Regulation of Protein Kinase C

  • Y. A. Hannun
Part of the Developments in Oncology book series (DION, volume 67)


Protein kinase C has emerged as a key element in the transduction of the effects of growth factors, hormones, and neurotransmitters (1). The enzyme was initially discovered by Nishizuka and coworkers who defined a proteolytically activated kinase from rat brain. A number of discoveries by that group led to the recognition of the significance of protein kinase C as an important regulator of tumor promotion, cell regulation, and cell differentiation. Initial characterization of the enzyme by Nishizuka and coworkers led to the identification that the proenzyme could be activated in the presence of membranes and calcium. Further studies led to the identification that the neutral lipid, diacylglycerol (DAG), caused potent activation of the enzyme and significantly reduced its calcium requirement to the low micromolar and high nanomolar range, rendering the enzyme active at physiologic concentrations of calcium in the presence of DAG. This finding led Nishizuka and coworkers to implicate protein kinase C in the pathways mediating the effects of “calcium-mobilizing” agents in what had been termed as the “phosphatidylinositol (PI) cycle” (1). In this cycle, the action of a number of extracellular agents leads to the activation of phospholipase C which results in the cleavage of inositolphospholipids yielding inositol trisphosphate and DAG. Inositol trisphosphate mobilizes intracellular calcium while DAG activates protein kinase C. Another major discovery by Nishizuka’s group related to the finding that phorbol esters, potent tumor promoters, could directly activate protein kinase C with a mechanism similar to that of DAG. This finding again implicated protein kinase C in mediating the effects of phorbol esters on tumor promotion, cell differentiation, and a variety of other biological responses such as granule secretion and hormone release (1).


Protein Kinase Phorbol Ester Mixed Micelle Sphingolipid Metabolism Potent Tumor Promoter 
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.


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  1. 1.
    Nishizuka, Y. (1986) Science 233, 305–312PubMedCrossRefGoogle Scholar
  2. 2.
    Nishizuka, Y. (1988) Nature 334, 661–665PubMedCrossRefGoogle Scholar
  3. 3.
    Huang, K.P., Nakabayashi, H., and Huang, F.L. (1986) Proc. Natl. Acad. Sci. USA 83, 8535–8539PubMedCrossRefGoogle Scholar
  4. 4.
    Lee, M.H., and Bell, R.M. (1986) J. Biol. Chem. 261, 14867–14870PubMedGoogle Scholar
  5. 5.
    House, C, and Kemp, B.E. (1987) Science 238, 1726–1728PubMedCrossRefGoogle Scholar
  6. 6.
    Hannun, Y.A., Loomis, C.R., and Bell, R.M. (1985) J. Biol. Chem. 260, 10039–10043PubMedGoogle Scholar
  7. 7.
    Hannun, Y.A., and Bell, R.M. (1987) in Cell Calcium and the Control of Membrane Transport (Mandel, L.J., and Eaton, D.C., eds) pp. 230–240, Rockefeller University Press, New YorkGoogle Scholar
  8. 8.
    Ganong, B., Loomis, C.R., Hannun, Y.A., and Bell, R.M. (1986) Proc. Natl. Acad. Sci. USA 83, 1184–1188PubMedCrossRefGoogle Scholar
  9. 9.
    Huang, K.P., Chan, K.F., Singh, T, J., Nakabayashi, H., and Huang, F.L. (1986) J. Biol. Chem. 261, 12134–12140PubMedGoogle Scholar
  10. 10.
    Markovac, J., and Goldstein, G.W. (1988) Nature 334, 71–73PubMedCrossRefGoogle Scholar
  11. 11.
    Csermely, P., Szamel, M., Resch, K., and Somogyi, J. (1988) Biochem. Biophys. Res. Commun. 154, 578–583PubMedCrossRefGoogle Scholar
  12. 12.
    Murakami, K., Chan, S.Y., and Routtenberg, A. (1986) J. Biol. Chem. 261, 15424–15429PubMedGoogle Scholar
  13. 13.
    Hansson, A., Serhan, C.N., Haeggstrom, J., Ingelman-Sundberg, M., and Samuelsson, B. (1986) Biochem. Biophys. Res. Commun. 134, 1215–1222PubMedCrossRefGoogle Scholar
  14. 14.
    Oishi, K., Raynor, R.L., Charp, P.A., and Kuo, J.F. (1988) J. Biol. Chem. 263, 6865–6871PubMedGoogle Scholar
  15. 15.
    Hannun, Y.A., Loomis, C.R., Merrill, A.H., Jr., and Bell, R.M. (1986) J. Biol. Chem. 261, 12604– 12609PubMedGoogle Scholar
  16. 16.
    Merrill, A.H., Jr., Nimkar, S., Menaldino, D., Hannun, Y.A., Loomis, C, Bell, R.M., Tyagi, S.R., Lambeth, J.D., Stevens, V.L., Hunter, R., and Liotta, D.C. (1989) Biochemistry 28, 3138–3145PubMedCrossRefGoogle Scholar
  17. 17.
    Hannun, Y.A., and Bell, R.M. (1987) Science 235, 670–674PubMedCrossRefGoogle Scholar
  18. 18.
    Hannun, Y.A., and Bell, R.M. (1989) Science 243, 500–507PubMedCrossRefGoogle Scholar
  19. 19.
    Hannun, Y.A., and Bell, R.M. (1988) J. Biol. Chem. 263, 5124–5131PubMedGoogle Scholar
  20. 20.
    Hannun, Y.A., Foglesong, R.J., and Bell, R.M. (1989) J. Biol. Chem. 264, 9960–9966PubMedGoogle Scholar
  21. 21.
    Kariya, K., and Takai, Y. (1987) FEBS Lett. 219, 119–124PubMedCrossRefGoogle Scholar
  22. 22.
    Hannun, Y.A., Greenberg, C.S ., and Bell, R.M. (1987) J. Biol. Chem. 262, 13620–13626PubMedGoogle Scholar
  23. 23.
    Werner, M., Bielawska, A., and Hannun, Y.A. (submitted)Google Scholar
  24. 24.
    Obeid, L.M., Okazake, T., Karolak, L.A., and Hannun, Y.A. (1990) J. Biol. Chem. 265:2370–2374PubMedGoogle Scholar
  25. 25.
    Okazaki, T., Bell, R.M., and Hannun, Y.A. J. Biol. Chem. (1989) J. Biol. Chem, 264:19076–19080PubMedGoogle Scholar
  26. 26.
    Bishop, W.R. and Bell, R.M. (1988) Oncogene Res. 2, 205–218PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1991

Authors and Affiliations

  • Y. A. Hannun
    • 1
  1. 1.Departments of Medicine and Cell BiologyDuke University Medical CenterDurhamUSA

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