Event:979

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Event Title

Interference of NFAT complex formation at the site of nuclear cytokine promoters, Inhibition

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

Taxonomic Applicability

Name Scientific Name Evidence Links

Level of Biological Organization

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

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?

Evidence Supporting Taxonomic Applicability

References