{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:03:10Z","timestamp":1791558190915,"version":"4.3.4"},"reference-count":95,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T00:00:00Z","timestamp":1615161600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24590107"],"award-info":[{"award-number":["24590107"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21590086"],"award-info":[{"award-number":["21590086"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008670","name":"Terumo Foundation for Life Sciences and Arts","doi-asserted-by":"publisher","award":["-"],"award-info":[{"award-number":["-"]}],"id":[{"id":"10.13039\/501100008670","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nuclear factor of activated T cells (NFAT), which is the pharmacological target of immunosuppressants cyclosporine and tacrolimus, has been shown to play an important role not only in T cells (immune system), from which their name is derived, but also in many biological events. Therefore, functional and\/or structural abnormalities of NFAT are linked to the pathogenesis of diseases in various organs. The NFAT protein family consists of five isoforms, and each isoform performs diverse functions and has unique expression patterns in the target tissues. This diversity has made it difficult to obtain ideal pharmacological output for immunosuppressants that inhibit the activity of almost all NFAT family members, causing serious and wide-ranging side effects. Moreover, it remains unclear whether isoform-selective NFAT regulation can be achieved by targeting the structural differences among NFAT isoforms and whether this strategy can lead to the development of better drugs than the existing ones. This review summarizes the role of the NFAT family members in biological events, including the development of various diseases, as well as the usefulness of and problems associated with NFAT-targeting therapies, including those dependent on current immunosuppressants. Finally, we propose a novel therapeutic strategy based on the molecular mechanisms that enable selective regulation of specific NFAT isoforms.<\/jats:p>","DOI":"10.3390\/ijms22052725","type":"journal-article","created":{"date-parts":[[2021,3,8]],"date-time":"2021-03-08T12:12:18Z","timestamp":1615205538000},"page":"2725","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Isoform-Selective NFAT Inhibitor: Potential Usefulness and Development"],"prefix":"10.3390","volume":"22","author":[{"given":"Noriko","family":"Kitamura","sequence":"first","affiliation":[{"name":"Laboratory of Allergy and Immunology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1211-0410","authenticated-orcid":false,"given":"Osamu","family":"Kaminuma","sequence":"additional","affiliation":[{"name":"Laboratory of Allergy and Immunology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan"},{"name":"Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1126\/science.3260404","article-title":"Identification of putative regulator of ealry T cell activation genes","volume":"241","author":"Shaw","year":"1988","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3747","DOI":"10.1016\/S0021-9258(18)53757-1","article-title":"NF-ATp, a T lymphocyte DNA-binding protein that is a target for calcineurin and immunosuppressive drugs","volume":"268","author":"McCaffrey","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1128\/MCB.19.3.2300","article-title":"Requirement for transcription factor NFAT in interleukin-2 expression","volume":"19","author":"Chow","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0167-4889(00)00082-3","article-title":"The role of NF-AT transcription factors in T cell activation and differentiation","volume":"1498","author":"Serfling","year":"2000","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/32426","article-title":"The transcription factor NF-ATc is essential for cardiac valve formation","volume":"392","author":"Ranger","year":"1998","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2818","DOI":"10.1074\/jbc.M408741200","article-title":"The transcription factor NFAT3 mediates neuronal survival","volume":"280","author":"Benedito","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1002\/jcb.20675","article-title":"Calcium\/calmodulin signaling controls osteoblast growth and differentiation","volume":"97","author":"Zayzafoon","year":"2006","journal-title":"J. Cell. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1074\/jbc.RA118.002896","article-title":"NFAT5 up-regulates expression of the kidney-specific ubiquitin ligase gene Rnf183 under hypertonic conditions in inner-medullary collecting duct cells","volume":"294","author":"Maeoka","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S0003-9861(03)00130-9","article-title":"The role of NFAT5\/TonEBP in establishing an optimal intracellular environment","volume":"413","author":"Ho","year":"2003","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1101\/gad.1102703","article-title":"Transcriptional regulation by calcium, calcineurin, and NFAT","volume":"17","author":"Hogan","year":"2003","journal-title":"Genes Dev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1016-8478(23)13074-3","article-title":"Activation and deactivation of gene expression by Ca2+\/calcineurin-NFAT-mediated signaling","volume":"18","author":"Im","year":"2004","journal-title":"Mol. Cells"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1146\/annurev.immunol.15.1.707","article-title":"Transcription factors of the NFAT family: Regulation and function","volume":"15","author":"Rao","year":"1997","journal-title":"Annu. Rev. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S1097-2765(00)00053-8","article-title":"Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity","volume":"6","author":"Okamura","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2476","DOI":"10.1038\/sj.onc.1204386","article-title":"Partners in transcription: NFAT and AP-1","volume":"20","author":"Macian","year":"2001","journal-title":"Oncogene"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1128\/MCB.17.5.2475","article-title":"Expression of NFAT-family proteins in normal human T cells","volume":"17","author":"Lyakh","year":"1997","journal-title":"Mol. Cell. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2697","DOI":"10.1128\/MCB.15.5.2697","article-title":"NFATx, a novel member of the nuclear factor of activated T cells family that is expressed predominantly in the thymus","volume":"15","author":"Masuda","year":"1995","journal-title":"Mol. Cell. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/32419","article-title":"Role of the NF-ATc transcription factor in morphogenesis of cardiac valves and septum","volume":"392","author":"Timmerman","year":"1998","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/S0092-8674(01)00396-8","article-title":"Signals transduced by Ca2+\/calcineurin and NFATc3\/c4 pattern the developing vasculature","volume":"105","author":"Graef","year":"2001","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Mak, M.C., Lam, K.M., Chan, P.K., Lau, Y.B., Tang, W.H., Yeung, P.K., Ko, B.C., Chung, S.M., and Chung, S.K. (2011). Embryonic lethality in mice lacking the nuclear factor of activated T cells 5 protein due to impaired cardiac development and function. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0019186"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1073\/pnas.0308703100","article-title":"Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression","volume":"101","author":"Antos","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1126\/science.272.5263.892","article-title":"An enhanced immune response in mice lacking the transcription factor NFAT1","volume":"272","author":"Xanthoudakis","year":"1996","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/S1074-7613(00)80253-8","article-title":"Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice","volume":"4","author":"Hodge","year":"1996","journal-title":"Immunity"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"E1499","DOI":"10.1073\/pnas.1202068109","article-title":"Nuclear factor of activated T cells (NFATc4) is required for BDNF-dependent survival of adult-born neurons and spatial memory formation in the hippocampus","volume":"109","author":"Quadrato","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0092-8674(00)81573-1","article-title":"A calcineurin-dependent transcriptional pathway for cardiac hypertrophy","volume":"93","author":"Molkentin","year":"1998","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1016\/S1097-2765(02)00701-3","article-title":"NFATc2-mediated repression of cyclin-dependent kinase 4 expression","volume":"10","author":"Baksh","year":"2002","journal-title":"Mol. Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1096\/fj.02-0282fje","article-title":"NFATC2 transcription factor regulates cell cycle progression during lymphocyte activation: Evidence of its involvement in the control of cyclin gene expression","volume":"16","author":"Caetano","year":"2002","journal-title":"FASEB J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.4161\/cc.11.5.19518","article-title":"Transcriptional regulation of the c-Myc promoter by NFAT1 involves negative and positive NFAT-responsive elements","volume":"11","author":"Mognol","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/S1534-5807(02)00369-6","article-title":"Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts","volume":"3","author":"Takayanagi","year":"2002","journal-title":"Dev. Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1002\/jbmr.3689","article-title":"Cooperation of PU.1 With IRF8 and NFATc1 Defines Chromatin Landscapes During RANKL-Induced Osteoclastogenesis","volume":"34","author":"Izawa","year":"2019","journal-title":"J. Bone Miner. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17246","DOI":"10.1074\/jbc.M300528200","article-title":"A constitutively active NFATc1 mutant induces a transformed phenotype in 3T3-L1 fibroblasts","volume":"278","author":"Neal","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3714","DOI":"10.1038\/sj.emboj.7601246","article-title":"Overexpression of c-myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+\/calcineurin signaling pathway","volume":"25","author":"Buchholz","year":"2006","journal-title":"EMBO J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"29044","DOI":"10.1074\/jbc.M114.555235","article-title":"Genome-wide approaches reveal functional vascular endothelial growth factor (VEGF)-inducible nuclear factor of activated T cells (NFAT) c1 binding to angiogenesis-related genes in the endothelium","volume":"289","author":"Suehiro","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.yexcr.2014.03.008","article-title":"NFAT2 regulates COX-2 expression and modulates the integrin repertoire in endothelial cells at