Polyamines, DNA Methylation and Cell Differentiation

  • Olle Heby
  • Lo Persson
  • Steven S. Smith
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 250)


Cells that have become depleted of their putrescine and spermidine content, e. g. by treatment with 2-difluoromethyl-ornithine (DFMO), an enzyme-activated irreversible inhibitor of ornithine decarboxylase (Metcalf et al., 1978), grow slowly or not at all (Heby, 1981; Pegg, 1988). In addition to causing growth arrest, polyamine depletion has been found to induce or suppress cell differentiation (Heby et al., 1987). Teratocarci-noma stem cells belong to the category of cells that are induced to differentiate in response to putrescine and spermidine depletion (Heby et al., 1983; 1987; Schindler et al., 1983; Oredsson et al., 1985).


Ornithine Decarboxylase Methyl Group Donor Polyamine Synthesis Polyamine Depletion Swedish Natural Science Research Council 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bird, A. P., 1986, CpG-rich islands and the function of DNA methylation, Nature, 321: 209–213.PubMedCrossRefGoogle Scholar
  2. Busslinger, M., Hurst, J., and Flavell, R. A., 1983, DNA methylation and the regulation of globin gene expression, Cell, 34: 197–206.PubMedCrossRefGoogle Scholar
  3. Danzin, C., Claverie, N., Wagner, J., Grove, J., and Koch-Weser, J., 1982, Effect on prostatic growth of 2-difluoromethyl-ornithine, an effective inhibitor of ornithine decarboxy-lase, Biochem. J. 202: 175–181.PubMedGoogle Scholar
  4. Doerfler, W., 1983, DNA methylation and gene activity, Ann. Rev. Biochem., 52: 93–124.PubMedCrossRefGoogle Scholar
  5. Hardy, T. A., Baker, D. J., Newman, E. M., Sowers, L. C., Goodman, M. F., and Smith, S. S., 1987, Size of the directing moiety at carbon 5 of cytosine and the activity of human DNA (cytosine-5)methyltransferase, Biochem. Biophys. Res. Commun., 145: 146–152.PubMedCrossRefGoogle Scholar
  6. Heby, O., 1981, Role of polyamines in the control of cell proliferation and differentiation, Differentiation 19: 1–20.PubMedCrossRefGoogle Scholar
  7. Heby, O., Oredsson, S. M., Olsson, I., and Marton, L. J., 1983, A role for the polyamines in mouse embryonal carcinoma (F9 and PCC3) cell differentiation but not in human promyelo-cytic leukemia (HL-60) cell differentiation, Adv. Polyamine Res., 4: 727–742.Google Scholar
  8. Heby, O., Luk, G. D., and Schindler, J., 1987, Polyamine synthesis inhibitors act as both inducers and suppressors of cell differentiation, in: “Inhibition of Polyamine Metabolism”, P. P. McCann, A. E. Pegg, and A. Sjoerdsma, eds., Academic Press, New York, pp. 165–186.Google Scholar
  9. Holm, I., Wallon, M., Thorsson, L., and Heby, O., 1985, Methyl-glyoxal-bis(guanylhydrazone) (MGBG), an inhibitor of S-adenosylmethionine decarboxylase, interferes with α-di-fluoromethylornithine (DFMO)-induced growth arrest and differentiation of embryonal carcinoma cells, J. Cell Biol., 101: 246a.Google Scholar
  10. Mamont, P. S., Danzin, C., Wagner, J., Siat, M., Joder-Ohlenbusch, A.-M., and Claverie, N., 1982, Accumulation of decarboxylated S-adenosyl-L-methionine in mammalian cells as a consequence of the inhibition of putrescine biosynthesis, Eur. J. Biochem., 123: 499–504.PubMedCrossRefGoogle Scholar
  11. Metcalf, B. W., Bey, P., Danzin, C., Jung, M. J., Casara, P., Vevert, J. P., 1978, Catalytic irreversible inhibition of mammalian ornithine decarboxylase (EC by substrate and product analogues, J. Am. Chem. Soc., 100: 2551–2553.CrossRefGoogle Scholar
