Rapid shuttling of NF-AT in discrimination of Ca2+ signals and immunosuppression


CELLS need to distinguish between transient Ca2+ signals that induce events such as muscle contraction, secretion, adhesion and synaptic transmission, and sustained Ca2+ signals that are involved in cell proliferation and differentiation. The latter class of events is blocked in lymphocytes by the immunosuppressive drugs cyclosporin A and FK506, which inhibit calcineurin, a Ca2+-activated serine/threonine phosphatase necessary for the nuclear import of NF-AT transcription factors1–4. Here we report that sustained high concentrations of Ca2+, but not transient pulses, are required to maintain NF-AT transcription factors in the nucleus, where they participate in Ca2+-dependent induction of genes required for lymphocyte activation and proliferation. Furthermore, overexpression and constitutive nuclear localization of NF-AT, but not Jun, Fos, NF-κB, Oct or Ets family members, renders the interleukin-2 enhancer in Jurkat T lymphocytes resistant to FK506 and cyclosporin A. Thus a primary effect of these immunosuppressive reagents is to control the subcellular localization of the NF-AT family of transcription factors.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Klee, C. B., Crouch, T. H. & Krinks, M. H. Proc. Natl Acad. Sci. USA 76, 6270–6273 (1979).

    ADS  CAS  Article  Google Scholar 

  2. 2

    Liu, J. et al. Cell 66, 807–815 (1991).

    CAS  Article  Google Scholar 

  3. 3

    Clipstone, N. A. & Crabtree, G. R. Nature 357, 695–697 (1992).

    ADS  CAS  Article  Google Scholar 

  4. 4

    Flanagan, W. F., Cothesy, B., Bram, R. J. & Crabtree, G. R. Nature 352, 803–807 (1991).

    ADS  CAS  Article  Google Scholar 

  5. 5

    Nowell, P. C. Cancer Res. 20, 462–466 (1960).

    CAS  PubMed  Google Scholar 

  6. 6

    Whitney, R. B. & Sutherland, R. M. J. Cell Physiol. 80, 329–337 (1972).

    CAS  Article  Google Scholar 

  7. 7

    Tsien, R. Y., Rozzan, T. & Rink, T. Nature 295, 68–71 (1982).

    ADS  CAS  Article  Google Scholar 

  8. 8

    Weiss, A., Shields, R., Newton, M., Manger, B. & Imboden, J. J. Immunol. 138, 2169–2176 (1987).

    CAS  PubMed  Google Scholar 

  9. 9

    Shaw, K. T.-Y. et al. Proc. Natl Acad. Sci. USA 92, 11205–11209 (1995).

    ADS  CAS  Article  Google Scholar 

  10. 10

    Rao, A. Immunol. Today 15, 274–281 (1994).

    CAS  Article  Google Scholar 

  11. 11

    Crabtree, G. R. & Clipstone, N. A. Annu. Rev. Biochem. 63, 1045–1083 (1994).

    CAS  Article  Google Scholar 

  12. 12

    Hodge, M. R. et al. Immunity 4, 397–405 (1996).

    CAS  Article  Google Scholar 

  13. 13

    Northrop, J. P. et al. Nature 369, 497–502 (1994).

    ADS  CAS  Article  Google Scholar 

  14. 14

    Ho, S. N. et al. J. Biol. Chem. 270, 19898–19900 (1995).

    CAS  Article  Google Scholar 

  15. 15

    Hoey, T., Sun, Y.-L., Williamson, K. & Xu, X. Immunity 2, 461–472 (1995).

    CAS  Article  Google Scholar 

  16. 16

    Masuda, E. S., Naito, Y., Tokumitsu, H. et al. Mol. Cell Biol. 15, 2697–2706 (1995).

    CAS  Article  Google Scholar 

  17. 17

    Serafini, A. T., Lewis, R. S., Clipstone, N. A. et al. Immunity 3, 239–250 (1995).

    CAS  Article  Google Scholar 

  18. 18

    Fanger, C. M., Hoth, M., Crabtree, G. R. & Lewis, R. S. J. Cell Biol. 131, 655–667 (1995).

    CAS  Article  Google Scholar 

  19. 19

    Jain, J., Miner, Z. & Rao, A. J. Immunol. 151, 837–848 (1993).

    CAS  PubMed  Google Scholar 

  20. 20

    Ho, S. N., Biggar, S. R., Spencer, D. M., Schreiber, S. L. & Crabtree, G. R. Nature 382, 822–826 (1996).

    ADS  CAS  Article  Google Scholar 

  21. 21

    Emmel, E. A. et al. Science 246, 1617–1620 (1989).

    ADS  CAS  Article  Google Scholar 

  22. 22

    Su, B. et al. Cell 77, 727–736 (1994).

    Article  Google Scholar 

  23. 23

    Turner, C. A. Jr, Mack, D. H. & Davis, M. M. Cell 77, 297–306 (1994).

    CAS  Article  Google Scholar 

  24. 24

    McKnight, S. L. & Yamamoto, K. R. Transcriptional Regulation Vols I and II (Cold Spring Harbor Laboratory Press, New York, 1992).

    Google Scholar 

  25. 25

    Weintraub, H. et al. Science 251, 761–766 (1991).

    ADS  CAS  Article  Google Scholar 

  26. 26

    Courtois, G., Morgan, J. G., Campbell, L. A., Fourel, G. & Crabtree, G. R. Science 238, 688–692 (1987).

    ADS  CAS  Article  Google Scholar 

  27. 27

    Ho, A. M., Jain, J., Rao, A. & Hogan, P. G. J. Biol. Chem. 269, 28181–28186 (1994).

    CAS  PubMed  Google Scholar 

  28. 28

    Sander, B., Hoiden, I., Andersson, U., Moller, E. & Abrams, J. S. J. Immunol. Meth. 166, 201–214 (1993).

    CAS  Article  Google Scholar 

  29. 29

    Melton, D. A. et al. Nucleic Acids Res. 12, 7035–7056 (1984).

    CAS  Article  Google Scholar 

  30. 30

    Fiering, S. et al. Genes Dev. 4, 1823–1834 (1990).

    CAS  Article  Google Scholar 

Download references

Author information



Rights and permissions

Reprints and Permissions

About this article

Cite this article

Timmerman, L., Clipstone, N., Ho, S. et al. Rapid shuttling of NF-AT in discrimination of Ca2+ signals and immunosuppression. Nature 383, 837–840 (1996). https://doi.org/10.1038/383837a0

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing