Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase (original) (raw)

Nature volume 358, pages 70–73 (1992)Cite this article

Abstract

THE macrolide rapamycin induces cell cycle Gl arrest in yeast and in mammalian cells1–3, which suggests that an evolutionarily conserved, rapamycin-sensitive pathway may regulate entry into S phase. In mammals, rapamycin inhibits interleukin-2 receptor-induced S phase entry and subsequent T-cell proliferation4–6, resulting in immunosuppression. Here we show that interleukin-2 selectively stimulates the phosphor) lation and activation of p70 S6 kinase but not the _erk_-encoded MAP kinases and _rsk_-encoded S6 kinases7,8. Rapamycin completely and rapidly inhibits interleukin-2-induced phosphorylation and activation of p70 S6 kinase at concentrations comparable to those blocking S phase entry of T cells (0.05–0.2 nM). The structurally related macrolide FK506 competitively antagonizes the actions of rapamycin, indicating that these effects are mediated by FKBP, which binds the transition-state mimic structure common to both rapamycin and FK506 (refs 4, 6, 9–11). The selective blockade of the p70 S6 kinase activation cascade by the rapamycin–FKBP complex implicates this signalling pathway in the regulation of T cell entry into S phase.

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References

  1. Heitman, J., Movva, N. R. & Hall, M. N. Science 253, 905–909 (1991).
    Article ADS CAS Google Scholar
  2. Morris, R. E. Immun. Today 5, 137–140 (1991).
    Article Google Scholar
  3. Dumont F. J. et al. J. Immun. 144, 1418–1424 (1990).
    CAS Google Scholar
  4. Bierer, B. E. et al. Proc. natn. Acad. Sci. U.S.A. 87, 9231–9235 (1990).
    Article ADS CAS Google Scholar
  5. Dumont, F. J., Staruch, M. J., Koprak, S. L., Melino, M. R. & Sigal, N. H. J. Immun 144, 251–258 (1990).
    CAS PubMed Google Scholar
  6. Schreiber, S. L. Science 251, 283–287 (1991).
    Article ADS CAS Google Scholar
  7. Erikson, R. L. J. biol. Chem. 266, 6007–6010 (1992).
    Google Scholar
  8. Blenis, J. Cancer Cells 3, 1–4 (1991).
    Google Scholar
  9. Siekierka, J. J., Hung, S. H. Y., Poe, M., Lin, C. S. & Sigal, N. H. Nature 341, 755–757 (1989).
    Article ADS CAS Google Scholar
  10. Harding, M. W., Galat, A., Uehling, D. E. & Schreiber, S. L. Nature 341, 758–760 (1989).
    Article ADS CAS Google Scholar
  11. Standaert, R. F., Galat, A., Verdine, G. L. & Schreiber, S. L. Nature 346, 671–674 (1990).
    Article ADS CAS Google Scholar
  12. Miyazaki, T., Maruyama, M., Yamada, G., Hatakeyama, M. & Taniguchi, T. EMBO J. 10, 3191–3197 (1991).
    Article CAS Google Scholar
  13. Chung, J. Chen, R.-H. & Blenis, J. Molec. cell Biol. 11, 1868–1874 (1991).
    Article CAS Google Scholar
  14. Chen, R.-H., Chung, J. & Blenis, J. Molec. cell. Biol. 11, 1861–1867 (1991).
    Article CAS Google Scholar
  15. Cantrell, D. A. & Smith, K. A. Science 224, 1312–1316 (1984).
    Article ADS CAS Google Scholar
  16. Pelech, S. L., Olwin, B. B. & Krebs, E. G. Proc. natn. Acad. Sci. U.S.A. 83, 5968–5972 (1986).
    Article ADS CAS Google Scholar
  17. Price, D. J., Gunsalus, J. R. & Avruch, J. Proc. natn. Acad. Sci. U.S.A. 87, 7944–7948 (1990).
    Article ADS CAS Google Scholar
  18. Schreiber, S. L. & Crabtree, G. R. Immun. Today 13, 136–142 (1992).
    Article CAS Google Scholar
  19. Liu, J. et al. Cell 66, 807–815 (1991).
    Article CAS Google Scholar
  20. Friedman, J. & Weissman, I. Cell 66, 799–806 (1991).
    Article CAS Google Scholar
  21. Banerjee, P. et al. Proc. natn. Acad. Sci. U.S.A. 87, 8550–8554 (1990).
    Article ADS CAS Google Scholar
  22. Kozma, S. C. et al. Proc. natn. Acad. Sci. U.S.A. 87, 7365–7369 (1990).
    Article ADS CAS Google Scholar
  23. Chung, J., Kuo, C. J., Crabtree, G. R. & Blenis, J. Cell (in the press).

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Unit in Molecular and Genetic Medicine, Beckman Center, Stanford University School of Medicine, Stanford, California, 94305-5425, USA
    Calvin J. Kuo, Jongkyeong Chung, David F. Fiorentino, W. Michael Flanagan, John Blenis & Gerald R. Crabtree
  2. Department of Cellular and Molecular Physiology, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts, 02115, USA
    Jongkyeong Chung & John Blenis

Authors

  1. Calvin J. Kuo
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  2. Jongkyeong Chung
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  3. David F. Fiorentino
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  4. W. Michael Flanagan
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  5. John Blenis
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  6. Gerald R. Crabtree
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Kuo, C., Chung, J., Fiorentino, D. et al. Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase.Nature 358, 70–73 (1992). https://doi.org/10.1038/358070a0

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