Key Points
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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.
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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).
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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.
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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).
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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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References
Shaw, J. P. et al. Identification of a putative regulator of early T cell activation genes. Science 241, 202–205 (1988).
Flanagan, W. M., Corthesy, B., Bram, R. J. & Crabtree, G. R. Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature 352, 803–807 (1991).
Jain, J., McCaffrey, P. G., Valge-Archer, V. E. & Rao, A. Nuclear factor of activated T cells contains Fos and Jun. Nature 356, 801–804 (1992).
Jain, J. et al. The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun. Nature 365, 352–355 (1993).
McCaffrey, P. G. et al. Isolation of the cyclosporin-sensitive T cell transcription factor NFATp. Science 262, 750–754 (1993).
Northrop, J. P. et al. NF-AT components define a family of transcription factors targeted in T-cell activation. Nature 369, 497–502 (1994).
Hoey, T., Sun, Y. L., Williamson, K. & Xu, X. Isolation of two new members of the NF-AT gene family and functional characterization of the NF-AT proteins. Immunity 2, 461–472 (1995).
Liu, J. et al. Calcineurin is a common target of cyclophilin–cyclosporin A and FKBP–FK506 complexes. Cell 66, 807–815 (1991).
Hogan, P. G., Chen, L., Nardone, J. & Rao, A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 17, 2205–2232 (2003).
Macian, F. NFAT proteins: key regulators of T-cell development and function. Nature Rev. Immunol. 5, 472–484 (2005).
Zanoni, I. et al. CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT activation. Nature 460, 264–268 (2009). References 11 and 68 were the first studies to identify a role for Ca2+–NFAT signalling in DCs.
Shukla, U., Hatani, T., Nakashima, K., Ogi, K. & Sada, K. Tyrosine phosphorylation of 3BP2 regulates B cell receptor-mediated activation of NFAT. J. Biol. Chem. 284, 33719–33728 (2009).
Crist, S. A., Sprague, D. L. & Ratliff, T. L. Nuclear factor of activated T cells (NFAT) mediates CD154 expression in megakaryocytes. Blood 111, 3553–3561 (2008).
Negishi-Koga, T. & Takayanagi, H. Ca2+–NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol. Rev. 231, 241–256 (2009).
Winslow, M. M. et al. Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev. Cell 10, 771–782 (2006).
Heit, J. J. et al. Calcineurin/NFAT signalling regulates pancreatic β-cell growth and function. Nature 443, 345–349 (2006).
Horsley, V., Aliprantis, A. O., Polak, L., Glimcher, L. H. & Fuchs, E. NFATc1 balances quiescence and proliferation of skin stem cells. Cell 132, 299–310 (2008).
Robbs, B. K., Cruz, A. L., Werneck, M. B., Mognol, G. P. & Viola, J. P. Dual roles for NFAT transcription factor genes as oncogenes and tumor suppressors. Mol. Cell. Biol. 28, 7168–7181 (2008). This study showed that NFAT1 and NFAT2 can have opposing roles in cancer development.
Mancini, M. & Toker, A. NFAT proteins: emerging roles in cancer progression. Nature Rev. Cancer 9, 810–820 (2009).
Crabtree, G. R. & Schreiber, S. L. SnapShot: Ca2+–calcineurin–NFAT signaling. Cell 138, 210, 210.e1 (2009).
Miyakawa, H., Woo, S. K., Dahl, S. C., Handler, J. S. & Kwon, H. M. Tonicity-responsive enhancer binding protein, a rel-like protein that stimulates transcription in response to hypertonicity. Proc. Natl Acad. Sci. USA 96, 2538–2542 (1999).
Lopez-Rodriguez, C., Aramburu, J., Rakeman, A. S. & Rao, A. NFAT5, a constitutively nuclear NFAT protein that does not cooperate with Fos and Jun. Proc. Natl Acad. Sci. USA 96, 7214–7219 (1999).
Lopez-Rodriguez, C. et al. Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression. Proc. Natl Acad. Sci. USA 101, 2392–2397 (2004).
Lopez-Rodriguez, C. et al. Bridging the NFAT and NF-κB families: NFAT5 dimerization regulates cytokine gene transcription in response to osmotic stress. Immunity 15, 47–58 (2001).
Hogan, P. G., Lewis, R. & Rao, A. Molecular basis of calcium signalling in lymphocytes: STIM and ORAI. Annu. Rev. Immunol. 28, 491–533 (2010).
Feske, S. Calcium signalling in lymphocyte activation and disease. Nature Rev. Immunol. 7, 690–702 (2007).
Aramburu, J. et al. Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A. Science 285, 2129–2133 (1999).
Li, H., Rao, A. & Hogan, P. G. Interaction of calcineurin with substrates and targeting proteins. Trends Cell Biol. (in the press).
Müller, M. R. et al. Requirement for balanced Ca/NFAT signaling in hematopoietic and embryonic development. Proc. Natl Acad. Sci. USA 106, 7034–7039 (2009).
Arron, J. R. et al. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441, 595–600 (2006).
Gwack, Y. et al. A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT. Nature 441, 646–650 (2006). References 30 and 31 identified DYRKs as kinases of NFAT.
Beals, C. R., Sheridan, C. M., Turck, C. W., Gardner, P. & Crabtree, G. R. Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science 275, 1930–1934 (1997).
Okamura, H. et al. A conserved docking motif for CK1 binding controls the nuclear localization of NFAT1. Mol. Cell. Biol. 24, 4184–4195 (2004).
Zhou, B. et al. Regulation of the murine Nfatc1 gene by NFATc2. J. Biol. Chem. 277, 10704–10711 (2002).
Chuvpilo, S. et al. Autoregulation of NFATc1/A expression facilitates effector T cells to escape from rapid apoptosis. Immunity 16, 881–895 (2002).
Huang, G. N. et al. NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins. Science 319, 476–481 (2008). This study shows that cytoplasmic scaffolding proteins contribute to the regulation of NFAT activity.
Willingham, A. T. et al. A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science 309, 1570–1573 (2005). This paper describes the identification of a non-coding RNA repressor of NFAT.
Wu, W. et al. Proteolytic regulation of nuclear factor of activated T (NFAT) c2 cells and NFAT activity by caspase-3. J. Biol. Chem. 281, 10682–10690 (2006).
Yoeli-Lerner, M. et al. Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Mol. Cell 20, 539–550 (2005).
Yoeli-Lerner, M., Chin, Y. R., Hansen, C. K. & Toker, A. Akt/protein kinase b and glycogen synthase kinase-3β signaling pathway regulates cell migration through the NFAT1 transcription factor. Mol. Cancer Res. 7, 425–432 (2009).
Terui, Y., Saad, N., Jia, S., McKeon, F. & Yuan, J. Dual role of sumoylation in the nuclear localization and transcriptional activation of NFAT1. J. Biol. Chem. 279, 28257–28265 (2004).
Nayak, A. et al. Sumoylation of the transcription factor NFATc1 leads to its subnuclear relocalization and interleukin-2 repression by histone deacetylase. J. Biol. Chem. 284, 10935–10946 (2009).
Olabisi, O. A. et al. Regulation of transcription factor NFAT by ADP-ribosylation. Mol. Cell. Biol. 28, 2860–2871 (2008).
Valdor, R. et al. Regulation of NFAT by poly(ADP-ribose) polymerase activity in T cells. Mol. Immunol. 45, 1863–1871 (2008).
Sun, Z. et al. Requirement for RORγ in thymocyte survival and lymphoid organ development. Science 288, 2369–2373 (2000).
Shen, F., Hu, Z., Goswami, J. & Gaffen, S. L. Identification of common transcriptional regulatory elements in interleukin-17 target genes. J. Biol. Chem. 281, 24138–24148 (2006).
Gomez-Rodriguez, J. et al. Differential expression of interleukin-17A and -17F is coupled to T cell receptor signaling via inducible T cell kinase. Immunity 31, 587–597 (2009).
Ghosh, S. et al. Hyperactivation of nuclear factor of activated T cells (NFAT1) in T cells attenuates severity of murine autoimmune encephalitis. Proc. Natl Acad. Sci. USA (in the press).
Bauquet, A. T. et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nature Immunol. 10, 167–175 (2009).
Ho, I. C., Hodge, M. R., Rooney, J. W. & Glimcher, L. H. The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4. Cell 85, 973–983 (1996).
