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1
Luo, C., E. Burgeon, and A. Rao. "Mechanisms of transactivation by nuclear factor of activated T cells-1." Journal of Experimental Medicine 184, no. 1 (July 1, 1996): 141–47. http://dx.doi.org/10.1084/jem.184.1.141.
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Nuclear factor of activated T cells-family proteins (NFAT1/NFATp, NFATc, NFAT3, and NFAT4/NFATx/NFATc3) play a key role in the transcription of cytokine genes and other genes during the immune response. We have defined the mechanisms of transactivation by NFAT1. NFAT1 possesses two transactivation domains whose sequences are not conserved in the other NFAT-family proteins, and a conserved DNA-binding domain that mediates the recruitment of cooperating nuclear transcription factors even when it is expressed in the absence of other regions of the protein. The activity of the NH2-terminal transactivation domain is modulated by an adjacent regulatory region that contains several conserved sequence motifs represented only in the NFAT family. Our results emphasize the multiple levels at which NFAT-dependent transactivation is regulated, and predict significant differences in the architecture of cooperative transcription complexes containing different NFAT-family proteins.
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Masuda, E. S., Y. Naito, H. Tokumitsu, D. Campbell, F. Saito, C. Hannum, K. Arai, and N. Arai. "NFATx, a novel member of the nuclear factor of activated T cells family that is expressed predominantly in the thymus." Molecular and Cellular Biology 15, no. 5 (May 1995): 2697–706. http://dx.doi.org/10.1128/mcb.15.5.2697.
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The nuclear factor of activated T cells (NFAT) regulates cytokine gene expression in T cells through cis-acting elements located in the promoters of cytokine genes. Here, we report the cDNA cloning, chromosomal localization, and initial characterization of a transcription factor related to NFATp and NFATc. The novel molecule, designated NFATx, exhibits in its middle a region very similar to the Rel homology domain in NFATc and NFATp. The amino-terminal region of NFATx also shows significant similarities to corresponding sequences in NFATc and NFATp and contains three copies of a conspicuous 17-residue motif of unknown function. We provide evidence showing that NFATx can reconstitute binding to the NFAT-binding site from the interleukin 2 promoter when combined with AP1 (c-Fos/c-Jun) polypeptides and that NFATx is capable of activating transcription of the interleukin 2 promoter in COS-7 cells when stimulated with phorbol ester and calcium ionophore. NFATx mRNA is preferentially and remarkably found in the thymus and at lower levels in peripheral blood leukocytes. The expression pattern of NFATx, together with its functional activity, strongly suggests that NFATx plays a role in the regulation of gene expression in T cells and immature thymocytes.
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Lunde, Ida G., Heidi Kvaløy, Bjørg Austbø, Geir Christensen, and Cathrine R. Carlson. "Angiotensin II and norepinephrine activate specific calcineurin-dependent NFAT transcription factor isoforms in cardiomyocytes." Journal of Applied Physiology 111, no. 5 (November 2011): 1278–89. http://dx.doi.org/10.1152/japplphysiol.01383.2010.
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Norepinephrine (NE) and angiotensin II (ANG II) are primary effectors of the sympathetic adrenergic and the renin-angiotensin-aldosterone systems, mediating hypertrophic, apoptotic, and fibrotic events in the myocardium. As NE and ANG II have been shown to affect intracellular calcium in cardiomyocytes, we hypothesized that they activate the calcium-sensitive, prohypertrophic calcineurin-nuclear factor of activated T-cell (NFATc) signaling pathway. More specifically, we have investigated isoform-specific activation of NFAT in NE- and ANG II-stimulated cardiomyocytes, as it is likely that each of the four calcineurin-dependent isoforms, c1-c4, play specific roles. We have stimulated neonatal ventriculocytes from C57/B6 and NFAT-luciferase reporter mice with ANG II or NE and quantified NFAT activity by luciferase activity and phospho-immunoblotting. ANG II and NE increased calcineurin-dependent NFAT activity 2.4- and 1.9-fold, measured as luciferase activity after 24 h of stimulation, and induced protein synthesis, measured by radioactive leucine incorporation after 24 and 72 h. To optimize measurements of NFAT isoforms, we examined the specificity of NFAT antibodies on peptide arrays and by immunoblotting with designed blocking peptides. Western analyses showed that both effectors activate NFATc1 and c4, while NFATc2 activity was regulated by NE only, as measured by phospho-NFAT levels. Neither ANG II nor NE activated NFATc3. As today's main therapies for heart failure aim at antagonizing the adrenergic and renin-angiotensin-aldosterone systems, understanding their intracellular actions is of importance, and our data, through validating a method for measuring myocardial NFATs, indicate that ANG II and NE activate specific NFATc isoforms in cardiomyocytes.
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Wu, Chia-Cheng, Shu-Ching Hsu, Hsiu-ming Shih, and Ming-Zong Lai. "Nuclear Factor of Activated T Cells c Is a Target of p38 Mitogen-Activated Protein Kinase in T Cells." Molecular and Cellular Biology 23, no. 18 (September 15, 2003): 6442–54. http://dx.doi.org/10.1128/mcb.23.18.6442-6454.2003.
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ABSTRACT p38 mitogen activated protein kinase (MAPK) is essential for T-cell activation. Here we demonstrated that nuclear factor of activated T cells (NFAT) is a direct target of p38 MAPK. Inhibition of p38 MAPK led to selective inactivation of NFAT in T cells. We further linked a strict requirement of p38 MAPK to activation of NFATc. A stimulatory effect of p38 MAPK on at least four other stages of NFATc activation was found. First, the p38 MAPK cascade activated the NFATc promoter and induced the transcription of NFATc mRNA. Second, p38 MAPK mildly increased the mRNA stability of NFATc. Third, p38 MAPK enhanced the translation of NFATc mRNA. Fourth, p38 MAPK promoted the interaction of NFATc with the coactivator CREB-binding protein. In contrast, p38 MAPK moderately enhanced the expulsion of NFATc from the nucleus in T cells. Therefore, p38 MAPK has opposite effects on different stages of NFATc activation. All together, the overall effect of p38 MAPK on NFATc in T cells is clear activation.
5
Aramburu, J., L. Azzoni, A. Rao, and B. Perussia. "Activation and expression of the nuclear factors of activated T cells, NFATp and NFATc, in human natural killer cells: regulation upon CD16 ligand binding." Journal of Experimental Medicine 182, no. 3 (September 1, 1995): 801–10. http://dx.doi.org/10.1084/jem.182.3.801.
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The putative factors that couple the signal transduction from surface receptors to the activation of cytokine synthesis in natural killer (NK) cells have not been elucidated. We report here that the nuclear factor of activated T cells (NFATp), a cyclosporin A (CsA)-sensitive factor that regulates the transcription of several cytokines, mediates CD16-induced activation of cytokine genes in human NK cells. CD16 (Fc gamma RIIIA)-induced expression of cytokine mRNA in NK cells occurs via a CsA-sensitive and Ca(2+)-dependent mechanism. Stimulation of NK cells with CD16 ligands induces NFAT-like DNA binding activity in the nuclear extracts from these cells, as detected in electrophoretic mobility shift assays. This occurs with fast kinetics after stimulation, via a CsA-sensitive and Ca(2+)-dependent mechanism that does not require de novo protein synthesis. NK cell NFAT is present in the cytosol of nonstimulated cells, migrates to the nucleus upon stimulation, and can associate with AP-1. Two distinct molecules, NFATp and NFATc, have been reported to mediate NFAT activity. The results of supershift assays using NFATp- and NFATc- specific antibodies indicate that NK cell activation early after CD16 ligand binding involves primarily, if not exclusively, NFATp, and Western blot analysis shows that this has the same electrophoretic mobility (approximately 120 kD) as that of T lymphocytes. NK cells do not express NFATc constitutively, but NFATc mRNA accumulation is induced in these cells within 2 h of stimulation with CD16 ligands. However, supershift assays using the available mAb recognizing the T cell NFATc revealed no detectable NFATc protein in nuclear and cytoplasmic extracts from CD16- or phorbol ester-stimulated cells at any time tested, up to 4 h. These results provide the first direct evidence that both CsA-sensitive transcription factors, NFATp and NFATc, are expressed in human NK cells, and that their activation and/or expression can be regulated in primary cells by a single stimulus, that, in the case of CD16 in NK cells, results in early activation of NFATp and subsequently induced expression of NFATc mRNA.
6
Martínez-Martínez, S., P. Gómez del Arco, A. L. Armesilla, J. Aramburu, C. Luo, A. Rao, and J. M. Redondo. "Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells." Molecular and Cellular Biology 17, no. 11 (November 1997): 6437–47. http://dx.doi.org/10.1128/mcb.17.11.6437.
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Dithiocarbamates (DTCs) have recently been reported as powerful inhibitors of NF-kappaB activation in a number of cell types. Given the role of this transcription factor in the regulation of gene expression in the inflammatory response, NF-kappaB inhibitors have been suggested as potential therapeutic drugs for inflammatory diseases. We show here that DTCs inhibited both interleukin 2 (IL-2) synthesis and membrane expression of antigens which are induced during T-cell activation. This inhibition, which occurred with a parallel activation of c-Jun transactivating functions and expression, was reflected by transfection experiments at the IL-2 promoter level, and involved not only the inhibition of NF-kappaB-driven reporter activation but also that of nuclear factor of activated T cells (NFAT). Accordingly, electrophoretic mobility shift assays (EMSAs) indicated that pyrrolidine DTC (PDTC) prevented NF-kappaB, and NFAT DNA-binding activity in T cells stimulated with either phorbol myristate acetate plus ionophore or antibodies against the CD3-T-cell receptor complex and simultaneously activated the binding of AP-1. Furthermore, PDTC differentially targeted both NFATp and NFATc family members, inhibiting the transactivation functions of NFATp and mRNA induction of NFATc. Strikingly, Western blotting and immunocytochemical experiments indicated that PDTC promoted a transient and rapid shuttling of NFATp and NFATc, leading to their accelerated export from the nucleus of activated T cells. We propose that the activation of an NFAT kinase by PDTC could be responsible for the rapid shuttling of the NFAT, therefore transiently converting the sustained transactivation of this transcription factor that occurs during lymphocyte activation, and show that c-Jun NH2-terminal kinase (JNK) can act by directly phosphorylating NFATp. In addition, the combined inhibitory effects on NFAT and NF-KB support a potential use of DTCs as immunosuppressants.
7
Wang, Qingding, Yuning Zhou, Lindsey N. Jackson, Sara M. Johnson, Chi-Wing Chow, and B. Mark Evers. "Nuclear factor of activated T cells (NFAT) signaling regulates PTEN expression and intestinal cell differentiation." Molecular Biology of the Cell 22, no. 3 (February 2011): 412–20. http://dx.doi.org/10.1091/mbc.e10-07-0598.
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The nuclear factor of activated T cell (NFAT) proteins are a family of transcription factors (NFATc1–c4) involved in the regulation of cell differentiation and adaptation. Previously we demonstrated that inhibition of phosphatidylinositol 3-kinase or overexpression of PTEN enhanced intestinal cell differentiation. Here we show that treatment of intestinal-derived cells with the differentiating agent sodium butyrate (NaBT) increased PTEN expression, NFAT binding activity, and NFAT mRNA expression, whereas pretreatment with the NFAT signaling inhibitor cyclosporine A (CsA) blocked NaBT-mediated PTEN induction. Moreover, knockdown of NFATc1 or NFATc4, but not NFATc2 or NFATc3, attenuated NaBT-induced PTEN expression. Knockdown of NFATc1 decreased PTEN expression and increased the phosphorylation levels of Akt and downstream targets Foxo1 and GSK-3α/β. Furthermore, overexpression of NFATc1 or the NFATc4 active mutant increased PTEN and p27kip1 expression and decreased Akt phosphorylation. In addition, pretreatment with CsA blocked NaBT-mediated induction of intestinal alkaline phosphatase (IAP) activity and villin and p27kip1 expression; knockdown of either NFATc1 or NFATc4 attenuated NaBT-induced IAP activity. We provide evidence showing that NFATc1 and NFATc4 are regulators of PTEN expression. Importantly, our results suggest that NFATc1 and NFATc4 regulation of intestinal cell differentiation may be through PTEN regulation.
8
Amasaki, Yoshiharu, Esteban S. Masuda, Ryu Imamura, Ken-ichi Arai, and Naoko Arai. "Distinct NFAT Family Proteins Are Involved in the Nuclear NFAT-DNA Binding Complexes from Human Thymocyte Subsets." Journal of Immunology 160, no. 5 (March 1, 1998): 2324–33. http://dx.doi.org/10.4049/jimmunol.160.5.2324.
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Abstract The nuclear factor of activated T cells (NFAT) is involved in the transcriptional induction of cytokine and other immunoregulatory genes during an immune response. Among four distinct NFAT family members identified to date, mRNAs of NFAT1, NFATc, and NFATx are expressed in the thymus. Here, we report the distribution of these three NFAT family members in human fetal thymocyte subsets and in peripheral mature T cells. We show that NFATx mRNA was expressed in all T lymphocyte subsets tested and was highest in CD4+CD8+ double positive (DP) thymocytes. Conversely, NFAT1 mRNA was preferentially expressed in the mature CD4+ single positive (SP) populations. NFATc mRNA was present at low levels in all subsets but strongly induced upon treatment with phorbol ester and calcium ionophore. Interestingly, we detected NFAT-DNA binding complexes in DP thymocytes, albeit at lower levels than in CD4 SP cells. Corresponding to the mRNA expression, we observed that NFATx was responsible for the NFAT-DNA binding in DP thymocytes. Moreover, this DNA binding was inhibited by cyclosporin A, indicating that NFATx nuclear translocation was regulated by the calcineurin phosphatase in DP thymocytes. For the CD4 SP populations, NFAT1 and NFATc, and to some extent NFATx, were responsible for the NFAT-DNA binding complexes. These results indicate that NFAT family members are differentially regulated during the development of T cells, and that NFATx may play a distinct role in calcineurin-dependent signaling in DP thymocytes.
9
SUGIMOTO, TOSHIRO, MASAKAZU HANEDA, HIROTAKA SAWANO, KEIJI ISSHIKI, SHIRO MAEDA, DAISUKE KOYA, KEN INOKI, HITOSHI YASUDA, ATSUNORI KASHIWAGI, and RYUICHI KIKKAWA. "Endothelin-1 Induces Cyclooxygenase-2 Expression Via Nuclear Factor of Activated T-Cell Transcription Factor in Glomerular Mesangial Cells." Journal of the American Society of Nephrology 12, no. 7 (July 2001): 1359–68. http://dx.doi.org/10.1681/asn.v1271359.
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Abstract. Nuclear factor of activated T cells (NFAT) originally was identified as a T-cell—specific transcription factor whose activity is regulated by calcineurin, one of the serine-threonine phosphatases. Recent studies have shown that NFAT also is expressed in nonlymphoid cells and plays an important role in various cell functions. It is widely known that treatment with cyclosporin A (CsA), which can inhibit calcineurin/NFAT signaling, results in glomerular dysfunction characterized by a decrease of GFR or glomerulosclerosis, suggesting that NFAT might regulate the glomerular function. However, the precise function of NFAT in glomerular cells remains to be clarified. Herein, evidence has been produced that NFAT2/NFATc, one of five known NFAT isoforms, is expressed in glomerular mesangial cells. Stimulation of mesangial cells with endothelin-1 caused translocation of NFAT2 into the nucleus with a concomitant increase in NFAT2 DNA-binding activity, both of which were inhibited by CsA. Furthermore, CsA inhibited endothelin-1—induced cyclooxygenase-2 (COX-2) expression in mesangial cells. NFAT2 bound directly to the GGAAA sequence, which is the minimal consensus sequence for NFAT binding, in a promoter region of ratCOX-2gene, and it enhanced the reporter activity of rat COX-2 promoter in mesangial cells. These findings provide the first evidence that NFAT2 is expressed and regulates COX-2 gene expression in mesangial cells. These results will contribute to evaluation of the precise roles of NFAT in glomerular functions and the CsA-induced nephrotoxicity.
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Liu, Yewei, Zoltán Cseresnyés, William R. Randall, and Martin F. Schneider. "Activity-dependent nuclear translocation and intranuclear distribution of NFATc in adult skeletal muscle fibers." Journal of Cell Biology 155, no. 1 (October 1, 2001): 27–40. http://dx.doi.org/10.1083/jcb.200103020.
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TTranscription factor nuclear factor of activated T cells NFATc (NFATc1, NFAT2) may contribute to slow-twitch skeletal muscle fiber type–specific gene expression. Green fluorescence protein (GFP) or FLAG fusion proteins of either wild-type or constitutively active mutant NFATc [NFATc(S→A)] were expressed in cultured adult mouse skeletal muscle fibers from flexor digitorum brevis (predominantly fast-twitch). Unstimulated fibers expressing NFATc(S→A) exhibited a distinct intranuclear pattern of NFATc foci. In unstimulated fibers expressing NFATc–GFP, fluorescence was localized at the sarcomeric z-lines and absent from nuclei. Electrical stimulation using activity patterns typical of slow-twitch muscle, either continuously at 10 Hz or in 5-s trains at 10 Hz every 50 s, caused cyclosporin A–sensitive appearance of fluorescent foci of NFATc–GFP in all nuclei. Fluorescence of nuclear foci increased during the first hour of stimulation and then remained constant during a second hour of stimulation. Kinase inhibitors and ionomycin caused appearance of nuclear foci of NFATc–GFP without electrical stimulation. Nuclear translocation of NFATc–GFP did not occur with either continuous 1 Hz stimulation or with the fast-twitch fiber activity pattern of 0.1-s trains at 50 Hz every 50 s. The stimulation pattern–dependent nuclear translocation of NFATc demonstrated here could thus contribute to fast-twitch to slow-twitch fiber type transformation.
11
Li, Song-Zhe, Bradley W. McDill, Paul A. Kovach, Li Ding, William Y. Go, Steffan N. Ho, and Feng Chen. "Calcineurin-NFATc signaling pathway regulates AQP2 expression in response to calcium signals and osmotic stress." American Journal of Physiology-Cell Physiology 292, no. 5 (May 2007): C1606—C1616. http://dx.doi.org/10.1152/ajpcell.00588.2005.
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The aquaporin (AQP)2 channel mediates the reabsorption of water in renal collecting ducts in response to arginine vasopressin (AVP) and hypertonicity. Here we show that AQP2 expression is induced not only by the tonicity-responsive enhancer binding protein (TonEBP)/nuclear factor of activated T cells (NFAT)5-mediated hypertonic stress response but also by the calcium-dependent calcineurin-NFATc pathway. The induction of AQP2 expression by the calcineurin-NFATc pathway can occur in the absence of TonEBP/NFAT5. Mutational and chromatin immunoprecipitation analyses revealed the existence of functional NFAT binding sites within the proximal AQP2 promoter responsible for regulation of AQP2 by NFATc proteins and TonEBP/NFAT5. Contrary to the notion that TonEBP/NFAT5 is the only Rel/NFAT family member regulated by tonicity, we found that hypertonicity promotes the nuclear translocation of NFATc proteins for the subsequent induction of AQP2 expression. Calcineurin activity was also found to be involved in the induction of TonEBP/NFAT5 expression by hypertonicity, thus further defining the signaling mechanisms that underlie the TonEBP/NFAT5 osmotic stress response pathway. The coordinate regulation of AQP2 expression by both osmotic stress and calcium signaling appears to provide a means to integrate diverse extracellular signals into optimal cellular responses.
