholar
  42. 42.
    Woodgett, J. R., Gould, K. L., and Hunter, T., 1986, Substrate specificity of protein kinase C. Use of synthetic peptides corresponding to physiological sites as probes for substrate recognition requirements, Eur. J. Biochem. 161: 177–184.PubMedCrossRefGoogle Scholar
  43. 43.
    House, C., Wettenhall, R. E. H., and Kemp, B. E., 1987, The influence of basic residues on the substrate specificity of protein kinase C, J. Biol. Chem. 262: 772–777.PubMedGoogle Scholar
  44. 44.
    Kishimoto, A., Nishiyama, K., Nakanishi, H., Uratsuji, Y., Nomura, H., Takeyama, Y., and Nishizuka, Y., 1985, Studies on the phosphorylation of myelin basic protein by protein kinase C and adenosine 3’:5’monophosphate-dependent protein kinase, J. Biol. Chem. 260: 12492–12499.PubMedGoogle Scholar
  45. 45.
    Turner, R. S., and Kuo, J. F., 1985, Phospholipid-sensitive Caz+-dependent protein kinase (protein kinase C): The enzyme, substrates, and regulation, in: Phospholipids and Cellular Regulation, Vol. 2 ( J. F. Kuo, ed.), pp. 75–110, CRC Press, Boca Raton, Florida.Google Scholar
  46. 46.
    Jeffrey, A. M., and Liskamp, R. M. J., 1986, Computer-assisted molecular modeling of tumor promoters: Rationale for the activity of phorbol esters, teleocidin B, and aplysiatoxin, Proc. Natl. Acad. Sci. USA 83: 241–245.PubMedCrossRefGoogle Scholar
  47. 47.
    Wender, P. A., Koehler, K. F., Sharkey, N. A., Dell’Aquila, M. L., and Blumberg, P. M., 1986, Analysis of the phorbol ester pharmacophore on protein kinase C as a guide to the rational design of new classes of analogs, Proc. Natl. Acad. Sci. USA 83: 4214–4218.PubMedCrossRefGoogle Scholar
  48. 48.
    Kraft, A. S., Smith, J. B., and Berkow, R. L., 1986, Bryostatin, an activator of the calcium phospholipiddependent protein kinase, blocks phorbol ester-induced differentiation of human promyelocytic leukemia cells HL-60, Proc. Natl. Acad. Sci. USA 83: 1334–1338.PubMedCrossRefGoogle Scholar
  49. 49.
    Leach, K. L., and Blumberg, P. M., 1985, Modulation of protein kinase C activity and [3H]phorbol 12,13dibutyrate binding by various tumor promoters in mouse brain cytosol, Cancer Res. 45: 1958–1963.PubMedGoogle Scholar
  50. 50.
    Hansson, A., Serhan, C. N., Haeggstrom, J., Ingelman-Sundberg, M., Samuelsson, B., and Morris, J., 1986, Activation of protein kinase C by lipoxin A and other eicosanoids. Intracellular action of oxygenation products of arachidonic acid, Biochem. Biophys. Res. Commun. 134: 1215–1222.PubMedCrossRefGoogle Scholar
  51. 51.
    Murakami, K., Chan, S. Y., and Routtenberg, A., 1986, Protein kinase C activation by cis-fatty acid in the absence of Cat+ and phospholipids, J. Biol. Chem. 261: 15424–15429.PubMedGoogle Scholar
  52. 52.
    Ito, M., Tanaka, T., Inagaki, M., Nakanishi, K., and Hidaka, H., 1986, N-(6-Phenylhexyl)-5-chloro-1naphthalene sulfonamide, a novel activator of protein kinase C, Biochemistry 25: 4179–4184.PubMedCrossRefGoogle Scholar
  53. 53.
    Hidaka, H., Inagaki, M., Kawamoto, S., and Sasaki, Y., 1984, Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C, Biochemistry 23: 5036–5041.PubMedCrossRefGoogle Scholar
  54. 54.
    Kase, H., Iwahashi, K., Nakanishi, S., Matsuda, Y., Yamada, K., Takahashi, M., Murakata, C., Sato, A., and Kaneko, M., 1987, K-252 compounds, novel and potent inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinases, Biochem. Biophys. Res. Commun. 142: 436–440.PubMedCrossRefGoogle Scholar
  55. 55.
    Tamaoki, T., Nomoto, H., Takahashi, I., Kato, Y., Morimoto, M., and Tornita, F., 1986, Staurosporine, a potent inhibitor of phospholipid/Ca + + dependent protein kinase, Biochem. Biophys. Res. Commun. 135: 397–402.PubMedCrossRefGoogle Scholar
  56. 56.
    Schwantke, N., and Le Peuch, C. J., 1984, A protein kinase C inhibitory activity is present in rat brain homogenate, FEBS Lett. 177: 36–40.PubMedCrossRefGoogle Scholar
  57. 57.