Fehr, T. et al. A CD8 T cell-intrinsic role for the calcineurin–NFAT pathway for tolerance induction in vivo. Blood 115, 1280–1287 (2010).
Baine, I., Abe, B. T. & Macian, F. Regulation of T-cell tolerance by calcium/NFAT signaling. Immunol. Rev. 231, 225–240 (2009).
Macian, F. et al. Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109, 719–731 (2002).
Heissmeyer, V. et al. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nature Immunol. 5, 255–265 (2004).
Puga, I., Rao, A. & Macian, F. Targeted cleavage of signaling proteins by caspase 3 inhibits T cell receptor signaling in anergic T cells. Immunity 29, 193–204 (2008).
Hsiao, H. W. et al. Deltex1 is a target of the transcription factor NFAT that promotes T cell anergy. Immunity 31, 72–83 (2009).
Nurieva, R. I. et al. The E3 ubiquitin ligase GRAIL regulates T cell tolerance and regulatory T cell function by mediating T cell receptor-CD3 degradation. Immunity 32, 670–680 (2010).
Soto-Nieves, N. et al. Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance. J. Exp. Med. 206, 867–876 (2009).
Josefowicz, S. Z. & Rudensky, A. Control of regulatory T cell lineage commitment and maintenance. Immunity 30, 616–625 (2009).
Lal, G. et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J. Immunol. 182, 259–273 (2009).
Tone, Y. et al. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nature Immunol. 9, 194–202 (2008).
Zheng, Y. et al. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463, 808–812 (2010). References 61 and 62 show that NFAT contributes to the regulation of FOXP3 expression in iT Reg cells by binding to regulatory elements in the Foxp3 gene.
Huehn, J., Polansky, J. K. & Hamann, A. Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage? Nature Rev. Immunol. 9, 83–89 (2009).
Bopp, T. et al. NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+ CD25+ regulatory T cells. J. Exp. Med. 201, 181–187 (2005).
Wu, Y. et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375–387 (2006). This paper identified NFAT as a transcriptional partner of FOXP3 in T Reg cells and showed that it controls the expression of IL-2, CD25 and CTLA4.
Hu, H., Djuretic, I., Sundrud, M. S. & Rao, A. Transcriptional partners in regulatory T cells: Foxp3, Runx and NFAT. Trends Immunol. 28, 329–332 (2007).
Sumpter, T. L., Payne, K. K. & Wilkes, D. S. Regulation of the NFAT pathway discriminates CD4+CD25+ regulatory T cells from CD4+CD25− helper T cells. J. Leukoc. Biol. 83, 708–717 (2008).
Goodridge, H. S., Simmons, R. M. & Underhill, D. M. Dectin-1 stimulation by Candida albicans yeast or zymosan triggers NFAT activation in macrophages and dendritic cells. J. Immunol. 178, 3107–3115 (2007).
Grunig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 (1998).
Monticelli, S., Solymar, D. C. & Rao, A. Role of NFAT proteins in IL13 gene transcription in mast cells. J. Biol. Chem. 279, 36210–36218 (2004).
Klein, M. et al. Specific and redundant roles for NFAT transcription factors in the expression of mast cell-derived cytokines. J. Immunol. 177, 6667–6674 (2006).
Walczak-Drzewiecka, A., Ratajewski, M., Wagner, W. & Dastych, J. HIF-1α is up-regulated in activated mast cells by a process that involves calcineurin and NFAT. J. Immunol. 181, 1665–1672 (2008).
Ulleras, E. et al. NFAT but not NF-κB is critical for transcriptional induction of the prosurvival gene A1 after IgE receptor activation in mast cells. Blood 111, 3081–3089 (2008).
Hardy, R. R. B-1 B cell development. J. Immunol. 177, 2749–2754 (2006).
Berland, R. & Wortis, H. H. Normal B-1a cell development requires B cell-intrinsic NFATc1 activity. Proc. Natl Acad. Sci. USA 100, 13459–13464 (2003). This study demonstrated that NFAT2 is required for the development of B-1a cells.
Winslow, M. M., Gallo, E. M., Neilson, J. R. & Crabtree, G. R. The calcineurin phosphatase complex modulates immunogenic B cell responses. Immunity 24, 141–152 (2006).