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YELLATURU, Chandrahasa R., Salil K. GHOSH, R. K. RAO, Lisa K. JENNINGS, Aviv HASSID, and Gadiparthi N. RAO. "A potential role for nuclear factor of activated T-cells in receptor tyrosine kinase and G-protein-coupled receptor agonist-induced cell proliferation." Biochemical Journal 368, no. 1 (November 15, 2002): 183–90. http://dx.doi.org/10.1042/bj20020347.
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We have studied the role of nuclear factor of activated T-cells (NFAT) transcription factors in the induction of vascular smooth muscle cell (VSMC) growth by platelet-derived growth factor-BB (PDGF-BB) and thrombin, the receptor tyrosine kinase (RTK) and G-protein-coupled receptor (GPCR) agonists, respectively. NFATc1 but not NFATc2 or NFATc3 was translocated from the cytoplasm to the nucleus upon treatment of VSMCs with PDGF-BB or thrombin. Translocation of NFATc1 was followed by an increase in NFAT—DNA binding activity and NFAT-dependent reporter gene expression. Cyclosporin A (CsA), a potent and specific inhibitor of calcineurin, a calcium/calmodulin-dependent serine phosphatase involved in the dephosphorylation and activation of NFATs, blocked NFAT—DNA binding activity and NFAT-dependent reporter gene expression induced by PDGF-BB and thrombin. CsA also completely inhibited PDGF-BB- and thrombin-induced VSMC growth, as measured by DNA synthesis and cell number. In addition, forced expression of the NFAT-competing peptide VIVIT for calcineurin binding significantly attenuated the DNA synthesis induced by PDGF-BB and thrombin in VSMCs. Together, these findings for the first time demonstrate a role for NFATs in RTK and GPCR agonist-induced growth in VSMCs.
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Kiani, Alexander, Hanna Kuithan, Friederike Kuithan, Satu Kyttaelae, Ivonne Habermann, Martin Bornhaeuser, and Gerhard Ehninger. "Specific Regulation of NFAT (Nuclear Factors of Activated T Cells) Expression in CD34+ Cells Differentiating into Diverse Hematopoietic Lineages." Blood 108, no. 11 (November 16, 2006): 4213. http://dx.doi.org/10.1182/blood.v108.11.4213.4213.
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Abstract NFAT (Nuclear Factor of Activated T cells) transcription factors are a family of five proteins that are primarily known for their central role in the regulation of inducible gene expression in activated T cells. It is now clear that NFAT proteins are also expressed in various non-immune cell types, where they regulate the expression of genes involved in such diverse cellular processes as proliferation, apoptosis and differentiation. We have previously shown that NFATc2 is strongly expressed in human CD34+ cells and megakaryocytes, but not in purified peripheral blood neutrophil granulocytes and monocytes. Furthermore, granulocytic differentiation of CD34+ cells in vitro was paralleled by the rapid and profound suppression of NFATc2 mRNA and protein. The function of NFATc2 in CD34+ cells, however, is unknown, and no information exists on the expression or regulation of other NFAT family members in CD34+ cells or during heamtopoietic differentiation. To provide a systematic basis for further functional analysis, we established in the present study a comprehensive expression profile of all five NFAT family members in CD34+ cells and during their in vitro differentiation into neutrophil, eosinophil, erythroid and megakaryocytic lineages. CD34+ cells were purified from umbilical cord blood and cultured in the presence of cytokines or cytokine combinations inducing differentiation of the respective lineages. At several time-points during the culture, the efficacy and specificity of the differentiation was monitored by morphological examination of cytospin preparations as well as by analysis of lineage-specific cell surface markers. By quantitative RT-PCR, NFATc3 and NFAT5 were the NFAT family member found to be most prominently expressed in CD34+ cells of both peripheral blood and umbilical cord blood, as well as in the immature CD34+CD38− subpopulation of cells. NFAT expression during the differentiation of umbilical cord blood CD34+ cells into the diverse hematopoietic lineages followed a family member- and lineage-specific pattern. Neutrophil differentiation was accompanied by a rapid suppression of transcript level for all NFAT family members. In contrast, eosinophil, erythrocyte and megakaryocyte differentiation was paralleled by an upregulation of NFATc3, NFATc1/NFATc3 and NFATc1 mRNA, respectively. The most obvious lineage-specific pattern was observed for NFATc4, where transcript levels were low in CD34+ cells and either not or only transiently increased in neutrophil, eosinophil and erythrocyte differentiation; in contrast, they were specifically upregulated about 10-fold in the megakaryocytic lineage. The expression profile of NFAT family members in developing hematopoietic cells of diverse lineages presented here will allow predicting and directly assessing the role of individual NFAT family members in hematopoietic differentiation.
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Märklin, Melanie, Samuel Holzmayer, Martin R. Mueller, and Helmut R. Salih. "Crosstalk between NFAT and NFκB Signaling Regulates NK Cell Immunosurveillance." Blood 142, Supplement 1 (November 28, 2023): 1183. http://dx.doi.org/10.1182/blood-2023-184446.
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One of the major transcriptional regulators in lymphoid cells is NFAT (Nuclear Factor of Activated T Cells), controlling lymphocyte development and activity. The role of NFAT signaling is well defined in T cells, the cytotoxic lymphocytes of the adaptive immunity. However, surprisingly little is known regarding the relevance of this transcription factor family in NK cells as effector cells of the innate immunity. Available data indicate that NFAT activity is dispensable for development of NK cells, whereas effects of the immunosuppressive drugs cyclosporin A and tacrolimus, that inhibit calcineurin and consecutively NFAT, implicate an involvement of the NFAT family in NK cell function. We here employed different genetic mouse models and functional analyses to unravel the role of NFAT1 (NFATc2) and NFAT2 (NFATc1) in NK cell reactivity. In vitro knockout (KO) of NFAT1 (NFATc2) or NFAT2 (NFATc1) enhanced NK cell degranulation and resulted in increased production of granzyme B and perforin upon stimulation of activating receptors like NK1.1 or Nkp46 or upon co-culture with different leukemia and solid tumor cells. In line, cytotoxicity assays revealed increased lysis of YAC-1 and B16F10 tumor cells by both NFAT1- and NFAT2-deficient NK cells as compared to wildtype (WT) controls. The inhibitory effect of NFAT transcription factors on NK cell effector function could also be confirmed in vivo by employing WT and NFAT KO animals in syngeneic B16F10 melanoma, RMA-S lymphoma and LL/2-luc lung carcinoma models, which revealed a significantly reduced tumor burden in NFAT1 and NFAT2 KO mice. Furthermore, we detected higher numbers of tumor infiltrating NK cells in NFAT KO mice, which suggested improved NK cell migration and homing to the tumor side. Comparative analyses with single NFAT as well as NFAT1+NFAT2 double KO and WT animals further confirmed the inhibitory effect of NFAT1 and NFAT2 and pointed to additive effects of NFAT1 and NFAT2 in NK cell tumor immunosurveillance. Proteomics analysis of NK cells from the different NFAT KO strains revealed altered expression of molecules which are regulating chemokine receptor expression as well as a decreased expression of NFκB inhibitory molecules, like NFKBIB (NFKB inhibitor beta) Commd6 (COMM domain containing 6). NFκB signaling was shown to regulate granzyme B and perforin synthesis and expression. Thus, we suggest that NFAT1 and NFAT2 inhibit NFκB signaling in NK cells, and NFAT1 and NFAT2 KO reinforce NFκB induced granzyme B and perforin expression and thereby increase NK cell cytotoxicity. Taken together, our results identify NFAT as a negative regulator of NK cell function. In addition, we provide the first evidence for a direct functional involvement of NFAT1 and NFAT2 in NK cell antitumor reactivity by regulation tumor infiltration and cytotoxicity of NK cell.
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Zanotti, Stefano, and Ernesto Canalis. "Notch Suppresses Nuclear Factor of Activated T Cells (Nfat) Transactivation and Nfatc1 Expression in Chondrocytes." Endocrinology 154, no. 2 (December 21, 2012): 762–72. http://dx.doi.org/10.1210/en.2012-1925.
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Notch1 to Notch4 transmembrane receptors determine cell fate, and release of the Notch intracellular domain (NICD) in the cytoplasm induces gene expression. Notch regulates endochondral ossification, but it is not clear whether Notch interacts with signals controlling chondrocyte differentiation. Nuclear factor of activated T cells (Nfatc) transcription factors regulate chondrogenesis, and we asked whether Notch modifies Nfat signaling in chondrocytes. Notch was induced in teratocarcinoma ATDC5 chondrogenic cells infected with a retroviral vector, where the cytomegalovirus (CMV) promoter directs NICD expression. NICD suppressed chondrocyte differentiation and inhibited Nfat transactivation and Nfatc1 expression. Notch was activated in chondrocytes from RosaNotch mice, where the Rosa26 promoter is upstream of a loxP-flanked STOP cassette and NICD. To excise the STOP cassette and express NICD, RosaNotch chondrocytes were infected with an adenoviral vector where the CMV promoter directs Cre expression (Ad-CMV-Cre). Notch1 and Notch2 mediate the effects of Notch in skeletal cells, and to inhibit Notch signaling, chondrocytes from mice homozygous for Notch1 and Notch2 alleles targeted with loxP sites were infected with Ad-CMV-Cre. NICD suppressed chondrogenic nodules formation and expression of selected chondrocyte gene markers, induced Col10a1 and Mmp13, and suppressed Nfat transactivation and Nfatc1 expression, whereas inactivation of Notch1 and Notch2 did not affect chondrocyte differentiation. To investigate Nfatc1 function in chondrocytes, Nfatc1 was induced in RosaNotch chondrocytes overexpressing NICD or controls. Nfatc1 suppressed chondrocyte differentiation and opposed Col10a1 induction by Notch. In conclusion, Notch suppresses Nfat transactivation in chondrocytes and Notch and Nfatc1 regulate chondrocyte differentiation.
