Skip to main content
SpringerLink
Log in

Pleiotropic drug resistance in cystic fibrosis fibroblasts: Increased resistance to cyclic AMP

  • Published:
Somatic Cell Genetics

Abstract

In previous studies, cystic fibrosis (CF) fibroblasts were demonstrated to be resistant to the cytotoxic effects of ouabain, dexamethasone, and the sex hormones, dihydrotestosterone, 17β-estradiol, and progesterone. We now show that CF fibroblasts also exhibit greatly increased resistance to the cytotoxic effects of exogenous dibutyryl cyclic AMP (cAMP), as well as to isoproterenol and theophylline, drugs which are known to increase endogenous levels of cAMP. CF cells were also shown to have normal amounts of [3H]cAMP binding to protein kinase as well as normal amounts of cAMP-stimulated protein kinase activity. Phosphodiesterase in CF cells was also found to be stimulated by cAMP to the same degree as in normal cells. These findings suggest that there is no detectable protein kinase deficiency in CF cells. CF cells thus appear to be unlike some cAMP-resistant mutants described by others which are defective in protein kinase activity and cAMP regulation of phosphodiesterase levels. The cross-resistance of CF fibroblasts to ouabain, steroid hormones, and cAMP may provide a unique opportunity to study the biochemical events involved in the metabolism of these drugs as well as the basic biochemical defect in a common human genetic disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Literature cited

  1. Epstein, J., and Breslow, J. L. (1977).Proc. Natl. Acad. Sci. U.S.A. 74:1676–1679.

    PubMed  Google Scholar 

  2. Epstein, J., Breslow, J. L., and Davidson, R. L. (1977).Proc. Natl. Acad. Sci. U.S.A.,74:5642–5646.

    PubMed  Google Scholar 

  3. Breslow, J. L., Epstein, J., and Fontaine, J. H. (1978).Cell 13:663–669.

    PubMed  Google Scholar 

  4. Breslow, J. L., Epstein, J., Vayo, M. M., and Fontaine, J. H. (1977).Exp. Cell Res. 110:399–407.

    PubMed  Google Scholar 

  5. Lelievre, L., Paraf, A., Charlemagne, D., and Sheppard, J. R. (1977).Exp. Cell Res. 104:191–197.

    PubMed  Google Scholar 

  6. Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. (1951).J. Biol. Chem. 193:265–275.

    PubMed  Google Scholar 

  7. Insel, P. A., Bourne, H. R., Coffino, P., and Tomkins, G. M. (1975).Science 190:896–898.

    PubMed  Google Scholar 

  8. Gilman, A. G. (1970).Proc. Natl. Acad. Sci. U.S.A. 67:305–312.

    PubMed  Google Scholar 

  9. Beavo, J. A., Hardman, J. G., and Sutherland, E. W. (1970).J. Biol. Chem. 245:5649–5655.

    PubMed  Google Scholar 

  10. Manganiello, V. C., and Breslow, J. (1974).Biochim. Biophys. Acta 362:509–520.

    PubMed  Google Scholar 

  11. Appleman, M. M., Thompson, W. J., and Russell, T. R. (1973). InAdvances in Cyclic Nucleotide Research (eds.) Greengard, P., and Robison, G. A. (Raven Press, New York), Vol. 3, pp. 65–98.

    Google Scholar 

  12. Kuo, J. F., and Greengard, P. (1969).Proc. Natl. Acad. Sci. U.S.A. 64:1349–1355.

    PubMed  Google Scholar 

  13. Erlichman, J., Rubin, C. S., and Rosen, O. M. (1973).J. Biol. Chem. 248:7607–7609.

    PubMed  Google Scholar 

  14. Beavo, J. A., Bechtel, P. J., and Krebs, E. G. (1975). InAdvances in Cyclic Nucleotide Research (eds.) Drummond, P., Greengard, P., and Robison, G. A. (Raven Press, New York), Vol. 5, pp. 241–252.

