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Differential activation of transcription factors induced by Ca2+ response amplitude and duration

Nature volume 386, pages 855–858 (1997)Cite this article

Abstract

An increase in the intracellular calcium ion concentration ([Ca2+]i) controls a diverse range of cell functions, including adhesion, motility, gene expression and proliferation1,2. Calcium signalling patterns can occur as single transients, repetitive oscillations or sustained plateaux2,3, but it is not known whether these patterns are responsible for encoding the specificity of cellular responses. We report here that the amplitude and duration of calcium signals in B lymphocytes controls differential activation of the pro–inflammatory transcriptional regulators NF-κB, c-Jun N-terminal kinase (JNK) and NFAT. NF-κB and JNK are selectively activated by a large transient [Ca2+]i rise, whereas NFAT is activated by a low, sustained Ca2+ plateau. Differential activation results from differences in the Ca2+ sensitivities and kinetic behaviour of the three pathways. Our results show how downstream effectors can decode information contained in the amplitude and duration of Ca2+ signals, revealing a mechanism by which a multifunctional second messenger such as Ca2+ can achieve specificity in signalling to the nucleus.

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References

  1. Ghosh, A. & Greenberg, M. E. Calcium signaling in neurons: molecular mechanisms and cellular consequences. Science 268, 239–247 (1995).

    Article  ADS  CAS  Google Scholar 

  2. Berridge, M. J. Inositol trisphosphate and calcium signalling. Nature 361, 315–325 (1993).

    Article  ADS  CAS  Google Scholar 

  3. Clapham, D. E. Calcium signaling. Cell 80, 259–268 (1995).

    Article  CAS  Google Scholar 

  4. Crabtree, G. R. & Clipstone, N. A. Signal transmission between the plasma membrane and nucleus of T lymphocytes. Annu. Rev. Biochem. 63, 1045–1083 (1994).

    Article  CAS  Google Scholar 

  5. Gold, M. R. & DeFranco, A. L. Biochemistry of B lymphocyte activation. Adv. Immunol. 55, 221–295 (1994).

    Article  CAS  Google Scholar 

  6. Fanger, C. M., Hoth, M., Crabtree, G. R. & Lewis, R. S. Characterization of T cell mutants with defects in capacitative calcium entry: genetic evidence for the physiological roles of CRAC channels. J. Cell Biol. 131, 655–667 (1995).

    Article  CAS  Google Scholar 

  7. Bauerle, P. A. & Henkel, T. Function and activation of NF-κB in the immune system. Annu. Rev. Immunol. 12, 141–179 (1994).

    Article  Google Scholar 

  8. Frantz, B. et al. Calcineurin acts in synergy with PMA to inactivate I kappa B/MAD3, an inhibitor of NF-κB. EMBO J. 13, 861–870 (1994).

    Article  CAS  Google Scholar 

  9. Su, B. et al. JNK is involved in signal integration during costimulation of T lymphocytes. Cell 77, 727–736 (1994).

    Article  Google Scholar 

  10. Karin, M. & Hunter, T. Transcriptional control by protein phosphorylation: signal transmission from the cell surface to the nucleus. Curr. .Biol. 5, 747–757 (1995).

    Article  CAS  Google Scholar 

  11. Negulescu, P. A., Shastri, N. & Cahalan, M. D. Intracellular calcium dependence of gene expression in single T lymphocytes. Proc. Natl Acad. Sci. USA 91, 2873–2877 (1994).

    Article  ADS  CAS  Google Scholar 

  12. Timmerman, L. A., Clipstone, N. A., Ho, S. N., Northrop, J. P. & Crabtree, G. R. Rapid shuttling of NF-AT in discrimination of Ca2+ signals and immunosuppression. Nature 383, 837–840 (1996).

    Article  ADS  CAS  Google Scholar 

  13. Shibasaki, F., Price, E. R., Milan, D. & McKeon, F. Role of kinases and the phosphatase calcineurin in the nuclear shuttling of transcription factor NF-AT4. Nature 382, 370–373 (1996).

    Article  ADS  CAS  Google Scholar 

  14. Rao, A. NF-ATp: a transcription factor required for the coordinate induction of several cytokine genes. Immunol. Today 15, 274–281 (1994).

    Article  CAS  Google Scholar 

  15. Goodnow, C. C. et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334, 676–682 (1988).

    Article  ADS  CAS  Google Scholar 

  16. DiDonato, J. A., Mercurio, F. & Karin, M. Phosphorylation of I-κBα precedes but is not sufficient for its dissociation from NF-κB. Mol. Cell. Biol. 15, 1302–1311 (1995).