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Kiani, Alexander, Francisco J. Garcı́a-Cózar, Ivonne Habermann, Stefanie Laforsch, Toni Aebischer, Gerhard Ehninger, and Anjana Rao. "Regulation of interferon-γ gene expression by nuclear factor of activated T cells." Blood 98, no. 5 (September 1, 2001): 1480–88. http://dx.doi.org/10.1182/blood.v98.5.1480.
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Transcription factors of the nuclear factor of activated T cells (NFAT) family are thought to regulate the expression of a variety of inducible genes such as interleukin-2 (IL-2), IL-4, and tumor necrosis factor-α. However, it remains unresolved whether NFAT proteins play a role in regulating transcription of the interferon- γ (IFN-γ) gene. Here it is shown that the transcription factor NFAT1 (NFATc2) is a major regulator of IFN-γ production in vivo. Compared with T cells expressing NFAT1, T cells lacking NFAT1 display a substantial IL-4–independent defect in expression of IFN-γ mRNA and protein. Reduced IFN-γ production by NFAT1−/−× IL-4−/− T cells is observed after primary in vitro stimulation of naive CD4+ T cells, is conserved through at least 2 rounds of T-helper cell differentiation, and occurs by a cell-intrinsic mechanism that does not depend on overexpression of the Th2-specific factors GATA-3 and c-Maf. Concomitantly, NFAT1−/−× IL-4−/− mice show increased susceptibility to infection with the intracellular parasiteLeishmania major. Moreover, IFN-γ production in a murine T-cell clone is sensitive to the selective peptide inhibitor of NFAT, VIVIT. These results suggest that IFN-γ production by T cells is regulated by NFAT1, most likely at the level of gene transcription.
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Chaudhry, M. Zeeshan, Lisa Borkner, Upasana Kulkarni, Friederike Berberich-Siebelt, and Luka Cicin-Sain. "NFAT signaling is indispensable for persistent memory responses of MCMV-specific CD8+ T cells." PLOS Pathogens 20, no. 2 (February 12, 2024): e1012025. http://dx.doi.org/10.1371/journal.ppat.1012025.
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Cytomegalovirus (CMV) induces a unique T cell response, where antigen-specific populations do not contract, but rather inflate during viral latency. It has been proposed that subclinical episodes of virus reactivation feed the inflation of CMV-specific memory cells by intermittently engaging T cell receptors (TCRs), but evidence of TCR engagement has remained lacking. Nuclear factor of activated T cells (NFAT) is a family of transcription factors, where NFATc1 and NFATc2 signal downstream of TCR in mature T lymphocytes. We show selective impacts of NFATc1 and/or NFATc2 genetic ablations on the long-term inflation of MCMV-specific CD8+ T cell responses despite largely maintained responses to acute infection. NFATc1 ablation elicited robust phenotypes in isolation, but the strongest effects were observed when both NFAT genes were missing. CMV control was impaired only when both NFATs were deleted in CD8+ T cells used in adoptive immunotherapy of immunodeficient mice. Transcriptome analyses revealed that T cell intrinsic NFAT is not necessary for CD8+ T cell priming, but rather for their maturation towards effector-memory and in particular the effector cells, which dominate the pool of inflationary cells.
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Rinne, Andreas, Nidhi Kapur, Jeffery D. Molkentin, Steven M. Pogwizd, Donald M. Bers, Kathrin Banach, and Lothar A. Blatter. "Isoform- and tissue-specific regulation of the Ca2+-sensitive transcription factor NFAT in cardiac myocytes and heart failure." American Journal of Physiology-Heart and Circulatory Physiology 298, no. 6 (June 2010): H2001—H2009. http://dx.doi.org/10.1152/ajpheart.01072.2009.
Full textAbstract:
Nuclear factors of activated T cells (NFATs) are Ca2+-sensitive transcription factors that have been implicated in hypertrophy, heart failure (HF), and arrhythmias. Cytosolic NFAT is activated by dephosphorylation by the Ca2+-sensitive phosphatase calcineurin, resulting in translocation to the nucleus, which is opposed by kinase activity, rephosphorylation, and nuclear export. Four different NFAT isoforms are expressed in the heart. The activation and regulation of NFAT in adult cardiac myocytes, which may depend on the NFAT isoform and cell type, are not fully understood. This study compared basal localization, import, and export of NFATc1 and NFATc3 in adult atrial and ventricular myocytes to identify isoform- and tissue-specific regulatory mechanisms of NFAT activation under physiological conditions and in HF. NFAT-green fluorescent protein fusion proteins and NFAT immunocytochemistry were used to analyze NFAT regulation in adult cat and rabbit myocytes. NFATc1 displayed basal nuclear localization in atrial and ventricular myocytes, an effect that was attenuated by reducing intracellular Ca2+ concentration and inhibiting calcineurin, and enhanced by the inhibition of nuclear export. In contrast, NFATc3 was localized to the cytoplasm but could be driven to the nucleus by angiotensin II and endothelin-1 stimulation in atrial, but not ventricular, cells. Inhibition of nuclear export (by leptomycin B) facilitated nuclear localization in both cell types. Ventricular myocytes from HF rabbits showed increased basal nuclear localization of endogenous NFATc3 and reduced responsiveness of NFAT translocation to phenylephrine stimulation. In control myocytes, Ca2+ overload, leading to spontaneous Ca2+ waves, induced substantial translocation of NFATc3 to the nucleus. We conclude that the activation of NFAT in adult cardiomyocytes is isoform and tissue specific and is tightly controlled by nuclear export. NFAT is activated in myocytes from HF animals and may be secondary to Ca2+ overload.
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Zhou, Yuning, Qingding Wang, Zheng Guo, Heidi L. Weiss, and B. Mark Evers. "Nuclear factor of activated T-cell c3 inhibition of mammalian target of rapamycin signaling through induction of regulated in development and DNA damage response 1 in human intestinal cells." Molecular Biology of the Cell 23, no. 15 (August 2012): 2963–72. http://dx.doi.org/10.1091/mbc.e12-01-0037.
Full textAbstract:
The nuclear factor of activated T-cell (NFAT) proteins are a family of transcription factors (NFATc1–c4) involved in the regulation of cell differentiation. We identified REDD1, a negative regulator of mammalian target of rapamycin (mTOR) through the tuberous sclerosis complex (TSC1/2 complex), as a new molecular target of NFATc3. We show that treatment with a combination of phorbol 12-myristate 13-acetate (PMA) plus ionophore A23187 (Io), which induces NFAT activation, increased REDD1 mRNA and protein expression and inhibited mTOR signaling; pretreatment with the calcineurin inhibitor cyclosporin A (CsA), an antagonist of NFAT signaling, decreased REDD1 induction and mTOR inhibition. Knockdown of NFATc3, not NFATc1, NFATc2, or NFATc4, attenuated PMA/Io-induced REDD1 expression. Treatment with PMA/Io increased REDD1 promoter activity and increased NFATc3 binding to the REDD1 promoter. Overexpression of NFATc3 increased REDD1 mRNA and protein expression and increased PMA/Io-mediated REDD1 promoter activity. Treatment with PMA/Io increased expression of the goblet cell differentiation marker MUC2; these changes were attenuated by pretreatment with CsA or knockdown of REDD1 or NFATc3. Overexpression of NFATc3 increased, while knockdown of TSC2 decreased, MUC2 expression. We provide evidence showing NFATc3 inhibits mTOR via induction of REDD1. Our results suggest a role for the NFATc3/REDD1/TSC2 axis in the regulation of intestinal cell differentiation.
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Märklin, Melanie, Samuel Holzmayer, Kübra Kaban, Martin R. Müller, and Helmut R. Salih. "Abstract 2104: NK cell immunosurveillance of tumors is regulated by NFAT1 and NFAT2." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2104. http://dx.doi.org/10.1158/1538-7445.am2022-2104.
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Abstract NK cells are lymphoid components of innate immunity and play an important role in tumor immunosurveillance. One of the major transcriptional regulators in lymphoid cells is NFAT (Nuclear Factor of Activated T cells), controlling lymphocyte development and activity. However, while the role of NFAT signaling is well defined in T cells, the cytotoxic lymphocytes of adaptive immunity, surprisingly little is known regarding the relevance of this transcription factor family in NK cells as effector cells of innate immunity. Available data indicate that NFAT activity is dispensable for development of NK cells. However, several lines of evidence including reports on the effects of the immunosuppressive drugs cyclosporin A and tacrolimus, which mediate their effects through inhibition of calcineurin and consecutively NFAT, implicate an involvement of the NFAT family in NK cell function. We here employed different genetic mouse models to unravel the role of NFAT1 (NFATc2) and NFAT2 (NFATc1) in NK cell reactivity. When NK cells with knockout (KO) of NFAT1 or NFAT2 compared to NK cells of control mice (WT) were employed in in vitro analyses, lack of either NFAT was found to surprisingly result in enhanced NK cell degranulation as well as increased production of granzyme B and perforin upon stimulation of activating receptors like NK1.1 or Nkp46 or upon co-culture with different leukemia and solid tumor tumor cells. In line, cytotoxicity assays revealed increased lysis of YAC-1 and B16F10 tumor cells by both NFAT1- and NFAT2-deficient NK cells as compared to WT controls. The inhibitory effect of NFAT transcription factors on NK cell effector function could also be confirmed in vivo by employing WT and NFAT KO animals in syngeneic B16F10 melanoma and RMA-S flank tumor models, which revealed a significantly reduced tumor burden in NFAT1 and NFAT2 KO mice. Comparative analyses with single NFAT as well as NFAT1+NFAT2 double KO and WT animals further confirmed the inhibitory effect of NFAT1 and NFAT2 and pointed to additive effects of NFAT1 and NFAT2 in NK cell tumor immunosurveillance. Taken together, our results provide the first evidence for the direct functional involvement of NFAT1 and NFAT2 in NK cell antitumor reactivity and, in contrast to T and B cells, identify NFAT as a negative regulator of NK cell function. Citation Format: Melanie Märklin, Samuel Holzmayer, Kübra Kaban, Martin R. Müller, Helmut R. Salih. NK cell immunosurveillance of tumors is regulated by NFAT1 and NFAT2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2104.
