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  • Review Article
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NFAT, immunity and cancer: a transcription factor comes of age

Nature Reviews Immunology volume 10, pages 645–656 (2010)Cite this article

Subjects

Key Points

  • Nuclear factor of activated T cells (NFAT) transcription factors are activated by cell surface receptors that are coupled to Ca2+ mobilization, which induce the activation of calmodulin and calcineurin. Calcineurin dephosphorylates multiple phosphoserines in the regulatory domain, leading to the nuclear translocation of NFAT. In the nucleus, NFAT cooperates with multiple transcriptional partners to initiate and maintain specific gene expression programmes, which vary with cell type and stimulation conditions.

  • The activity of NFAT transcription factors is regulated by a complex network that includes stromal interaction molecule (STIM)–ORAI signalling pathways, regulators of Ca2+ homeostasis, calcineurin, calcineurin regulators, NFAT kinases and post-translational modifications (including sumoylation, ubiquitylation and ADP-ribosylation).

  • NFAT transcription factors are of primary importance during T cell activation and differentiation. Recent studies have revealed that they also have an important role in other immune cell types, including dendritic cells, mast cells, B cells, natural killer T (NKT) cells and megakaryocytes. NFAT proteins are also involved in various developmental programmes, including those of the heart, skeletal muscle, smooth muscle, vasculature, neurons, bone, pancreas and skin.

  • The last few years have provided important new insights into the role of NFAT proteins in T cell tolerance. NFAT proteins are of key importance for the induction of anergy-inducing genes such as gene related to anergy in lymphocytes (GRAIL), itchy homolog E3 ubiquitin protein ligase (ITCH), Casitas B-lineage lymphoma B (CBL-B), caspase 3, deltex and numerous others. NFAT proteins also regulate forkhead box P3 (FOXP3) expression in induced regulatory T cells, and have been shown to cooperate with FOXP3 to regulate the expression of interleukin-2 (IL-2), CD25 and cytotoxic T lymphocyte antigen 4 (CTLA4).

  • NFAT transcription factors control tumour cell proliferation and homeostasis by modulating the expression of cyclin-dependent kinase 4 (CDK4) and cyclin A2, and by regulating apoptosis. They also have an important role in regulating tumour cell migration and angiogenesis. Dysregulation of the Ca2+–NFAT signalling pathway has been reported in many different types of cancer, including haematological malignancies, breast cancer and pancreatic adenocarcinomas.

Abstract

Nuclear factor of activated T cells (NFAT) was first identified more than two decades ago as a major stimulation-responsive DNA-binding factor and transcriptional regulator in T cells. It is now clear that NFAT proteins have important functions in other cells of the immune system and regulate numerous developmental programmes in vertebrates. Dysregulation of these programmes can lead to malignant growth and cancer. This Review focuses on recent advances in our understanding of the transcriptional functions of NFAT proteins in the immune system and provides new insights into their potential roles in cancer development.

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Figure 1: The Ca2+–NFAT signalling pathway.
Figure 2: NFAT and T cell anergy.
Figure 3: The role of NFAT in regulatory T cells.
Figure 4: The multiple roles of NFAT in the pathogenesis of cancer.

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Acknowledgements

This work was supported by grants from the Deutsche Krebshilfe, the Cancer Research Institute and the Fortüne program of the University of Tübingen to M.R.M, and grants from the National Institutes of Health and the Juvenile Diabetes Research Foundation to A.R.

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Authors and Affiliations

  1. Department of Haematology, Oncology and Immunology, University of Tübingen, Medizinische Klinik und Poliklinik, Otfried-Müller-Strasse 10, 72076, Tübingen, Germany

    Martin R. Müller

  2. Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, 02115, Massachusetts, USA

    Anjana Rao

  3. Program in Cellular and Molecular Medicine, Children's Hospital Boston, Immune Disease Institute, 200 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Anjana Rao

  4. La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, 92037, California, USA

    Anjana Rao

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Correspondence to Martin R. Müller.

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Competing interests

Anjana Rao is a founder and scientific advisor of CalciMedia, a company with an interest in developing small-molecule inhibitors of the STIM–ORAI–calcineurin–NFAT pathway to treat immune disorders and cancer.

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Glossary

Ubiquitylation

The attachment of the small protein ubiquitin to lysine residues that are present in other proteins; this often tags these proteins for rapid cellular degradation.

Sumoylation

The post-translational modification of proteins that involves the covalent attachment of small ubiquitin-related modifier (SUMO) and regulates the interactions of those proteins with other macromolecules.

Anergy

A state of unresponsiveness that is sometimes observed in T and B cells that are chronically stimulated or that are stimulated through the antigen receptor in the absence of co-stimulatory signals.

IPEX syndrome

A disease caused by mutations in forkhead box P3 (FOXP3). It is characterized by refractory enteritis and in some patients autoimmune endocrinopathies, autoimmune diabetes and thyroiditis. Unlike scurfy mice, peripheral-blood mononuclear cells from IPEX patients fail to produce cytokines after in vitro stimulation.

Small interfering RNA

(siRNA). Double-stranded RNAs (dsRNAs) with sequences that precisely match a given gene and that are able to 'knock down' the expression of that gene by directing RNA-degrading enzymes to destroy the encoded mRNA transcript. The two most common forms of dsRNAs used for gene silencing are short — usually 21 nucleotides long — siRNAs or the plasmid-delivered short hairpin RNAs (shRNAs).

T cell-independent type 2 antigens

Antigens that directly activate B cells. These antigens often contain multiple identical epitopes, which can crosslink B cell receptors.

Natural serum IgM

Antibodies that normally circulate in the blood of non-immunized mice. They are highly crossreactive and bind with low affinity to both microbial and self-antigens. A large proportion of natural IgM is derived from peritoneal B-1 cells.

Epithelial-to-mesenchymal transition

(EMT). A cell developmental programme that is characterized by decreased expression of E cadherin, loss of cell adhesion and increased cell motility.

Metastasize

To spread from one part of the body to another.

Angiogenesis

The development of new blood vessels from existing blood vessels. It is frequently associated with tumour development and inflammation.

Tyrosine kinase inhibitors

Drugs that specifically inhibit tyrosine kinases, which are important for cancer development and progression.

Oncogene

A gene that when overexpressed or when incorporating a gain-of-function mutation contributes to oncogenesis.

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Müller, M., Rao, A. NFAT, immunity and cancer: a transcription factor comes of age. Nat Rev Immunol 10, 645–656 (2010). https://doi.org/10.1038/nri2818

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