    McDonald, J. R., and Walsh, M. P., 1985, Caz+-binding proteins from bovine brain including a potent inhibitor of protein kinase C, Biochem. J. 232: 559–567.PubMedGoogle Scholar
  58. 58.
    Hannun, Y. A., and Bell, R. M., 1987, Lysosphingolipids inhibit protein kinase C: Implications for the sphingolipidoses, Science 235: 670–674.PubMedCrossRefGoogle Scholar
  59. 59.
    Hannun, Y. A., Loomis, C. R., Merrill, A. H., Jr., and Bell, R. M., 1986, Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets, J. Biol. Chem. 261: 12604–12609.PubMedGoogle Scholar
  60. 60.
    Kraft, A. S., and Anderson, W. B., 1983, Phorbol esters increase the amount of Caz+, phospholipiddependent protein kinase associated with plasma membrane, Nature (Lond.) 301: 621–623.CrossRefGoogle Scholar
  61. 61.
    Hirota, K., Hirota, T., Aguilera, G., and Catt, K. J., 1986, Gonadotropin release and redistribution of calcium-activated, phospholipid-dependent protein kinase in phorbol-stimulated rat pituitary cells, Arch. Biochem. Biophys. 249: 557–562.PubMedCrossRefGoogle Scholar
  62. 62.
    Melloni, E., Pontremoli, S., Michetti, M., Sacco, O., Sparatore, B., and Horecker, B. L., 1986, The involvement of calpain in the activation of protein kinase C in neutrophils stimulated by phorbol myristic acid, J. Biol. Chem. 261: 4101–4105.PubMedGoogle Scholar
  63. 63.
    Tapley, P. M., and Murray, A. W., 1985, Evidence that treatment of platelets with phorbol ester causes proteolytic activation of Ca2 + -activated, phospholipid-dependent protein kinase, Eur. J. Biochem. 151: 419–423.PubMedCrossRefGoogle Scholar
  64. 64.
    Balazovich, K. J., Smolen, J. E., and Boxer, L. A., 1986, Caz+ and phospholipid-dependent protein kinase (protein kinase C) activity is not necessarily required for secretion by human neutrophils, Blood 68: 810–817.PubMedGoogle Scholar
  65. 65.
    Jeng, A. Y., Lichti, U., Strickland, J. E., and Blumberg, P. M., 1985, Similar effects of phospholipase C and phorbol ester tumor promoters on primary mouse epidermal cells, Cancer Res. 45: 5714–5721.PubMedGoogle Scholar
  66. 66.
    Jetten, A. M., Ganong, B. R., Vandenbark, G. R., Shirley, J. E., and Bell, R. M., 1985, Role of protein kinase C in diacylglycerol-mediated induction of ornithine decarboxylase and reduction of epidermal growth factor binding, Proc. Natl. Acad. Sci. USA 82: 1941–1945.PubMedCrossRefGoogle Scholar
  67. 67.
    Mayorek, N., and Bar-Tana, J., 1985, Inhibition of diacylglycerol acyltransferase by 2-bromooctanoate in cultured rat hepatocytes, J. Biol. Chem. 260: 6528–6532.PubMedGoogle Scholar
  68. 68.
    Blumberg, P. M., Sharkey, N. A., Konig, B., Jaken, S, Leach, K. L., and Jeng, A. Y., 1984, Membrane and cytosolic receptors for the phorbol ester tumor promoters, in: Cancer cells, Vol. 1 ( A. J. Levine, G. F. Vande Woude, W. C. Topp, and J. D. Watson, eds.), pp. 245–251, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.Google Scholar
  69. 69.
    Chida, K., Kato, N., and Kuroki, T., 1986, Down regulation of phorbol diester receptors by proteolytic degradation of protein kinase C in a cultured cell line of fetal rat skin keratinocytes, J. Biol. Chem. 261: 13013–13018.PubMedGoogle Scholar
  70. 70.
    Dunn, J. A., Jeng, A. Y., Yuspa, S. H., and Blumberg, P. M., 1985, Heterogeneity of [3H]phorbol 12,13dibutyrate binding in primary mouse keratinocytes at different stages of maturation, Cancer Res. 45: 5540–5546.PubMedGoogle Scholar
  71. 71.
    Gilman, A. G., 1984, G proteins and dual control of adenylate cyclase, Cell 36: 577–579.PubMedCrossRefGoogle Scholar
  72. 72.
    Katada, T., Gilman, A. G., Watanabe, Y., Bauer, S., and Jakobs, K. H., 1985, Protein kinase C phosphorylates the inhibitory guanine-nucleotide-binding regulatory component and apparently suppresses its function in hormonal inhibition of adenylate cyclase, Eur. J. Biochem. 151: 431–437.PubMedCrossRefGoogle Scholar
  73. 73.
    Kelleher, D. J., Pessin, J. E., Ruoho, A. E., and Johnson, G. L., 1984, Phorbol ester induces desensitization of adenylate cyclase and phosphorylation of the ß-adrenergic receptor in turkey erythrocytes, Proc. Natl. Acad. Sci. USA 81: 4316–4320.PubMedCrossRefGoogle Scholar
  74. 74.
