Key Event Overview
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AOPs Including This Key Event
|AOP Name||Event Type||Essentiality|
|The Adverse Outcome Pathway on binding of FK506-binding protein 12 (FKBP12) by calcineurin inhibitors leading to immunosuppression||KE||Strong|
Level of Biological Organization
How this Key Event works
Activated NFAT that has localized to the nucleus binds cooperatively at the site of the Interleukin-2 (IL-2) promoter with activator protein AP-1, which is a heterodimer comprising a Fos and a Jun protein (Schreiber and Crabtree 1992, Jain et al. 1992), thereby inducing transcription of IL-2 (Jain et al. 1993). FK506, by interfering with NFAT nuclear localization, hinders the formation of the functional NFAT complexes necessary to binding at the site of IL-2 promoters (Flanagan et al. 1991). NFAT also binds at the site of IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF) promoters (Foletta et al. 1998). Additionally, NFAT binds cooperatively at the site of IL-2, IL-4, and TNF promoters as well as at the site of IL-3 and IL-4 enhancers with avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF), early growth response 1 (EGR1), early growth response 4 (EGR4), interferon-regulatory factor 4 (IRF4), octamer-binding transcription factor (OCT), and other transcriptional partners to induce transcription of a variety of cytokines (Macian 2005).
How it is Measured or Detected
Inhibition of generation of NFAT/AP-1 complex can be detected by gel shift assay. Jain et al. (1992) conducted that nuclear extracts from unstimulated or stimulated Ar-5 T cells were applied to the gel shift assays with radio-labelled murine NFAT oligonucleotide. Suppression of mRNA levels of cytokines can be measured by RNase protection assay in vitro and ex vivo.
Evidence Supporting Taxonomic Applicability
FK506-induced interference with NFAT/AP-1 complex formation at the promoter site of the IL-2 gene might be in common among mammalian T cells including humans and rodents. Synthesis of IL-3, IL-4, IL-5 and GM-CSF by T cells might also be inhibited with FK506 by similar mechanisms as those of IL-2.
 Schreiber, SL., and Crabtree, GR. (1992). The mechanism of action of cyclosporin A and FK506. Immunology Today 13(4): 136-42.
 Jain, J., McCaffrey, P. G., Valge-Archer, V. E. and Rao, A. (1992). Nuclear factor of activated T cells contains Fos and Jun. Nature. 356(6372): 801-804.
 Jain, J., Miner, Z. and Rao, A. (1993). Analysis of the preexisting and nuclear forms of nuclear factor of activated T cells. Journal of immunology. 151(2): 837-848.
 Flanagan, W.M., Corthésy, B., Bram, R.J. and Crabtree, G.R. (1991). Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature 352 (6338): 803-7.
 Foletta, V.C., Segal, D.H. and Cohen, D.R. (1998). Transcriptional regulation in the immune system: all roads lead to AP-1. Journal of leukocyte biology 63 (2): 139-52.
 Macian, F. (2005). NFAT proteins: key regulators of T-cell development and function. Nature reviews. Immunology. 5(6): 472-84.
 Rao, A., Luo, C., and Hogan, PG. (1997). Transcription factors of the NFAT family: regulation and function. Annual Review of Immunology 15: 707-47.
 Bhattacharyya, S., Deb, J., Patra, A.K., Thuy Pham, D.A., Chen, W., Vaeth, M., Berberich-Siebelt, F., Klein-Hessling, S., Lamperti, E.D., Reifenberg, K., Jellusova, J., Schweizer, A., Nitschke, L., Leich, E., Rosenwald, A., Brunner, C., Engelmann, S., Bommhardt, U., Avots, A., Müller, M.R., Kondo, E. and Serfling, E. (2011). NFATc1 affects mouse splenic B cell function by controlling the calcineurin-NFAT signaling network. The Journal of experimental medicine 208 (4): 823-39.