  12. Oliva, A., Galletti, P., Zappia, V., Paik, W. K., and Kim, S., 1980, Studies on substrate specificity of S-adenosyl-methionine: protein-carboxyl methyltransferase from calf brain, Eur. J. Biochem., 104: 595–602.PubMedCrossRefGoogle Scholar
  13. Oredsson, S. M., Billgren, M., and Heby, O., 1985, Induction of F9 embryonal carcinoma cell differentiation by inhibition of polyamine synthesis, Eur. J. Cell Biol., 38: 335–343.PubMedGoogle Scholar
  14. Oredsson, S. M., Kanje, M., Mamont, P. S., Wagner, J., and Heby, O., 1986, Polyamine depletion increases cellular ribo-nucleotide levels, Mol. Cell. Biochem., 70: 89–96.PubMedCrossRefGoogle Scholar
  15. Pedrali-Noy, G., and Weissbach, A., 1986, Mammalian DNA methyl-transferases prefer poly(dl-dC) as substrate, J. Biol. Chem., 261: 7600–7602.PubMedGoogle Scholar
  16. Pegg, A. E., 1988, Polyamine metabolism and its importance in neoplastic growth and as a target for chemotherapy, Cancer Res., 48: 759–774.PubMedGoogle Scholar
  17. Pegg, A. E., Pösö, H., Shuttleworth, K., and Bennett, R. A., 1982, Effect of inhibition of polyamine synthesis on the content of decarboxylated S-adenosylmethionine, Biochem. J., 202: 519–526.PubMedGoogle Scholar
  18. Pegg, A. E., Wechter, R. S., Clark, R. S., Wiest, L., and Erwin, B. G., 1986, Acetylation of decarboxylated S-adenosylmethionine by mammalian cells, Biochemistry. 25: 379–384.PubMedCrossRefGoogle Scholar
  19. Pösö, H., and Pegg, A. E., 1982, Comparison of S-adenosylmethionine decarboxylases from rat liver and muscle, Biochemistry. 21: 3116–3122.PubMedCrossRefGoogle Scholar
  20. Razin, A., and Cedar, H., 1984, DNA methylation in eukaryotic cells, Int. Rev. Cytol., 92: 159–185.PubMedCrossRefGoogle Scholar
  21. Razln, A., and Riggs, A. D., 1980, DNA methylation and gene function, Science, 210: 604–610.CrossRefGoogle Scholar
  22. Schindler, J., Kelly, M., and McCann, P. P., 1983, Inhibition of ornithine decarboxylase induces embryonal carcinoma cell differentiation, Biochem. Biophys. Res. Commun., 114: 410–417.PubMedCrossRefGoogle Scholar
  23. Smith, S. S., Hardy, T. A., and Baker, D. J., 1987, Human DNA (cytosine-5) methyltransferase selectively methylates duplex DNA containing mispairs, Nucleic Acids Res., 15: 6899–6916.PubMedCrossRefGoogle Scholar
  24. Young, P. R., and Tilghman, S. M., 1984, Induction of α-feto-protein synthesis in differentiating F9 teratocarcinoma cells is accompanied by a genome-wide loss of DNA methylation, Mol. Cell. Biol., 4: 898–907.PubMedGoogle Scholar
  25. Zappia, V., Zydek-Cwick, C. R., and Schlenk, F., 1969, The specificity of S-adenosylmethionine derivatives in methyl transfer reactions, J. Biol. Chem., 244: 4499–4509.PubMedGoogle Scholar
  26. Zappia, V., Galletti, P., Oliva, A., and Porcelli, M., 1983, Methods for the preparation and assay of S-adenosyl-(5′)-3-methylthiopropylamine (decarboxylated adenosyl-methionine, Meth. Enzymol., 94: 73–80.CrossRefGoogle Scholar
  27. Zucker, K. E., Riggs, A. D., and Smith, S. S., 1985, Purification of human DNA(cytosine-5-)-methyltransferase, J. Cell. Biochem., 29: 337–349.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Olle Heby
    • 1
  • Lo Persson
    • 2
  • Steven S. Smith
    • 3
  1. 1.Departments of ZoophysiologyUniversity of LundLundSweden
  2. 2.Departments of PhysiologyUniversity of LundLundSweden
  3. 3.Molecular SurgeryCity of Hope National Medical CenterDuarteUSA

Personalised recommendations