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

Nature. 1996 Oct 31;383(6603):837-40. doi: 10.1038/383837a0.


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 factors. 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-kappaB, 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.

MeSH terms

  • Animals
  • Biological Transport
  • Calcineurin
  • Calcium / metabolism*
  • Calmodulin-Binding Proteins / metabolism
  • Cell Line
  • Cell Nucleus / metabolism
  • Cyclosporine / pharmacology*
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • Interleukin-2 / genetics
  • Jurkat Cells
  • Lymphocyte Activation
  • Mice
  • NFATC Transcription Factors
  • Nuclear Proteins*
  • Phosphoprotein Phosphatases / metabolism
  • Signal Transduction*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Tacrolimus / pharmacology*
  • Transcription Factors / metabolism*
  • Transfection


  • Calmodulin-Binding Proteins
  • DNA-Binding Proteins
  • Immunosuppressive Agents
  • Interleukin-2
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Transcription Factors
  • Cyclosporine
  • Calcineurin
  • Phosphoprotein Phosphatases
  • Calcium
  • Tacrolimus