Mechanisms Involved in Ornithine Decarboxylase Induction by 12-O-Tetradecanoylphorbol-13-Acetate, a Potent Mouse Skin Tumor Promoter and an Activator of Protein Kinase C

  • Ajit K. Verma
  • J. T. Hsieh
  • R. C. Pong
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 250)


Ornithine decarboxylase (ODC, EC which decarboxylates ornithine to form putrescine, is the key enzyme in mammalian polyamine biosynthesis. ODC is characterized by its inducibility and rapid turnover rate (half life∼15 min). ODC activity in quiescent cells is extremely low and is increased within a few hours in response to many different stimuli, including hormones, growth factors, and tumor promoters. In general the induction of ODC activity and subsequent accumulation of putrescine constitute a part of a cascade of biochemical events that accompany cell proliferation and differentiation (1, 2).


Ornithine Decarboxylase Mouse Skin Tumor Phorbol Ester Receptor Epidermal Ornithine Decarboxylase Mouse Skin Tumor Promoter 


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  1. 1.
    A.E. Pegg, Recent advances in the biochemistry of polyamines in eukaryotes, Biochem. J. 234: 249 (1986).PubMedGoogle Scholar
  2. 2.
    A.E. Pegg, Polyamine Metabolism and Its Importance in Neoplastic Growth and as a Target for Chemotherapy, Cancer Res. 48: 759 (1988).PubMedGoogle Scholar
  3. 3.
    T.G. O’Brien, R.C. Simsiman, and R.K. Boutwell, Induction of polyamine-biosynthetic enzymes in mouse epidermis by tumor promoting agents, Cancer Res. 35: 1662 (1975).PubMedGoogle Scholar
  4. 4.
    A.K. Verma and R.K. Boutwell, Inhibition of carcinogenesis by inhibitors of putrescine biosynthesis, in: Inhibition of Polyamine Metabolism: “Biological Significance and Basis of New Therapies”, McCann, P.P., Pegg, A.E., Sjoerdsma, A. eds., pp 249, Academic Press, Inc., Orlando, Florida (1987).Google Scholar
  5. 5.
    A.K. Verma, D. Erickson, and B.J. Dolnick, Increased mouse epidermal ornithine decarboxylase activity by the tumour promoter 12-0-tetradecanoylphorbol-13-acetate involves increased amounts of both enzyme protein and messenger RNA, Biochem. J. 237: 297 (1986).PubMedGoogle Scholar
  6. 6.
    S.K. Gilmour, A.K. Verma, T. Madara, and T.G. O’Brien, Regulation of ornithine decarboxylase gene expression in mouse epidermis and epidermal tumors during two-stage tumorigenesis, Cancer Res. 47: 1221 (1987).PubMedGoogle Scholar
  7. 7.
    A.K. Verma, Inhibition of tumor promoter 12-0-tetradecanoylphorbol-13-acetate-induced synthesis of mouse epidermal ornithine decarboxylase messenger RNA and diacylglycerol-promoted mouse skin tumor formation by retinoic acid, Cancer Res. 48: 2168 (1988).PubMedGoogle Scholar
  8. 8.
    A.K. Verma, R.C. Pong, and D. Erickson, Involvement of protein kinase C in ornithine decarboxylase gene expression in primary culture of newborn mouse epidermal cells and in skin tumor promotion by 12-0-tetradecano-ylphorbol-13-acetate, Cancer Res. 46: 6149 (1986).PubMedGoogle Scholar
  9. 9.
    J.T. Hsieh and A.K. Verma, Involvement of protein kinase C in the transcriptional regulation of ornithine decarboxylase gene expression by 12-0-tetradecanoylphorbol-13-acetate in T24 human bladder carcinoma cells, Arch. Biochem. Biophys. 262: 326 (1988).PubMedCrossRefGoogle Scholar
  10. 10.
    A. Katz and C. Kahana, Transcriptional activation of mammalian ornithine decarboxylase during stimulated growth, Mol. Cell. Biol. 7: 2641 (1987).PubMedGoogle Scholar
  11. 11.
    F.G. Berger, D. Loose, D.H. Meisner, and G. Watson, Androgen induction of messenger RNA in mouse kidney is posttranslational, Biochemistry 25: 1170 (1986).PubMedCrossRefGoogle Scholar
  12. 12.
    U. Kikkawa, Y. Takai, Y. Tanaka, R. Miyake, and Y. Nishizuka, Protein kinase C as a possible receptor protein of tumor-promoting phorbol esters, J. Biol. Chem. 258: 11442 (1983).PubMedGoogle Scholar
  13. 13.
    J.E. Neidel, L.J. Kuhn, and G.R. Vandenbark, Phorbol diester receptor copurifies with protein kinase C, Proc. Natl. Acad. Sci. USA 80: 36 (1983).CrossRefGoogle Scholar
  14. 14.
    C.L. Ashendel, J.M. Staller, and R.K. Boutwell, Solubilization, purification, and reconstitution of a phorbol ester receptor from the particulate protein fraction of mouse brain, Cancer Res. 43: 4327 (1983).PubMedGoogle Scholar