Haylett, R. S., Koch, N. & Rink, L. MHC class II molecules activate NFAT and the ERK group of MAPK through distinct signaling pathways in B cells. Eur. J. Immunol. 39, 1947–1955 (2009).
de Gorter, D. J., Vos, J. C., Pals, S. T. & Spaargaren, M. The B cell antigen receptor controls AP-1 and NFAT activity through Ras-mediated activation of Ral. J. Immunol. 178, 1405–1414 (2007).
Bendelac, A., Savage, P. B. & Teyton, L. The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336 (2007).
Lazarevic, V. et al. The gene encoding early growth response 2, a target of the transcription factor NFAT, is required for the development and maturation of natural killer T cells. Nature Immunol. 10, 306–313 (2009).
Ferroni, P., Santilli, F., Guadagni, F., Basili, S. & Davi, G. Contribution of platelet-derived CD40 ligand to inflammation, thrombosis and neoangiogenesis. Curr. Med. Chem. 14, 2170–2180 (2007).
Gallo, E. M., Ho, L., Winslow, M. M., Staton, T. L. & Crabtree, G. R. Selective role of calcineurin in haematopoiesis and lymphopoiesis. EMBO Rep. 9, 1141–1148 (2008).
Kiani, A. et al. Expression analysis of nuclear factor of activated T cells (NFAT) during myeloid differentiation of CD34+ cells: regulation of Fas ligand gene expression in megakaryocytes. Exp. Hematol. 35, 757–770 (2007).
Baksh, S. et al. NFATc2-mediated repression of cyclin-dependent kinase 4 expression. Mol. Cell 10, 1071–1081 (2002).
Carvalho, L. D. et al. The NFAT1 transcription factor is a repressor of cyclin A2 gene expression. Cell Cycle 6, 1789–1795 (2007).
Ranger, A. M., Oukka, M., Rengarajan, J. & Glimcher, L. H. Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development. Immunity 9, 627–635 (1998).
Kondo, E. et al. NF-ATc2 induces apoptosis in Burkitt's lymphoma cells through signaling via the B cell antigen receptor. Eur. J. Immunol. 33, 1–11 (2003).
Neal, J. W. & Clipstone, N. A. A constitutively active NFATc1 mutant induces a transformed phenotype in 3T3-L1 fibroblasts. J. Biol. Chem. 278, 17246–17254 (2003).
Mani, S. A. et al. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).
Jauliac, S. et al. The role of NFAT transcription factors in integrin-mediated carcinoma invasion. Nature Cell Biol. 4, 540–544 (2002).
Chen, M. & O'Connor, K. L. Integrin α6β4 promotes expression of autotaxin/ENPP2 autocrine motility factor in breast carcinoma cells. Oncogene 24, 5125–5130 (2005).
Liu, S. et al. Expression of autotaxin and lysophosphatidic acid receptors increases mammary tumorigenesis, invasion, and metastases. Cancer Cell 15, 539–550 (2009).
Yiu, G. K. & Toker, A. NFAT induces breast cancer cell invasion by promoting the induction of cyclooxygenase-2. J. Biol. Chem. 281, 12210–12217 (2006).
Zhang, H. et al. Dual activity lysophosphatidic acid receptor pan-antagonist/autotaxin inhibitor reduces breast cancer cell migration in vitro and causes tumor regression in vivo. Cancer Res. 69, 5441–5449 (2009).
Graef, I. A., Chen, F., Chen, L., Kuo, A. & Crabtree, G. R. Signals transduced by Ca2+/calcineurin and NFATc3/c4 pattern the developing vasculature. Cell 105, 863–875 (2001).
Nagy, J. A., Dvorak, A. M. & Dvorak, H. F. VEGF-A and the induction of pathological angiogenesis. Annu. Rev. Pathol. 2, 251–275 (2007).
Dvorak, H. F. Discovery of vascular permeability factor (VPF). Exp. Cell Res. 312, 522–526 (2006).
Jinnin, M. et al. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nature Med. 14, 1236–1246 (2008).
Hernandez, G. L. et al. Selective inhibition of vascular endothelial growth factor-mediated angiogenesis by cyclosporin A: roles of the nuclear factor of activated T cells and cyclooxygenase 2. J. Exp. Med. 193, 607–620 (2001).
Baek, K. H. et al. Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature 459, 1126–1130 (2009).