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Lo, Yu-Hsun, Chia-Chen Wu, Hsiu-Ming Shih, and Ming-Zong Lai. "Promyelocytic leukemia protein specifically augments the activation of NFAT (136.11)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 136.11. http://dx.doi.org/10.4049/jimmunol.182.supp.136.11.
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Abstract Promyelocytic leukemia (PML) protein is a tumor suppressor with complicated action mechanisms not yet fully understood. Nuclear factor of activated T cells (NFAT) is an important factor for T cell functions. In this study, we found that PML specifically enhanced the transcription activation of NFAT. In PML-null mouse embryonic fibroblasts, no transcription activity of NFAT could be detected. There was a selective requirement of PML isoform in NFAT activation: PML-I and PML-VI, but not PML-IV, increased NFAT transactivation. PML specifically promoted the expression of many, but not all, NFAT targeted genes, including TNF Ą, TRAIL and Cbl-b. A specific binding of PML to NFATc was found by GST pull down assay and immuno-precipitation. The interaction of PML with NFATc in vivo was further confirmed by ChIP and DNA affinity precipitation assay (DAPA) analysis. Knockdown of PML was associated with reduced nuclear presence of NFAT. The unexpected coupling of PML with NFAT reveals a novel mechanism underlying the diverse physiological functions of PML.
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Masuda, Tatsuya, Hirohito Kubota, Naoya Sakuramoto, Asuka Hada, Ayaka Horiuchi, Asami Sasaki, Kanako Takeda, et al. "RUNX-NFAT Axis As a Novel Therapeutic Target for AML and T Cell Immunity." Blood 136, Supplement 1 (November 5, 2020): 25–26. http://dx.doi.org/10.1182/blood-2020-143458.
Full textAbstract:
Runt-related transcription factor (RUNX) transcription factors are essential regulators of diverse developmental processes. In mammals, there are three RUNX genes, RUNX1, RUNX2, and RUNX3. All RUNX proteins contain a highly conserved DNA-binding domain, called the runt-homology domain (RHD), which is responsible for DNA-binding and interaction with a partner, core binding factor subunit β (CBFβ). They regulate transcription of target genes, involving hematopoietic differentiation, cell cycle regulation, p53 pathways, and so on. From our previous studies, we assume that compensation mechanism is present among the RUNX family members. RUNX plays pivotal roles in leukemogenesis and inhibition of RUNX has now been widely recognized as a novel strategy in anti-leukemic therapies. However, common mechanism via RUNX in diverse acute myeloid leukemia (AML) remains elusive. Here, we demonstrate that targeting RUNX-nuclear factor of activated T cells 2 (NFATC2) axis is an effective strategy to suppress drug-resistant (DR)-acute promyelocytic leukemia (APL) cells. Silencing of RUNX and NFATC2 in DR-APL cells suppressed cell growth and induced apoptotic cell death. Next, by RNA-seq analysis of several AML patient cohorts, we confirmed that a strong positive correlation between RUNX family (RUNX1,2,3: Pan RUNX) and NFAT family (NFATC1,2,3,4, NFAT5: Pan NFAT) exists not only in APL but also in all hematopoietic malignancies and that AML forms the Pan RUNX high-Pan NFAT high expression cluster. Inspection of the NFATC1-3 promoter revealed the RUNX binding sequence, and direct transcriptionally regulation of NFATC1-3 by RUNX family was confirmed in both chromatin immunoprecipitation (ChIP)-seq analysis and dual luciferase reporter assay. We believe that RUNX-NFAT axis could be an important target in diverse AML. Next, considering the well-established role of RUNX and NFATC2 in T cell immunity, we also apply targeting RUNX-NFATC2 strategy to suppress T cell activation and xenogeneic graft-versus-host disease (GVHD).The expansion of donor T cells requires IL-2, and aGVHD has been defined as a Th1-mediated disease. It is now well known that RUNX, especially RUNX1 and RUNX3 , are highly expressed in T cells, and directly regulate Th1 cytokine genes. As immunosuppressive approach for the prevention or treatment of aGVHD, calcineurin inhibitors, cyclosporine A and tacrolimus, inhibit GVHD by preventing the activation of NFAT, and steroid inhibits transcription of proinflammatory genes. We suppose that targeting RUNX can downregulate NFAT and also cytokine genes in T cell. RUNX1 knockdown and PanRUNX knockdown led to deceased NFATC2 and cytokine gene expression in cytokine-producing Jurkat cell line. It was also confirmed that by inhibiting the RUNX family and suppressing the NFATC2 family at the transcriptional level, the amount of the total NFATC family was significantly reduced compared with the drug that suppresses the nuclear translocation of NFATc2.The importance of RUNX-NFATC2 axis in T cell immunity was also exactly confirmed by the rescue experiments. Finally, to achieve "cluster regulation of RUNX (CROX)" strategy, we have been developing a novel RUNX inhibitor: chlorambucil-conjugated pyrrole-imidazole (PI) polyamides (Chb-M') that targets consensus RUNX-binding sequences, and specifically inhibits binding of RUNX family members. So, Chb-M' can switch off the RUNX target genes efficiently. In diverse AML including APL, core binding factor (CBF)-AML, mixed lineage leukemia (MLL)-rearranged AML, and AML-M0 and so on, Chb-M' was remarkably effective, and suppressed the expression of NFAT family in the protein level and induced apoptotic cell death. ChbM' also had a prominent effect in the AMLPDX model.The importance of RUNX-NFAT axis in AML was confirmed by the pharmacological rescue experiments using phorbol 12-myristate 13-acetate (PMA) and Ionomycin stimulation. Chb-M' also suppressed NFATC2 and cytokine gene expression in peripheral blood mononuclear cells (PBMC) and ameliorated GVHD for xenogeneic GVHD mouse model by transplanting human PBMC into immunodeficient mice. Taken together, we show RUNX could be a novel therapeutic target against diverse AML and GVHD through targeting RUNX-NFAT axis. Disclosures No relevant conflicts of interest to declare.
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Reppert, Sarah, Ildiko Boross, Michael Koslowski, Özlem Türeci, Hans-Anton Lehr, Laurie H. Glimcher, and Susetta Finotto. "The role of NFATc1 in tumor T cell responses to lung cancer (101.6)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 101.6. http://dx.doi.org/10.4049/jimmunol.184.supp.101.6.
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Abstract Nuclear factor of activated T cells (NFAT) proteins represent a Ca2+/calcineurin- regulated family of transcription factors that control T cell differentiation processes. Specifically NFATc1 and NFATc2 are highly expressed in peripheral T cells and activate the IL-2 and IL-4 promoters, suggesting that the Ca2+-regulated calcineurin/NFAT cascade controls alternative pathways of T cell activation and peripheral tolerance. NFATc1 is strongly activated upon antigen dependent T cell receptor engagement and induces genes that are involved in T cell effector function. In this study we describe that patients affected by lung Adenocarcinoma showed increased NFATc1 mRNA and protein levels in their lungs suggesting an involvement of NFATc1 on lung tumor development. To define the role of NFATc1 on lung cancer we start to analyze NFATc1 deficient mice in a murine model of lung Melanoma. Since NFATc1-deficient mice die at the embryonic stage, we bred conditional NFATc1 mice with CD4-Cre mice to gain insight into the role of NFATc1 in tumor T cell responses. Our preliminary results in this model showed a reduced tumor area in NFATc1-deficient mice compared to wild type mice. We also demonstrated here, that naïve T cells, isolated from NFATc1-deficient mice, produced less IL-17 under Th17- skewing conditions compared to those isolated from wild-type mice indicating a pathogenetic effect mediated by NFATc1 via IL-17 in lung tumor that must be further investigated.
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Robbs, Bruno K., Andre L. S. Cruz, Miriam B. F. Werneck, Giuliana P. Mognol, and João P. B. Viola. "Dual Roles for NFAT Transcription Factor Genes as Oncogenes and Tumor Suppressors." Molecular and Cellular Biology 28, no. 23 (September 22, 2008): 7168–81. http://dx.doi.org/10.1128/mcb.00256-08.
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ABSTRACT Nuclear factor of activated T cells (NFAT) was first described as an activation and differentiation transcription factor in lymphocytes. Several in vitro studies suggest that NFAT family members are redundant proteins. However, analysis of mice deficient for NFAT proteins suggested different roles for the NFAT family of transcription factors in the regulation of cell proliferation and apoptosis. NFAT may also regulate several cell cycle and survival factors influencing tumor growth and survival. Here, we demonstrate that two constitutively active forms of NFAT proteins (CA-NFAT1 and CA-NFAT2 short isoform) induce distinct phenotypes in NIH 3T3 cells. Whereas CA-NFAT1 expression induces cell cycle arrest and apoptosis in NIH 3T3 fibroblasts, CA-NFAT2 short isoform leads to increased proliferation capacity and induction of cell transformation. Furthermore, NFAT1-deficient mice showed an increased propensity for chemical carcinogen-induced tumor formation, and CA-NFAT1 expression subverted the transformation of NIH 3T3 cells induced by the H-rasV12 oncogene. The differential roles for NFAT1 are at least partially due to the protein C-terminal domain. These results suggest that the NFAT1 gene acts as a tumor suppressor gene and the NFAT2 short isoform acts gene as an oncogene, supporting different roles for the two transcription factors in tumor development.
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Kamioka, Yuto, Yukihiko Hiroshima, Shinnosuke Kawahara, Masaaki Murakawa, Naoto Yamamoto, Hiroshi Tamagawa, Takashi Oshima, Yohei Miyagi, Yasushi Rino, and Soichiro Morinaga. "Impact of nuclear factor of activated T cells (NFAT) families as a poor prognostic factor in pancreatic cancer patients." Journal of Clinical Oncology 40, no. 4_suppl (February 1, 2022): 584. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.584.