    Article  CAS  Google Scholar 

  17. Verma, I. M., Stevenson, J. K., Schwarz, E. M., Van Antwerp, D. & Miyamoto, S. Rel/NF-κB/IκB family: intimate tales of association and dissociation. Genes Dev. 9, 2723–2735 (1995).

    Article  CAS  Google Scholar 

  18. Gupta, S., Campbell, D., Dérijard, B. & Davis, R. J. Transcription factor ATF-2 regulation by the JNK signal transduction pathway. Science 267, 389–393 (1995).

    Article  ADS  CAS  Google Scholar 

  19. Healy, J. I. et al. Different nuclear signals are activated by the B cell receptor during positive versus negative signaling. Immunity (in the press).

  20. Flanagan, W. M., Corthésy, B., Bram, R. J. & Crabtree, G. R. Nuclear association of a T-cell transcription factor blocked by FK506 and cyclosporin A. Nature 352, 803–807 (1991).

    Article  ADS  CAS  Google Scholar 

  21. Cambier, J. C., Pleiman, C. M. & Clark, M. R. Signal transduction by the B cell antigen receptor and its coreceptors. Annu. Rev. Immunol. 12, 457–486 (1994).

    Article  CAS  Google Scholar 

  22. Ernst, P. & Smale, S. T. Combinatorial regulation of transcription 1: general aspects of transcriptional control. Immunity 2, 311–319 (1995).

    Article  CAS  Google Scholar 

  23. Gu, X. & Spitzer, N. C. Distinct aspects of neuronal differentiation encoded by frequency of spontaneous Ca2+ transients. Nature 375, 784–787 (1995).

    Article  ADS  CAS  Google Scholar 

  24. Gajewski, T. F., Lancki, D. W., Stack, R. & Fitch, F. W. “Anergy” of THO helper T lymphocytes induces downregulation of TH1 characteristics and a transition to a TH2-like phenotype. J. Exp. Med. 179, 481–491 (1994).

    Article  CAS  Google Scholar 

  25. Gajewski, T. F., Schell, S. R. & Fitch, F. W. Evidence implicating utiilization of different T cell receptor-associated signaling pathways by TH1 and TH2 clones. J. Immunol. 144, 4110–4120 (1990).

    CAS  PubMed  Google Scholar 

  26. Sloan-Lancaster, J., Steinberg, T. H. & Allen, P. M. Selective activation of the calcium signaling pathway by altered peptide ligands. J. Exp. Med. 184, 1525–1530 (1996).

    Article  CAS  Google Scholar 

  27. Wilson, H. A. et al. The B lymphocyte calcium response to anti-Ig is diminished by membrane immunoglobulin cross-linkage to the Fc gamma receptor. J. Immunol. 138, 1712–1718 (1987).

    CAS  PubMed  Google Scholar 

  28. Choquet, D., Partiseti, M., Amigorena, S., Bonnerot, C. & Fridman, W. Cross-linking of IgG receptors inhibits membrane immunoglobulin-stimulated calcium influx in B lymphocytes. J. Biol. Chem. 121, 355–363 (1993).

    CAS  Google Scholar 

  29. Cyster, J. et al. Regulation of B-lymphocyte negative and positive selection by tyrosine phosphatase CD45. Nature 381, 325–328 (1996).

    Article  ADS  CAS  Google Scholar 

  30. Dolmetsch, R. & Lewis, R. S. Signaling between intracellular Ca2+ stores and depletion-activated Ca2+ channels generates [Ca2+]i oscillations in T lymphocytes. J. Gen. Physiol. 103, 365–388 (1994).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Molecular and Cellular Physiology and Neurosciences Program,

    Ricardo E. Dolmetsch & Richard S. Lewis

  2. Program in Immunology, Stanford University School of Medicine, Stanford, California, 94305, USA

    Richard S. Lewis, Christopher C. Goodnow & James I. Healy

  3. Department of Microbiology and Immunology and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, 94305, USA

    Christopher C. Goodnow & James I. Healy

Authors
  1. Ricardo E. Dolmetsch
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  2. Richard S. Lewis
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  3. Christopher C. Goodnow
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  4. James I. Healy
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Dolmetsch, R., Lewis, R., Goodnow, C. et al. Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386, 855–858 (1997). https://doi.org/10.1038/386855a0

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