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Partners in transcription: NFAT and AP-1

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Abstract

Combinatorial regulation is a powerful mechanism that enables tight control of gene expression, via integration of multiple signaling pathways that induce different transcription factors required for enhanceosome assembly. The four calcium-regulated transcription factors of the NFAT family act synergistically with AP-1 (Fos/Jun) proteins on composite DNA elements which contain adjacent NFAT and AP-1 binding sites, where they form highly stable ternary complexes to regulate the expression of diverse inducible genes. Concomitant induction of NFAT and AP-1 requires concerted activation of two different signaling pathways: calcium/calcineurin, which promotes NFAT dephosphorylation, nuclear translocation and activation; and protein kinase C (PKC)/Ras, which promotes the synthesis, phosphorylation and activation of members of the Fos and Jun families of transcription factors. A fifth member of the NFAT family, NFAT5, controls the cellular response to osmotic stress, by a mechanism that requires dimer formation and is independent of calcineurin or of interactionwith AP-1. Pharmacological interference with theNFAT:AP-1 interaction may be useful in selective manipulation of the immune response. Balanced activation of NFAT and AP-1 is known to be required for productive immune responses, but the role of NFAT:AP-1 interactions in other cell types and biological processes remains to be understood.

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Acknowledgements

We thank Lin Chen for Figure 3. This work was supported by NIH grants CA42471 and AI40127 (to A Rao) and by a special fellowship from the Leukemia and Lymphoma Society (to C Lopez-Rodriguez).

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  1. Department of Pathology, Harvard Medical School and the Center for Blood Research, 200 Longwood Avenue, Boston, 02115, Massachusetts, MA, USA

    Fernando Macián, Cristina López-Rodríguez & Anjana Rao

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  1. Fernando Macián
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Macián, F., López-Rodríguez, C. & Rao, A. Partners in transcription: NFAT and AP-1. Oncogene 20, 2476–2489 (2001). https://doi.org/10.1038/sj.onc.1204386

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