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584 Background: Pancreatic cancer microenvironment is crucial in cancer development, and cancer-stromal interactions have been recognized as important targets for cancer therapy. Nuclear factor of activated T-cells (NFAT) has been found in T cells as a transcriptional activator of IL-2, and known to be involved in various processes including the immune system. In cancer tissues, NFAT has been reported to be involved in metastasis. In breast and colorectal cancers, NFATc2 and NFAT5 have been reported to interact with integrins to promote cancer cell migration. On the other hand, in pancreatic cancer, NFAT5 has been reported to be a poor prognostic factor via regulation of PGK1 transcription. In the present study, we evaluated the expression of NFATc2 and NFAT5 in pancreatic cancer and examined their relationship with prognosis. Methods: One hundred and sixty five pancreatic cancer patients who underwent curative-intrent resection at our hospital between 2010 and 2020 were included in this study. We performed immunostaining for NFATc2 and NFAT5 using the tissue micro array. We evaluated the expression of NFATc2 and NFAT5 protein and examined their correlation with clinicopathological factors. Results: Of the 165 pancreatic cancer cases, we detected increased NFATc2 protein expression in cytoplasm of cancer cells in 53 cases (32.1%) and NFAT5 in 104 cases (63.0%), and NFATc2/NFAT5 co-expression in 43 cases (26.1%). NFATc2 expression was not correlated with any clinicopathological factors, NFAT5 expression was correlated with venous invasion (p = 0.047), and NFATc2/NFAT5 co-expression was slightly correlated with Stage (p = 0.054). Relapse free survival (RFS) was estimated in all 165 patients. There was no significant difference for RFS in either NFATc2-high group or NFAT5-high group (p = 0.314 or p = 0.574), however, NFATc2/NFAT5 co-expression group showed significantly poor RFS (p = 0.023). Overall survival (OS) was also estimated in all 165 patients. There was no significant difference for OS in either NFATc2-high group or NFAT5-high group (p = 0.146 or p = 0.529), however, NFATc2/NFAT5 co-expression group showed significantly poor survival (p = 0.006). In multivariate analysis, lymphatic invasion, curability and NFATc2/NFAT5 co-expression were independent prognostic factors for RFS, and lymphatic invasion, curability, presence of adjuvant therapy and NFATc2/NFAT5 co-expression were independent prognostic factors for OS. Conclusions: In pancreatic cancer, NFATc2/NFAT5 co-expression was suggested to be involved in the critical process of pancreatic cancer progression, and may be a novel therapeutic target.
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Xu, Tianhao, Ashleigh Keller, and Gustavo J. Martinez. "NFAT1 and NFAT2 differentially regulate CTL differentiation upon acute viral infection." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 189.5. http://dx.doi.org/10.4049/jimmunol.202.supp.189.5.
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Abstract CD8+ T cell differentiation orchestrated by transcription regulators is critical for balancing pathogen eradication and long-term immunity by effector and memory CTLs respectively. The transcription factor Nuclear Factor of Activated T cells (NFAT) family members are known for their roles in T cell development and activation but still largely undetermined in CD8+ T cell differentiation in vivo. Here, we interrogated the role of two NFAT family members, NFAT1 and NFAT2, in the effector and memory phase of CD8+ T cell differentiation using LCMVArm acute infection model. We found that NFAT1 is critical for effector population generation whereas NFAT2 is required for promoting memory CTLs in a cell-intrinsic manner. Moreover, we found that mice lacking both NFAT1 and NFAT2 in T cells display a significant increase in KLRG1hi and CD127hi population and are unable to clear an acute viral infection. NFAT-deficient CTLs showed different degrees of impaired IFN-g and TNF-a expression with NFAT1 being mainly responsible for IFN-g production as well as for antigen-specific cytotoxicity. To further comprehend the molecular mechanisms behind this differential CTL commitment upon deficiency of NFAT members, we performed RNA-seq analysis. Our results have identified genes uniquely regulated by NFAT1 or NFAT2, and we are in the process of further understanding how this differential transcriptome translates into the observed distinct CTL differentiation. Overall, our results suggest that NFAT1 and NFAT2 have distinct roles in mediating CD8+ T cell differentiation and function.
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Yang, Teddy T. C., Hee Yun Suk, XiaoYong Yang, Opeyemi Olabisi, Raymond Y. L. Yu, Jorge Durand, Linda A. Jelicks, et al. "Role of Transcription Factor NFAT in Glucose and Insulin Homeostasis." Molecular and Cellular Biology 26, no. 20 (August 14, 2006): 7372–87. http://dx.doi.org/10.1128/mcb.00580-06.
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ABSTRACT Compromised immunoregulation contributes to obesity and complications in metabolic pathogenesis. Here, we demonstrate that the nuclear factor of activated T cell (NFAT) group of transcription factors contributes to glucose and insulin homeostasis. Expression of two members of the NFAT family (NFATc2 and NFATc4) is induced upon adipogenesis and in obese mice. Mice with the Nfatc2 −/− Nfatc4 −/− compound disruption exhibit defects in fat accumulation and are lean. Nfatc2 −/− Nfatc4 −/− mice are also protected from diet-induced obesity. Ablation of NFATc2 and NFATc4 increases insulin sensitivity, in part, by sustained activation of the insulin signaling pathway. Nfatc2 −/− Nfatc4 −/− mice also exhibit an altered adipokine profile, with reduced resistin and leptin levels. Mechanistically, NFAT is recruited to the transcription loci and regulates resistin gene expression upon insulin stimulation. Together, these results establish a role for NFAT in glucose/insulin homeostasis and expand the repertoire of NFAT function to metabolic pathogenesis and adipokine gene transcription.
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Pontrelli, Paola, Margherita Gigante, Federica Spadaccino, Giuseppe Stefano Netti, Marilisa Saldarelli, Luigi Balducci, Maddalena Gigante, et al. "CD40 Cross-Linking Induces Migration of Renal Tumor Cell through Nuclear Factor of Activated T Cells (NFAT) Activation." International Journal of Molecular Sciences 22, no. 16 (August 18, 2021): 8871. http://dx.doi.org/10.3390/ijms22168871.
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CD40 crosslinking plays an important role in regulating cell migration, adhesion and proliferation in renal cell carcinoma (RCC). CD40/CD40L interaction on RCC cells activates different intracellular pathways but the molecular mechanisms leading to cell scattering are not yet clearly defined. Aim of our study was to investigate the main intracellular pathways activated by CD40 ligation and their specific involvement in RCC cell migration. CD40 ligation increased the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun NH (2)-terminal kinase (JNK) and p38 MAPK. Furthermore, CD40 crosslinking activated different transcriptional factors on RCC cell lines: AP-1, NFkB and some members of the Nuclear Factor of Activated T cells (NFAT) family. Interestingly, the specific inhibition of NFAT factors by cyclosporine A, completely blocked RCC cell motility induced by CD40 ligation. In tumor tissue, we observed a higher expression of NFAT factors and in particular an increased activation and nuclear migration of NFATc4 on RCC tumor tissues belonging to patients that developed metastases when compared to those who did not. Moreover, CD40-CD40L interaction induced a cytoskeleton reorganization and increased the expression of integrin β1 on RCC cell lines, and this effect was reversed by cyclosporine A and NFAT inhibition. These data suggest that CD40 ligation induces the activation of different intracellular signaling pathways, in particular the NFATs factors, that could represent a potential therapeutic target in the setting of patients with metastatic RCC.
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Pham, Lan V., Archito T. Tamayo, Linda C. Yoshimura, Yen-Chiu Lin-Lee, and Richard J. Ford. "Constitutive NF-κB and NFAT activation in aggressive B-cell lymphomas synergistically activates the CD154 gene and maintains lymphoma cell survival." Blood 106, no. 12 (December 1, 2005): 3940–47. http://dx.doi.org/10.1182/blood-2005-03-1167.
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Abnormalities in B-lymphocyte CD40 ligand (CD154) expression have been described for a number of immunologic diseases, including B-cell lymphomas. Although functional analysis of the CD154 gene and protein has been extensive, little is known about the mechanisms controlling CD154 expression in activated T cells, and even less is known for normal and malignant B cells. In this study we describe the transcriptional mechanism controlling CD154 expression in large B-cell lymphoma (LBCL). We show that the nuclear factor of activated T cells (NFAT) transcription factor is also constitutively activated in LBCL. We demonstrate that the constitutively active NFATc1 and c-rel members of the NFAT and nuclear factor–κB (NF-κB) families of transcription factors, respectively, directly interact with each other, bind to the CD154 promoter, and synergistically activate CD154 gene transcription. Down-regulation of NFATc1 or c-rel with small interfering RNA (siRNA) or chemical inhibitors inhibits CD154 gene transcription and lymphoma cell growth. These findings suggest that targeting NF-κB and NFAT, by inhibiting the expression of these transcription factors, or interdicting their interaction may provide a therapeutic rationale for patients with non-Hodgkin lymphoma of B-cell origin, and possibly other disorders that display dysregulated CD154 expression.
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Cron, Randy Q., Susan J. Bort, Yunxia Wang, Mark W. Brunvand, and David B. Lewis. "T Cell Priming Enhances IL-4 Gene Expression by Increasing Nuclear Factor of Activated T Cells." Journal of Immunology 162, no. 2 (January 15, 1999): 860–70. http://dx.doi.org/10.4049/jimmunol.162.2.860.