Qin, L. et al. Down syndrome candidate region 1 isoform 1 mediates angiogenesis through the calcineurin-NFAT pathway. Mol. Cancer Res. 4, 811–820 (2006).
Kulkarni, R. M., Greenberg, J. M. & Akeson, A. L. NFATc1 regulates lymphatic endothelial development. Mech. Dev. 126, 350–365 (2009).
Norrmen, C. et al. FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1. J. Cell Biol. 185, 439–457 (2009).
Marafioti, T. et al. The NFATc1 transcription factor is widely expressed in white cells and translocates from the cytoplasm to the nucleus in a subset of human lymphomas. Br. J. Haematol. 128, 333–342 (2005).
Akimzhanov, A. et al. Epigenetic changes and suppression of the nuclear factor of activated T cell 1 (NFATC1) promoter in human lymphomas with defects in immunoreceptor signaling. Am. J. Pathol. 172, 215–224 (2008). References 104 and 105 provide a systematic analysis of NFAT deregulation in different human lymphomas.
Glud, S. Z. et al. A tumor-suppressor function for NFATc3 in T-cell lymphomagenesis by murine leukemia virus. Blood 106, 3546–3552 (2005). This is the first paper to show that NFAT can function as a tumour suppressor.
Pham, L. V., Tamayo, A. T., Yoshimura, L. C., Lin-Lee, Y. C. & Ford, R. J. Constitutive NF-κB and NFAT activation in aggressive B-cell lymphomas synergistically activates the CD154 gene and maintains lymphoma cell survival. Blood 106, 3940–3947 (2005).
Fu, L. et al. Constitutive NF-kB and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas. Blood 107, 4540–4548 (2006).
Medyouf, H. et al. Targeting calcineurin activation as a therapeutic strategy for T-cell acute lymphoblastic leukemia. Nature Med. 13, 736–741 (2007). This study showed that calcineurin can be a target for the treatment of haematological malignancies.
Gregory, M. A. et al. Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl. Cancer Cell 18, 74–87 (2010). This paper shows that activation of the Ca2+–NFAT-signalling pathway has an important role in the development of resistance to tyrosine kinase inhibitors.
Buchholz, M. et al. Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+/calcineurin signaling pathway. EMBO J. 25, 3714–3724 (2006).
Koenig, A. et al. NFAT-induced histone acetylation relay switch promotes c-Myc-dependent growth in pancreatic cancer cells. Gastroenterology 138, 1189–1199 (2010). References 111 and 112 were the first to show that Ca2+–NFAT-signalling contributes to the pathogenesis of pancreatic cancer.
Lehen'kyi, V., Flourakis, M., Skryma, R. & Prevarskaya, N. TRPV6 channel controls prostate cancer cell proliferation via Ca2+/NFAT-dependent pathways. Oncogene 26, 7380–7385 (2007).
Flockhart, R. J., Armstrong, J. L., Reynolds, N. J. & Lovat, P. E. NFAT signalling is a novel target of oncogenic BRAF in metastatic melanoma. Br. J. Cancer 101, 1448–1455 (2009).
Sales, K. J. et al. Prostaglandin F(2α)-F-prostanoid receptor regulates CXCL8 expression in endometrial adenocarcinoma cells via the calcium–calcineurin–NFAT pathway. Biochim. Biophys. Acta 1793, 1917–1928 (2009).
Sales, K. J. et al. Interleukin-11 in endometrial adenocarcinoma is regulated by prostaglandin F2α-F-prostanoid receptor interaction via the calcium–calcineurin–nuclear factor of activated T cells pathway and negatively regulated by the regulator of calcineurin-1. Am. J. Pathol. 176, 435–445 (2010).
Muller, M. R. & Rao, A. Linking calcineurin activity to leukemogenesis. Nature Med. 13, 669–671 (2007).
Noguchi, H. et al. A new cell-permeable peptide allows successful allogeneic islet transplantation in mice. Nature Med. 10, 305–309 (2004).
Roehrl, M. H. et al. Selective inhibition of calcineurin–NFAT signaling by blocking protein–protein interaction with small organic molecules. Proc. Natl Acad. Sci. USA 101, 7554–7559 (2004).
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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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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DOI: https://doi.org/10.1038/nri2818
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