    Google Scholar 

  15. Daniel, V., Litwack, G., and Tomkins, G. M. (1973).Proc. Natl. Acad. Sci. U.S.A. 70:76–79.

    PubMed  Google Scholar 

  16. Coffino, P., Bourne, H. R., and Tomkins, G. M. (1975).J. Cell. Physiol. 85:603–610.

    PubMed  Google Scholar 

  17. Bourne, H. R., Coffino, P., and Tomkins, G. M. (1975).J. Cell. Physiol. 85:611–620.

    PubMed  Google Scholar 

  18. Buchwald, M. (1976).Proc. Natl. Acad. Sci. U.S.A. 73:2899–2903.

    PubMed  Google Scholar 

  19. Bourne, H. R., Tomkins, G. M., and Dion, S. (1973).Science 181:952–954.

    PubMed  Google Scholar 

  20. D'Armiento, M., Johnson, G. S., and Pastan, I. (1972).Proc. Natl. Acad. Sci. U.S.A. 69:459–462.

    PubMed  Google Scholar 

  21. Manganiello, V., and Vaughan, M. (1972).Proc. Natl. Acad. Sci. U.S.A. 69:269–273.

    PubMed  Google Scholar 

  22. Thompson, E. B., and Lippman, M. E. (1974).Metabolism 23:159–202.

    PubMed  Google Scholar 

  23. Mankovitz, R., Buchwald, M., and Baker, R. M. (1974).Cell 3:221–226.

    PubMed  Google Scholar 

  24. Lever, J. E., and Seegmiller, J. E. (1976).J. Cell. Physiol. 88:343–352.

    PubMed  Google Scholar 

  25. Baxter, J. D., Harris, A. W., Tomkins, G. M., and Cohn, M. (1971).Science 171:189–191.

    PubMed  Google Scholar 

  26. Sibley, C. H., and Tomkins, G. M. (1974).Cell 2:221–227.

    PubMed  Google Scholar 

  27. Yamamoto, K. R., Gehring, U., Stampfer, M. R., and Sibley, C. H. (1976). InRecent Progress in Hormone Research (ed.) Greep, R. O. (Academic Press, New York), Vol. 32, pp. 3–32.

    Google Scholar 

  28. Bourgeois, S., and Newby, R. F. (1977).Cell 11:423–430.

    PubMed  Google Scholar 

  29. Bourne, H. R., Coffino, P., and Tomkins, G. M. (1975).Science 187:750–752.

    PubMed  Google Scholar 

  30. Granner, D. K. (1974).Nature 259:572–573.

    Google Scholar 

  31. Schaffer, L. D., Chenoweth, M., and Dunn, A. (1969).Biochim. Biophys. Acta 192:304–309.

    PubMed  Google Scholar 

  32. Miller, T. B., Axton, J. H., and Park, C. R. (1971).J. Biol. Chem. 246:3672–3678.

    PubMed  Google Scholar 

  33. Axton, J. H., Friedman, N., Wong, E. H., Brimaux, J. P., Corbin, J. D., and Park, C. R. (1972).J. Biol. Chem. 247:3579–3588.

    PubMed  Google Scholar 

  34. Stellwagen, R. H. (1972).Biochem. Biophys. Res. Commun. 47:1144–1150.

    PubMed  Google Scholar 

  35. Van Rijn, H., Bevers, M. M., Van Wijk, R., and Wicks, W. D. (1974).J. Biol. Chem. 60:181–191.

    Google Scholar 

  36. Lemaire, I., and Coffino, P. (1977).Cell 11:149–155.

    PubMed  Google Scholar 

  37. Mommaerts, W. F. H. M., Illingworth, B., Pearson, C. M., Guillorey, R. J., and Seraydarian, K. (1959).Proc. Natl. Acad. Sci. U.S.A. 45:791–797.

    Google Scholar 

  38. Hug, G., Schubert, W. K., and Chuck, G. (1969).J. Clin. Invest. 48:704–715.

    PubMed  Google Scholar 

  39. Huijing, F., and Fernandes, J. (1969).Am. J. Hum. Genet. 21:275–284.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Metabolism Division, Department of Medicine, Children's Hospital Medical Center, 02115, Boston, Massachusetts

    J. Epstein, Jan L. Breslow, Michael J. Fitzsimmons & Margaret M. Vayo

  2. Department of Pediatrics, Harvard Medical School, 02115, Boston, Massachusetts

    J. Epstein, Jan L. Breslow, Michael J. Fitzsimmons & Margaret M. Vayo

  3. Division of Human Genetics, Department of Medicine, Children's Hospital Medical Center, 02115, Boston, Massachusetts

    J. Epstein

Authors
  1. J. Epstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jan L. Breslow
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael J. Fitzsimmons
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Margaret M. Vayo
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Epstein, J., Breslow, J.L., Fitzsimmons, M.J. et al. Pleiotropic drug resistance in cystic fibrosis fibroblasts: Increased resistance to cyclic AMP. Somat Cell Mol Genet 4, 451–464 (1978). https://doi.org/10.1007/BF01538866

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01538866

Keywords

Search

Navigation