the crossroads of angiogenesis and inflammation","volume":"324","author":"Mena","year":"2014","journal-title":"Exp. Cell Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.canlet.2015.03.005","article-title":"Nuclear factor of activated T cells in cancer development and treatment","volume":"361","author":"Shou","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1182\/blood-2011-12-397158","article-title":"The degree of BCR and NFAT activation predicts clinical outcomes in chronic lymphocytic leukemia","volume":"120","author":"Deglesne","year":"2012","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6947","DOI":"10.1158\/0008-5472.CAN-14-1592","article-title":"Nuclear factor of activated T-cell activity is associated with metastatic capacity in colon cancer","volume":"74","author":"Tripathi","year":"2014","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1038\/leu.2015.95","article-title":"NFATc1 as a therapeutic target in FLT3-ITD-positive AML","volume":"29","author":"Metzelder","year":"2015","journal-title":"Leukemia"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1128\/MCB.00501-15","article-title":"NFAT2 Isoforms Differentially Regulate Gene Expression, Cell Death, and Transformation through Alternative N-Terminal Domains","volume":"36","author":"Lucena","year":"2016","journal-title":"Mol. Cell. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1111\/j.1365-2141.2004.05313.x","article-title":"The NFATc1 transcription factor is widely expressed in white cells and translocates from the cytoplasm to the nucleus in a subset of human lymphomas","volume":"128","author":"Marafioti","year":"2005","journal-title":"Br. J. Haematol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/mc.22939","article-title":"PPP3CB contributes to poor prognosis through activating nuclear factor of activated T-cells signaling in neuroblastoma","volume":"58","author":"Shakhova","year":"2019","journal-title":"Mol. Carcinog."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7168","DOI":"10.1128\/MCB.00256-08","article-title":"Dual roles for NFAT transcription factor genes as oncogenes and tumor suppressors","volume":"28","author":"Robbs","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"May, S.L., Zhou, Q., Lewellen, M., Carter, C.M., Coffey, D., Highfill, S.L., Bucher, C.M., Matise, I., Morse, H.C., and O\u2019Sullivan, M.G. (2014). Nfatc2 and Tob1 have non-overlapping function in T cell negative regulation and tumorigenesis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0100629"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"62","DOI":"10.5732\/cjc.010.10156","article-title":"Expression and unique functions of four nuclear factor of activated T cells isoforms in non-small cell lung cancer","volume":"30","author":"Chen","year":"2011","journal-title":"Chin. J. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1053\/j.gastro.2011.11.001","article-title":"Restricted heterochromatin formation links NFATc2 repressor activity with growth promotion in pancreatic cancer","volume":"142","author":"Baumgart","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1084\/jem.20040474","article-title":"Nuclear factor of activated T cells balances angiogenesis activation and inhibition","volume":"199","author":"Zaichuk","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9361","DOI":"10.1038\/s41598-019-45731-w","article-title":"NFATc3 controls tumour growth by regulating proliferation and migration of human astroglioma cells","volume":"9","author":"Urso","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2835","DOI":"10.1038\/onc.2016.434","article-title":"Phosphorylation of NFAT3 by CDK3 induces cell transformation and promotes tumor growth in skin cancer","volume":"36","author":"Xiao","year":"2017","journal-title":"Oncogene"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2292","DOI":"10.1038\/onc.2009.499","article-title":"NFAT3 transcription factor inhibits breast cancer cell motility by targeting the Lipocalin 2 gene","volume":"29","author":"Fougere","year":"2010","journal-title":"Oncogene"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3546","DOI":"10.1182\/blood-2005-02-0493","article-title":"A tumor-suppressor function for NFATc3 in T-cell lymphomagenesis by murine leukemia virus","volume":"106","author":"Glud","year":"2005","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"12957","DOI":"10.1523\/JNEUROSCI.1064-09.2009","article-title":"Cognitive decline in Alzheimer\u2019s disease is associated with selective changes in calcineurin\/NFAT signaling","volume":"29","author":"Abdul","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3176","DOI":"10.1523\/JNEUROSCI.6439-11.2012","article-title":"Inhibition of the NFAT pathway alleviates amyloid \u03b2 neurotoxicity in a mouse model of Alzheimer\u2019s disease","volume":"32","author":"Hudry","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6567","DOI":"10.1093\/hmg\/ddu377","article-title":"A calcineurin- and NFAT-dependent pathway is involved in \u03b1-synuclein-induced degeneration of midbrain dopaminergic neurons","volume":"23","author":"Luo","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/S1074-7613(00)80660-3","article-title":"Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development","volume":"9","author":"Ranger","year":"1998","journal-title":"Immunity"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.cell.2006.05.042","article-title":"FOXP3 controls regulatory T cell function through cooperation with NFAT","volume":"126","author":"Wu","year":"2006","journal-title":"Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3831","DOI":"10.4049\/jimmunol.179.6.3831","article-title":"Induction of the CTLA-4 gene in human lymphocytes is dependent on NFAT binding the proximal promoter","volume":"179","author":"Gibson","year":"2007","journal-title":"J. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"991","DOI":"10.15252\/embr.201338233","article-title":"Regulatory T cells suppress CD4+ T cells through NFAT-dependent transcriptional mechanisms","volume":"15","author":"Shin","year":"2014","journal-title":"EMBO Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1084\/jem.20041538","article-title":"NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+ CD25+ regulatory T cells","volume":"201","author":"Bopp","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2837","DOI":"10.1002\/eji.200536618","article-title":"NFAT transcription factors in control of peripheral T cell tolerance","volume":"36","author":"Serfling","year":"2006","journal-title":"Eur. J. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"19453","DOI":"10.1038\/srep19453","article-title":"Transcription factor NFAT1 controls allergic contact hypersensitivity through regulation of activation induced cell death program","volume":"6","author":"Kwon","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3389\/fimmu.2020.00195","article-title":"The Role of Calcium-Calcineurin-NFAT Signaling Pathway in Health and Autoimmune Diseases","volume":"11","author":"Park","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1038\/ni.2113","article-title":"The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease","volume":"12","author":"Liu","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1002\/eji.201444638","article-title":"NFAT1 deficit and NFAT2 deficit attenuate EAE via different mechanisms","volume":"45","author":"Dietz","year":"2015","journal-title":"Eur. J. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1172\/JCI87880","article-title":"Transcription factor NFAT5 promotes macrophage survival in rheumatoid arthritis","volume":"127","author":"Choi","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/nature11868","article-title":"Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells","volume":"496","author":"Kleinewietfeld","year":"2013","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"329","DOI":"10.3233\/JAD-150065","article-title":"Reduced Incidence of Dementia in Solid Organ Transplant Patients Treated with Calcineurin Inhibitors","volume":"47","author":"Taglialatela","year":"2015","journal-title":"J. Alzheimers. Dis."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/S1074-7613(00)80188-0","article-title":"Manipulating immune responses with immunosuppressive agents that target NFAT","volume":"12","author":"Kiani","year":"2000","journal-title":"Immunity"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/17401","article-title":"Cyclosporine induces cancer progression by a cell-autonomous mechanism","volume":"397","author":"Hojo","year":"1999","journal-title":"Nature"},{"key":"ref_68","first-page":"3105","article-title":"Adverse effects associated with the use of FK 506","volume":"23","author":"Fung","year":"1991","journal-title":"Transplant. Proc."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"13522","DOI":"10.1073\/pnas.212504399","article-title":"Crystal structure of human calcineurin complexed with cyclosporin A and human cyclophilin","volume":"99","author":"Jin","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1091\/mbc.e03-10-0730","article-title":"Calcineurin regulates cyclin D1 accumulation in growth-stimulated fibroblasts","volume":"15","author":"Kahl","year":"2004","journal-title":"Mol. Biol. Cell"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1016\/S0006-291X(03)01552-3","article-title":"Calcineurin signaling in Saccharomyces cerevisiae: How yeast go crazy in response to stress","volume":"311","author":"Cyert","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.1093\/emboj\/17.11.3101","article-title":"Calcineurin preferentially synergizes with PKC-q to activate JNK and IL-2 promoter in T lymphocytes","volume":"17","author":"Werlen","year":"1998","journal-title":"EMBO J."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"22923","DOI":"10.1074\/jbc.274.33.22923","article-title":"Protein kinase C and calcineurin synergize to activate IkappaB kinase and NF-kappaB in T lymphocytes","volume":"274","author":"Trushin","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1126\/science.285.5436.2129","article-title":"Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A","volume":"285","author":"Aramburu","year":"1999","journal-title":"Science"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/nm994","article-title":"A new cell-permeable peptide allows successful allogeneic islet transplantation in mice","volume":"10","author":"Noguchi","year":"2004","journal-title":"Nat. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1111\/j.1747-0285.2006.00360.x","article-title":"A cell-permeable NFAT inhibitor peptide prevents pressure-overload cardiac hypertrophy","volume":"67","author":"Kuriyama","year":"2006","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Elloumi, H.Z., Maharshak, N., Rao, K.N., Kobayashi, T., Ryu, H.S., M\u00fchlbauer, M., Li, F., Jobin, C., and Plevy, S.E. (2012). A cell permeable peptide inhibitor of NFAT inhibits macrophage cytokine expression and ameliorates experimental colitis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0034172"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.imlet.2012.01.016","article-title":"Cell permeable NFAT inhibitory peptide Sim-2-VIVIT inhibits T-cell activation and alleviates allergic airway inflammation and hyper-responsiveness","volume":"143","author":"Choi","year":"2012","journal-title":"Immunol. Lett."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1111\/bph.12292","article-title":"NFAT2 inhibitor ameliorates diabetic nephropathy and podocyte injury in db\/db mice","volume":"170","author":"Zhang","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"424","DOI":"10.2337\/db18-0870","article-title":"Inhibition of NFAT Signaling Restores Microvascular Endothelial Function in Diabetic Mice","volume":"69","author":"McNeilly","year":"2020","journal-title":"Diabetes"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"7020","DOI":"10.1167\/iovs.13-12183","article-title":"The role of the NFAT signaling pathway in retinal neovascularization","volume":"54","author":"Bretz","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S1074-7613(00)80465-3","article-title":"Delayed lymphoid repopulation with defects in IL-4-driven responses produced by inactivation of NF-ATc","volume":"8","author":"Ranger","year":"1998","journal-title":"Immunity"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S1074-7613(00)80464-1","article-title":"The transcription factor NF-ATc1 regulates lymphocyte proliferation and Th2 cytokine production","volume":"8","author":"Yoshida","year":"1998","journal-title":"Immunity"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1182\/blood.V91.7.2223","article-title":"Regulation of allergic inflammation and eosinophil recruitment in mice lacking the transcription factor NFAT1: Role of interleukin-4 (IL-4) and IL-5","volume":"91","author":"Viola","year":"1998","journal-title":"Blood"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"6641","DOI":"10.1128\/IAI.71.11.6641-6647.2003","article-title":"Mice deficient in nuclear factor of activated T-cell transcription factor c2 mount increased Th2 responses after infection with Nippostrongylus brasiliensis and decreased Th1 responses after mycobacterial infection","volume":"71","author":"Erb","year":"2003","journal-title":"Infect. Immun."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"319","DOI":"10.4049\/jimmunol.180.1.319","article-title":"Differential contribution of NFATc2 and NFATc1 to TNF-alpha gene expression in T cells","volume":"180","author":"Kaminuma","year":"2008","journal-title":"J. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1128\/MCB.16.2.459","article-title":"Tumor necrosis factor alpha gene regulation in activated T cells involves ATF-2\/Jun and NFATp","volume":"16","author":"Tsai","year":"1996","journal-title":"Mol. Cell. Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"92","DOI":"10.4049\/jimmunol.1602113","article-title":"Downregulation of NFAT3 Due to Lack of T-Box Transcription Factor TBX5 Is Crucial for Cytokine Expression in T Cells","volume":"200","author":"Kaminuma","year":"2018","journal-title":"J. Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.molcel.2016.11.011","article-title":"Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident and Spatially Segregated Intracellular Ca2+ Signals","volume":"64","author":"Kar","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"23877","DOI":"10.1074\/jbc.273.37.23877","article-title":"Two-site interaction of nuclear factor of activated T cells with activated calcineurin","volume":"273","author":"Okamura","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"7130","DOI":"10.1073\/pnas.97.13.7130","article-title":"A second calcineurin binding site on the NFAT regulatory domain","volume":"97","author":"Park","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3197","DOI":"10.1096\/fj.201902229","article-title":"Identification of novel interacting regions involving calcineurin and nuclear factor of activated T cells","volume":"34","author":"Kitamura","year":"2020","journal-title":"FASEB J."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1126\/science.aad0836","article-title":"Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive","volume":"350","author":"Miyata","year":"2015","journal-title":"Science"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e20181853","DOI":"10.1084\/jem.20181853","article-title":"Lack of NFATc1 SUMOylation prevents autoimmunity and alloreactivity","volume":"218","author":"Xiao","year":"2021","journal-title":"J. Exp. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"16258","DOI":"10.1073\/pnas.1203870109","article-title":"Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3+ regulatory T cells","volume":"109","author":"Vaeth","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/5\/2725\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:34:59Z","timestamp":1760160899000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/5\/2725"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,8]]},"references-count":95,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["ijms22052725"],"URL":"https:\/\/doi.org\/10.3390\/ijms22052725","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,8]]}}}