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Abstract The repetitive activation of T cells (priming) enhances the expression of many cytokines, such as IL-4, but not others, such as IL-2. Molecular mechanisms underlying selective expression of cytokines by T cells remain poorly understood. Here we show that priming of CD4 T cells selectively enhances IL-4 expression relative to IL-2 expression by a transcriptional mechanism involving nuclear factor of activated T cells (NFAT) proteins. As detected by in vivo footprinting, priming markedly increases the activation-dependent engagement of the P0 and P1 NFAT-binding elements of the IL-4 promoter. Moreover, each proximal P element is essential for optimal IL-4 promoter activity. Activated primed CD4 T cells contain more NFAT1 and support greater NFAT-directed transcription than unprimed CD4 T cells, while activator protein 1 binding and activator protein 1-mediated transcription by both cell types is similar. Increased expression of wild-type NFAT1 substantially increases IL-4 promoter activity in unprimed CD4 T cells, suggesting NFAT1 may be limiting for IL-4 gene expression in this cell type. Furthermore, a truncated form of NFAT1 acts as a dominant-negative, reducing IL-4 promoter activity in primed CD4 T cells and confirming the importance of endogenous NFAT to increased IL-4 gene expression by effector T cells. NFAT1 appears to be the major NFAT family member responsible for the initial increased expression of IL-4 by primed CD4 T cells.
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Rinne, Andreas, and Lothar A. Blatter. "Activation of NFATc1 is directly mediated by IP3 in adult cardiac myocytes." American Journal of Physiology-Heart and Circulatory Physiology 299, no. 5 (November 2010): H1701—H1707. http://dx.doi.org/10.1152/ajpheart.00470.2010.
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The Ca2+-sensitive nuclear factor of activated T cell (NFAT) transcription factors are implicated in cardiac development and cellular remodeling associated with cardiac disease. In adult myocytes it is not resolved what specific Ca2+ signals control the activity of different NFAT isoforms in an environment that undergoes large changes of intracellular Ca2+ concentration with every heart beat. Cardiac myocytes possess the complete inositol 1,4,5-trisphosphate (IP3)/Ca2+-signaling cassette; however, its physiological and pathological significance has been a matter of ongoing debate. Therefore, we tested the hypothesis whether IP3 receptor activation regulates NFAT activity in cardiac myocytes. We used confocal microscopy to quantify the nuclear localization of NFATc1-green fluorescent protein (GFP) and NFATc3-GFP fusion proteins (quantified as the ratio of nuclear NFAT to cytoplasmic NFAT) in response to stimulation with neurohumoral agonists. In rabbit atrial myocytes, an overnight stimulation with endothelin-1, angiotensin II, and phenylephrine induced nuclear accumulation of NFATc1 that was sensitive to calcineurin inhibitors (cyclosporin A or inhibitor of NFAT-calcineurin association-6) and prevented by the IP3 receptor inhibitor 2-aminoethoxydiphenyl borate. Furthermore, a direct elevation of intracellular IP3 with a cell-permeable IP3 acetoxymethyl ester (10 μM) induced nuclear localization of NFATc1. With a fluorescence-based in vivo assay, we showed that endothelin-1 also enhanced the transcriptional activity of NFATc1 in atrial cells. The agonists failed to activate NFATc1 in rabbit ventricular cells, which express IP3 receptors at a lower density than atrial cells. They also did not activate NFATc3, an isoform that is highly influenced by nuclear export processes, in both cell types. Our data show that the second messenger IP3 is directly involved in the activation of NFATc1 in adult atrial cardiomyocytes.
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Aoki, Yosuke, Guohua Zhao, Daoming Qiu, Lingfang Shi, and Peter N. Kao. "CsA-sensitive purine-box transcriptional regulator in bronchial epithelial cells contains NF45, NF90, and Ku." American Journal of Physiology-Lung Cellular and Molecular Physiology 275, no. 6 (December 1, 1998): L1164—L1172. http://dx.doi.org/10.1152/ajplung.1998.275.6.l1164.
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Human bronchial epithelial (HBE) cells express interleukin (IL)-2 [Y. Aoki, D. Qiu, A. Uyei, and P. N. Kao. Am. J. Physiol. 272 ( Lung Cell. Mol. Physiol. 16): L276–L286, 1997]. 16HBE-transformed cells contain constitutive and inducible nuclear DNA-binding activity for the purine-box/nuclear factor (NF) of activated T cell (NFAT) target DNA sequence in the human IL-2 enhancer. Transcriptional activation through the purine-box DNA sequence requires stimulation with phorbol 12-myristate 13-acetate + ionomycin, and this activation is inhibited by cyclosporin A. Immunohistochemical staining of 16HBE cells demonstrates nuclear expression of the purine-box DNA-binding proteins NF45 and NF90 and no expression of NFATp or NFATc. NF90 and NF45 associate with the DNA-dependent protein kinase catalytic subunit and the DNA-targeting subunits Ku80 and Ku70 (N. S. Ting, P. N. Kao, D. W. Chan, L. G. Lintott, and S. P. Lees-Miller. J. Biol. Chem. 273: 2136–2145, 1998). Antibodies to Ku potently inhibit the purine-box DNA-binding complex. The purine-box transcriptional regulator in 16HBE cells likely comprises NF45, NF90, Ku80, Ku70, and the DNA-dependent protein kinase catalytic subunit.
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Zaichuk, Tetiana A., Emelyn H. Shroff, Rebekah Emmanuel, Stephanie Filleur, Thomas Nelius, and Olga V. Volpert. "Nuclear Factor of Activated T Cells Balances Angiogenesis Activation and Inhibition." Journal of Experimental Medicine 199, no. 11 (June 7, 2004): 1513–22. http://dx.doi.org/10.1084/jem.20040474.
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It has been demonstrated that vascular endothelial cell growth factor (VEGF) induction of angiogenesis requires activation of the nuclear factor of activated T cells (NFAT). We show that NFATc2 is also activated by basic fibroblast growth factor and blocked by the inhibitor of angiogenesis pigment epithelial–derived factor (PEDF). This suggests a pivotal role for this transcription factor as a convergence point between stimulatory and inhibitory signals in the regulation of angiogenesis. We identified c-Jun NH2-terminal kinases (JNKs) as essential upstream regulators of NFAT activity in angiogenesis. We distinguished JNK-2 as responsible for NFATc2 cytoplasmic retention by PEDF and JNK-1 and JNK-2 as mediators of PEDF-driven NFAT nuclear export. We identified a novel NFAT target, caspase-8 inhibitor cellular Fas-associated death domain–like interleukin 1β–converting enzyme inhibitory protein (c-FLIP), whose expression was coregulated by VEGF and PEDF. Chromatin immunoprecipitation showed VEGF-dependent increase of NFATc2 binding to the c-FLIP promoter in vivo, which was attenuated by PEDF. We propose that one possible mechanism of concerted angiogenesis regulation by activators and inhibitors may be modulation of the endothelial cell apoptosis via c-FLIP controlled by NFAT and its upstream regulator JNK.
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Urso, Katia, Arantzazu Alfranca, Sara Martínez-Martínez, Amelia Escolano, Inmaculada Ortega, Antonio Rodríguez, and Juan Miguel Redondo. "NFATc3 regulates the transcription of genes involved in T-cell activation and angiogenesis." Blood 118, no. 3 (July 21, 2011): 795–803. http://dx.doi.org/10.1182/blood-2010-12-322701.
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Abstract The nuclear factor of activated T cells (NFAT) family of transcription factors plays important roles in many biologic processes, including the development and function of the immune and vascular systems. Cells usually express more than one NFAT member, raising the question of whether NFATs play overlapping roles or if each member has selective functions. Using mRNA knock-down, we show that NFATc3 is specifically required for IL2 and cyclooxygenase-2 (COX2) gene expression in transformed and primary T cells and for T-cell proliferation. We also show that NFATc3 regulates COX2 in endothelial cells, where it is required for COX2, dependent migration and angiogenesis in vivo. These results indicate that individual NFAT members mediate specific functions through the differential regulation of the transcription of target genes. These effects, observed on short-term suppression by mRNA knock-down, are likely to have been masked by compensatory effects in gene-knockout studies.
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Liu, Xikui K., Xin Lin, and Sarah L. Gaffen. "Crucial Role for Nuclear Factor of Activated T Cells in T Cell Receptor-mediated Regulation of Human Interleukin-17." Journal of Biological Chemistry 279, no. 50 (September 30, 2004): 52762–71. http://dx.doi.org/10.1074/jbc.m405764200.
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The biological activities of the inflammatory cytokine interleukin (IL)-17 have been widely studied. However, comparatively little is known about how IL-17 expression is controlled. Here, we examined the basis for transcriptional regulation of the human IL-17 gene. IL-17 secretion was induced in peripheral blood mononuclear cells following anti-CD3 cross-linking to activate the T cell receptor (TCR), and costimulatory signaling through CD28 strongly enhanced CD3-induced IL-17 production. To definecis-acting elements important for IL-17 gene regulation, we cloned 1.25 kb of genomic sequence upstream of the transcriptional start site. This putative promoter was active in Jurkat T cells following CD3 and CD28 cross-linking, and its activity was inhibited by cyclosporin A and MAPK inhibitors. The promoter was also active in Hut102 T cells, which we have shown to secrete IL-17 constitutively. Overexpression of nuclear factor of activated T cells (NFAT) or Ras enhanced IL-17 promoter activity, and studies in Jurkat lines deficient in specific TCR signaling pathways provided supporting evidence for a role for NFAT. To delineate the IL-17 minimal promoter, we created a series of 5′ truncations and identified a region between -232 and -159 that was sufficient for inducible promoter activity. Interestingly, two NFAT sites were located within this region, which bound to NFATc1 and NFATc2 in nuclear extracts from Hut102 and Jurkat cells. Moreover, mutations of these sites dramatically reduced both specific DNA binding and reporter gene activity, and chromatin immunoprecipitation assays showed occupancy of NFAT at this regionin vivo. Together, these data show that NFAT is the crucial sensor of TCR signaling in the IL-17 promoter.