  15. 15.
    M. Castagna, Y. Takai, K. Kaibuchi, K. Sano, U. Kikkawa, and Y. Nishizuki, Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters, J. Biol. Chem. 257: 7847 (1982).PubMedGoogle Scholar
  16. 16.
    K.L. Leach and P.M. Blumberg, Modulation of protein kinase C activity and [3H]phorbol-12, 13-dibutyratebinding by various tumor promoters in mouse brain cytosol, Cancer Res. 45: 1958 (1985).PubMedGoogle Scholar
  17. 17.
    Y. Nishizuka, The role of protein kinase C in cell surface signal transduction and tumor promotion, Nature (Lond.) 308: 693 (1984).CrossRefGoogle Scholar
  18. 18.
    Y. Nishizuka, Prospectives on the role of protein kinase C in stimulus-response coupling, J. Natl. Cancer Inst. 76: 363 (1986).PubMedGoogle Scholar
  19. 19.
    T. Nakadate, S. Yamamoto, E. Aizu, and R. Kato, Inhibition of 12-0-tetradecanoylphorbol-13-acetate-induced tumor promotion and epidermal ornithine decarboxylase activity in mouse skin by palmitoylcarnitine, Cancer Res. 46: 1589 (1986).PubMedGoogle Scholar
  20. 20.
    T. Nakadate, S. Yamamoto, M. Ishii, and R. Kato, Inhibition of 12-0-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity by phospholipase A2 inhibitors and lipoxygenase inhibition, Cancer Res. 42: 2841 (1982).PubMedGoogle Scholar
  21. 21.
    R.C. Smart, M.T. Huang, and A.H. Conney, sn-1, 2-Diacylglycerols mimic the effects of 12-0-tetradecano-ylphorbol-13-acetate in vivo by inducing biochemical changes associated with tumor promotion in mouse epidermis, Carcinogenesis (Lond.) 7: 1865 (1986).CrossRefGoogle Scholar
  22. 22.
    A.M. Jetten, B.R. Ganong, G.R. Vandenbark, J.E. Shirley, and R.M. Bell, Role of protein kinase C in diacylglycerolmediated induction of ornithine decarboxylase and reduction of epidermal growth factor binding, Proc. Natl. Acad. Sci. USA 82: 1941 (1985).PubMedCrossRefGoogle Scholar
  23. 23.
    A.K. Verma, Protein kinase C activator L-α-dioctanoylglyce-rol: a potent stage II mouse skin tumor promoter, Cancer Res. 48: 1736 (1988).PubMedGoogle Scholar
  24. 24.
    R.C. Pong, J.T. Hsieh, M.F. Denning, and A.K. Verma, Protein kinase C-mediated phosphorylation of 37 and 40 kD polypeptides and increased transcription of the ornithine decarboxylase gene in the T24 human bladder carcinoma cells, Proc. Am. Assoc. Cancer Res. 29: 77 (1988).Google Scholar
  25. 25.
    S.K. Gilmour, N. Avdalovic, T. Madara, and T.G. O’Brien, Induction of ornithine decarboxylase by 12-0-tetradecano-ylphorbol-13-acetate in hamster fibroplasts, J.Biol.Chem. 260: 16439 (1985).PubMedGoogle Scholar
  26. 26.
    J.E. Seely, H. Pösö, and A.E. Pegg, Effect of androgens on turnover of ornithine decarboxylase in mouse kidney, J.Biol.Chem. 257: 7549 (1982).PubMedGoogle Scholar
  27. 27.
    D.H. Russell, Posttranslational modification of ornithine decarboxylase by its product putrescine, Biochem. Biophys. Res. Commun. 99: 1167 (1981).PubMedCrossRefGoogle Scholar
  28. 28.
    J.S. Heller, W.F. Fong, and E.S. Canellakis, Induction of a protein inhibitor to ornithine decarboxylase by the end product of its reaction, Proc. Natl. Acad. Sci. USA 73: 1858 (1976).PubMedCrossRefGoogle Scholar
  29. 29.
    A.K. Verma, C.L. Ashendel, and R.K. Boutwell, Inhibition by prostaglandin synthesis inhibitors of the induction of epidermal ornithine decarboxylase activity, the accumulation of prostaglandins, and tumor promotion caused by 12-0-tetradecanoylphorbol-13-acetate, Cancer Res. 40: 308 (1980).PubMedGoogle Scholar
  30. 30.
    A.K. Verma and D. Erickson, Induction of mouse epidermal ornithine decarboxylase by the tumor promoter 12-0-tetradecanoylphorbol-13-acetate: dependency on calcium availability, Arch. Biochem. Biophys. 247: 272 (1986).PubMedCrossRefGoogle Scholar
  31. 31.
    W.J. Kozumbo, J.L. Seed, and T.W. Kensler, Inhibition by 2(3)-tert-butyl-4-hydroxyanisole and other antioxidants of epidermal ornithine decarboxylase activity induced by 12-O-tetradecanoylphorbol-13-acetate, Cancer Res. 43: 2555 (1983).PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Ajit K. Verma
    • 1
  • J. T. Hsieh
    • 1
  • R. C. Pong
    • 1
  1. 1.Department of Human OncologyUniversity of Wisconsin Clinical Cancer CenterMadisonUSA

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