Resistance to cadmium mediated by ubiquitin-dependent proteolysis (original) (raw)

Nature volume 361, pages 369–371 (1993)Cite this article

Abstract

CADMIUM is a potent poison for living cells. In man, chronic exposure to low levels of cadmium results in damage to kidneys and has been linked to neoplastic disease and ageing, and acute exposure can cause damage to a variety of organs and tissues1. Cadmium reacts with thiol groups and can substitute for zinc in certain proteins2, but the reason for its toxicity in vivo remains uncertain. In eukaryotes, an important selective proteolysis pathway for the elimination of abnormal proteins that are generated under normal or stress conditions is ATP-dependent and mediated by the ubiquitin system3–5. Substrates of this pathway are first recognized by ubiquitin-conjugating enzymes5–7 (or auxiliary factors) which covalently attach ubiquitin, a small and highly conserved protein, to specific internal lysine residues of proteolytic substrates. Ubiquitinated substrates are then degraded by the proteasome, a multisubunit protease complex8–10. Here we show that expression of this ubiquitin-dependent proteolysis pathway in yeast is activated in response to cadmium exposure and that mutants deficient in specific ubiquitin-conjugating enzymes are hypersensitive to cadmium. Moreover, mutants in the proteasome are hypersensitive to cadmium, suggesting that cadmium resistance is mediated in part by degradation of abnormal proteins. This indicates that a major reason for cadmium toxicity may be cadmium-induced formation of abnormal proteins.

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References

  1. Stoeppler, M. & Piscator, M. (eds) Cadmium (Springer, Berlin, 1985).
  2. Vallee, B. L. & Ulmer, D. A. Rev. Biochem. 41, 91–129 (1972).
    Article CAS Google Scholar
  3. Finley, D. & Chau, V. A. Rev. Cell Biol. 7, 25–69 (1986).
    Article Google Scholar
  4. Hershko, A. Trends biochem. Sci. 16, 265–268 (1991).
    Article CAS Google Scholar
  5. Jentsch, S. Trends Cell Biol. 2, 98–103 (1992).
    Article CAS Google Scholar
  6. Jentsch, S., Seufert, W., Sommer, T. & Reins, H.-A. Trends biochem. Sci. 15, 195–198 (1990).
    Article CAS Google Scholar
  7. Jentsch, S. A. Rev. Genet. 26, 177–205 (1992).
    Article Google Scholar
  8. Hough, R., Pratt, G. & Rechsteiner, M. J. biol. Chem. 261, 2400–2408 (1986).
    CAS PubMed Google Scholar
  9. Waxman, L., Fagan, J. M. & Goldberg, A. L. J. biol. Chem. 262, 2451–2457 (1987).
    CAS Google Scholar
  10. Seufert, W. & Jentsch, S. EMBO J. 11, 3077–3080 (1992).
    Article CAS Google Scholar
  11. Seufert, W., McGrath, J. P. & Jentsch, S. EMBO J. 9, 4535–4541 (1990).
    Article CAS Google Scholar
  12. Seufert, W. & Jentsch, S. EMBO J. 9, 543–550 (1990).
    Article CAS Google Scholar
  13. Jentsch, S., McGrath, J. P. & Varshavsky, A. Nature 329, 131–134 (1987).
    Article CAS ADS Google Scholar
  14. Heinemeyer, W., Kleinschmidt, J. A., Saidowsky, J., Escher, C. & Wolf, D. H. EMBO J. 10, 555–562 (1991).
    Article CAS Google Scholar
  15. Finley, D., özkaynak, E. & Varshavsky, A. Cell 48, 1035–1046 (1987).
    Article CAS Google Scholar
  16. Hamer, D. H. A. Rev. Biochem. 55, 913–951 (1986).
    Article CAS Google Scholar
  17. Grill, E., Winnacker, E.-L. & Zenk, M. H. Science 230, 674–676 (1985).
    Article CAS ADS Google Scholar
  18. Ortiz, D. F. et al. EMBO J. 11, 3491–3499 (1992).
    Article CAS Google Scholar
  19. Sanchez, Y., Taulien, J., Borkovich, K. A. & Lindquist, S. EMBO J. 11, 2357–2364 (1992).
    Article CAS Google Scholar
  20. Van Nocker, S. & Vierstra, R. D. Proc. natn. Acad. Sci. U.S.A. 88, 10297–10301 (1991).
    Article CAS ADS Google Scholar
  21. Phelps, A., Schobert, C. T. & Wohlrab, H. Biochemistry 30, 248–252 (1991).
    Article CAS Google Scholar
  22. Broach, J. R., Strathern, J. N. & Hicks, J. B. Gene 8, 121–133 (1979).
    Article CAS Google Scholar
  23. Sherman, F., Fink, G. R. & Hicks, J. B. Methods in Yeast Genetics (Cold Spring Harbor Laboratory Press, New York, 1986).
    Google Scholar
  24. Ausubel, F. M. et al. (eds) Current Protocols in Molecular Biology (Green and Wiley, New York, 1991).

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Author notes

  1. Stefan Jentsch: To whom correspondence should be addressed.

Authors and Affiliations

  1. Friedrich-Miescher-Laboratorium der Max-Planck-Gesellschaft, Spemannstrasse 37-39, 7400, Tubingen, Germany
    Joern Jungmann, Hans-Albert Reins & Stefan Jentsch
  2. Institut fur Pflanzenphysiologie, Universitat Bayreuth, Postfach 3008, 8580, Bayreuth, Germany
    Christian Schobert

Authors

  1. Joern Jungmann
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  2. Hans-Albert Reins
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  3. Christian Schobert
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  4. Stefan Jentsch
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Jungmann, J., Reins, HA., Schobert, C. et al. Resistance to cadmium mediated by ubiquitin-dependent proteolysis.Nature 361, 369–371 (1993). https://doi.org/10.1038/361369a0

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