    Abdel-Latif, A. A., 1986, Calcium-mobilizing receptors, polyphosphoinositides, and the generation of second messengers, Pharmacol. Rev. 38: 227–272.PubMedGoogle Scholar
  75. 75.
    Berridge, M. J., 1986, Regulation of ion channels by inositol trisphosphate and diacylglycerol, J. Exp. Biol. 124: 323–335.PubMedGoogle Scholar
  76. 76.
    Connolly, T. M., Lawing, W. J., Jr., and Majerus, P. W., 1986, Protein kinase C phosphorylates human platelet inositol trisphosphate 5’-phosphomonoesterase, increasing the phosphatase activity, Cell 46: 951–958.PubMedCrossRefGoogle Scholar
  77. 77.
    Orellana, S. A., Solski, P. A., and Brown, J. H., 1985, Phorbol ester inhibits phosphoinositide hydrolysis and calcium mobilization in cultured astrocytoma cells, J. Biol. Chem. 260: 5236–5239.PubMedGoogle Scholar
  78. 78.
    Watson, S. P., and Lapetina, E. G., 1985, 1,2-Diacylglycerol and phorbol ester inhibit agonist-induced formation of inositol phosphates in human platelets: Possible implications for negative feedback regulation of inositol phospholipid hydrolysis, Proc. Natl. Acad. Sci. USA 82: 2623–2626.Google Scholar
  79. 79.
    Cochet, C., Gill, G. N., Meisenhelder, J., Cooper, J. A., and Hunter, T., 1984, C-kinase phosphorylates the epidermal growth factor receptor and reduces its epidermal growth factor-stimulated tyrosine protein kinase activity, J. Biol. Chem. 259: 2553–2558.PubMedGoogle Scholar
  80. 80.
    Downward, J., Waterfield, M. D., and Parker, P. J., 1985, Autophosphorylation and protein kinase C phosphorylation of the epidermal growth factor receptor. Effect on tyrosine kinase activity and ligand binding affinity, J. Biol. Chem. 260: 14538–14546.PubMedGoogle Scholar
  81. 81.
    Takayama, S., White, M. F., Lauris, V., and Kahn, R., 1984, Phorbol esters modulate insulin receptor phosphorylation and insulin action in cultured hepatoma cells, Proc. Natl. Acad. Sci. USA 81: 7797–7801.PubMedCrossRefGoogle Scholar
  82. 82.
    Berridge, M. J., 1986, Growth factors, oncogenes and inositol lipids, Cancer Surv. 5: 413–430.PubMedGoogle Scholar
  83. 83.
    Preiss, J., Loomis, C. R., Bishop, W. R., Stein, R., Niedel, J. E., and Bell, R. M., 1986, Quantitative measurement of sn-1,2-diacylglycerols present in platelets, hepatocytes, and ras-and sis-transformed normal rat kidney cells, J. Biol. Chem. 261: 8597–8600.PubMedGoogle Scholar
  84. 84.
    Ran, W., Dean, M., Levine, R. A., Henkle, C., and Campisi, J., 1986, Induction of c-fos and c-myc mRNA by epidermal growth factor or calcium ionophore is cAMP dependent, Proc. Natl. Acad. Sci. USA 83: 8216–8220.PubMedCrossRefGoogle Scholar
  85. 85.
    Grausz, J. D., Fradelizi, D., Dautry, F., Monier, R., and Lehn, P., 1986, Modulation of c-fos and c-myc mRNA levels in normal human lymphocytes by calcium ionophore A23187 and phorbol ester, Eur. J. Immunol. 16: 1217–1221.PubMedCrossRefGoogle Scholar
  86. 86.
    Hirata, F., Matsuda, K., Notsu, Y., Hattori, T., and Del Carmine, R., 1984, Phosphorylation at a tyrosine residue of lipomodulin in mitogen-stimulated murine thymocytes, Proc. Natl. Acad. Sci. USA 81: 4717–4721.PubMedCrossRefGoogle Scholar
  87. 87.
    Purchio, A. F., Gentry, L., and Shoyab, M., 1986, Phosphorylation of pp60“-‘r. by the TPA receptor kinase (protein kinase C), Virology 150: 524–529.PubMedCrossRefGoogle Scholar
  88. 88.
    Jeng, A. Y., Srivastava, S. K., Lacal, J. C., and Blumberg, P. M., 1987, Phosphorylation of ras oncogene product by protein kinase C, Biochem. Biophys. Res. Commun. 145: 782–788.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Arco Y. Jeng
    • 1
  • Peter M. Blumberg
    • 2
  1. 1.Research Department, Pharmaceuticals DivisionCiba-Geigy CorporationSummitUSA
  2. 2.Molecular Mechanisms of Tumor Promotion Section, Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer InstituteNational Institutes of HealthBethesdaUSA

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