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Ranger, Ann M., Louis C. Gerstenfeld, Jinxi Wang, Tamiyo Kon, Hyunsu Bae, Ellen M. Gravallese, Melvin J. Glimcher, and Laurie H. Glimcher. "The Nuclear Factor of Activated T Cells (Nfat) Transcription Factor Nfatp (Nfatc2) Is a Repressor of Chondrogenesis." Journal of Experimental Medicine 191, no. 1 (January 3, 2000): 9–22. http://dx.doi.org/10.1084/jem.191.1.9.
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Nuclear factor of activated T cells (NFAT) transcription factors regulate gene expression in lymphocytes and control cardiac valve formation. Here, we report that NFATp regulates chondrogenesis in the adult animal. In mice lacking NFATp, resident cells in the extraarticular connective tissues spontaneously differentiate to cartilage. These cartilage cells progressively differentiate and the tissue undergoes endochondral ossification, recapitulating the development of endochondral bone. Proliferation of already existing articular cartilage cells also occurs in some older animals. At both sites, neoplastic changes in the cartilage cells occur. Consistent with these data, NFATp expression is regulated in mesenchymal stem cells induced to differentiate along a chondrogenic pathway. Lack of NFATp in articular cartilage cells results in increased expression of cartilage markers, whereas overexpression of NFATp in cartilage cell lines extinguishes the cartilage phenotype. Thus, NFATp is a repressor of cartilage cell growth and differentiation and also has the properties of a tumor suppressor.
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Nilsson, Lisa M., Zheng-Wu Sun, Jenny Nilsson, Ina Nordström, Yung-Wu Chen, Jeffery D. Molkentin, Dag Wide-Swensson, Per Hellstrand, Marie-Louise Lydrup, and Maria F. Gomez. "Novel blocker of NFAT activation inhibits IL-6 production in human myometrial arteries and reduces vascular smooth muscle cell proliferation." American Journal of Physiology-Cell Physiology 292, no. 3 (March 2007): C1167—C1178. http://dx.doi.org/10.1152/ajpcell.00590.2005.
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The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. Confocal immunofluorescence and Western blot analysis revealed that endothelin-1 efficiently increases NFATc3 nuclear accumulation in native arteries. Endothelin-1 also stimulates NFAT-dependent transcriptional activity, as shown by a luciferase reporter assay. Both the agonist-induced NFAT nuclear accumulation and transcriptional activity were prevented by the calcineurin inhibitor CsA and by the novel NFAT blocker A-285222. Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries. Furthermore, by using small interfering RNA-mediated reduction of NFATc3, we show that this isoform is involved in the regulation of cell proliferation. Protein synthesis in intact arteries was investigated using autoradiography of [35S]methionine incorporation in serum-free culture. Inhibition of NFAT signaling did not affect overall protein synthesis or specifically the synthesis rates of major proteins associated with the contractile/cytoskeletal system. An intact contractile phenotype under these conditions was also shown by unchanged force response to depolarization or agonist stimulation. Our results demonstrate NFAT expression and activation in native human vessels and point out A-285222 as a powerful pharmacological blocker of NFAT signaling in the vasculature.
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Rengarajan, Jyothi, Kerri A. Mowen, Kathryn D. McBride, Erica D. Smith, Harinder Singh, and Laurie H. Glimcher. "Interferon Regulatory Factor 4 (IRF4) Interacts with NFATc2 to Modulate Interleukin 4 Gene Expression." Journal of Experimental Medicine 195, no. 8 (April 8, 2002): 1003–12. http://dx.doi.org/10.1084/jem.20011128.
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Proteins of the nuclear factor of activated T cells (NFAT) family of transcription factors are critical for lymphocyte activation in the immune system. In particular, NFATs are important regulators of inducible IL-4 gene expression. Interferon regulatory factor 4 (IRF4) is an immune system–restricted interferon regulatory factor that is required for lymphocyte activation, but its molecular functions in the T lineage remain to be elucidated. We demonstrate that IRF4 potently synergizes with NFATc2 to specifically enhance NFATc2-driven transcriptional activation of the IL-4 promoter. This function is dependent on the physical interaction of IRF4 with NFATc2. IRF4 synergizes with NFATc2 and the IL-4–inducing transcription factor, c-maf, to augment IL-4 promoter activity as well as to elicit significant levels of endogenous IL-4 production. Furthermore, naïve T helper cells from mice lacking IRF4 are compromised severely for the production of IL-4 and other Th2 cytokines. The identification of IRF4 as a partner for NFATc2 in IL-4 gene regulation provides an important molecular function for IRF4 in T helper cell differentiation.
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Chow, Chi-Wing, Mercedes Rincón, and Roger J. Davis. "Requirement for Transcription Factor NFAT in Interleukin-2 Expression." Molecular and Cellular Biology 19, no. 3 (March 1, 1999): 2300–2307. http://dx.doi.org/10.1128/mcb.19.3.2300.
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ABSTRACT The nuclear factor of activated T cells (NFAT) transcription factor is implicated in expression of the cytokine interleukin-2 (IL-2). Binding sites for NFAT are located in the IL-2 promoter. Furthermore, pharmacological studies demonstrate that the drug cyclosporin A inhibits both NFAT activation and IL-2 expression. However, targeted disruption of the NFAT1 and NFAT2 genes in mice does not cause decreased IL-2 secretion. The role of NFAT in IL-2 gene expression is therefore unclear. Here we report the construction of a dominant-negative NFAT mutant (dnNFAT) that selectively inhibits NFAT-mediated gene expression. The inhibitory effect of dnNFAT is mediated by suppression of activation-induced nuclear translocation of NFAT. Expression of dnNFAT in cultured T cells caused inhibition of IL-2 promoter activity and decreased expression of IL-2 protein. Similarly, expression of dnNFAT in transgenic mice also caused decreased IL-2 gene expression. These data demonstrate that NFAT is a critical component of the signaling pathway that regulates IL-2 expression.
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Park, Jungchan, Atsuko Takeuchi, and Surendra Sharma. "Characterization of a New Isoform of the NFAT (Nuclear Factor of Activated T Cells) Gene Family Member NFATc." Journal of Biological Chemistry 271, no. 34 (August 23, 1996): 20914–21. http://dx.doi.org/10.1074/jbc.271.34.20914.
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Park, Jungchan, Atsuko Takeuchi, and Surendra Sharma. "Characterization of a new isoform of the NFAT (nuclear factor of activated T cells) gene family member NFATc." Journal of Biological Chemistry 271, no. 52 (December 1996): 33705. http://dx.doi.org/10.1016/s0021-9258(19)78724-9.
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Park, Jungchan, Atsuko Takeuchi, and Surendra Sharma. "Characterization of a new isoform of the NFAT (nuclear factor of activated T cells) gene family member NFATc." Journal of Biological Chemistry 272, no. 36 (September 1997): 22974. http://dx.doi.org/10.1016/s0021-9258(19)65984-3.
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Ellert-Miklaszewska, Aleksandra, Agata Szymczyk, Katarzyna Poleszak, and Bozena Kaminska. "Delivery of the VIVIT Peptide to Human Glioma Cells to Interfere with Calcineurin-NFAT Signaling." Molecules 26, no. 16 (August 7, 2021): 4785. http://dx.doi.org/10.3390/molecules26164785.
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The activation of NFAT (nuclear factor of activated T cells) transcription factors by calcium-dependent phosphatase calcineurin is a key step in controlling T cell activation and plays a vital role during carcinogenesis. NFATs are overexpressed in many cancers, including the most common primary brain tumor, gliomas. In the present study, we demonstrate the expression of NFATs and NFAT-driven transcription in several human glioma cells. We used a VIVIT peptide for interference in calcineurin binding to NFAT via a conserved PxIxIT motif. VIVIT was expressed as a fusion protein with a green fluorescent protein (VIVIT-GFP) or conjugated to cell-penetrating peptides (CPP), Sim-2 or 11R. We analyzed the NFAT expression, phosphorylation, subcellular localization and their transcriptional activity in cells treated with peptides. Overexpression of VIVIT-GFP decreased the NFAT-driven activity and inhibited the transcription of endogenous NFAT-target genes. These effects were not reproduced with synthetic peptides: Sim2-VIVIT did not show any activity, and 11R-VIVIT did not inhibit NFAT signaling in glioma cells. The presence of two calcineurin docking sites in NFATc3 might require dual-specificity blocking peptides. The cell-penetrating peptides Sim-2 or 11R linked to VIVIT did not improve its action making it unsuitable for evaluating NFAT dependent events in glioma cells with high expression of NFATc3.
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Kyttaelae, Satu, Ivonne Habermann, Takashi Minami, Gerhard Ehninger, and Alexander Kiani. "Nuclear Factor of Activated T Cells Regulates Down Syndrome Critical Region 1 Gene Expression in Megakaryocytes." Blood 108, no. 11 (November 16, 2006): 1193. http://dx.doi.org/10.1182/blood.v108.11.1193.1193.
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Abstract The calcineurin-dependent NFAT (Nuclear Factors of Activated T cells) transcription factors were initially characterized as central mediators of inducible gene expression in activated T cells, but recently have also been implicated in regulating differentiation and function of a number of cell types outside the immune system. We have previously found that one member of the NFAT family, NFATc2, is strongly expressed in bone marrow megakaryocytes. The function of NFAT in this cell type, however, is unclear. The Down Syndrome Critical Region 1 (DSCR1) gene, located within the Down syndrome critical region of human chromosome 21, is overexpressed about 1,5-fold in patients with Down syndrome (DS) and has been implicated in the pathology of the disease. DSCR1 is a member of the calcipressin family of calcineurin inhibitors, and thereby serves as an endogenous suppressor of NFAT signalling. Furthermore, the expression of a specific isoform of the DSCR1 gene (exons 4–7) is thought to be regulated by NFAT, thus creating a potential regulatory feedback mechanism. Given the strong expression of NFATc2 in megakaryocytes, the complex interaction between DSCR1 and NFAT proteins, and the fact that DS children have a ~500-fold increased incidence of acute megakaryoblastic leukemia, we set out to analyze the expression and regulation of NFAT and DSCR1 in megakaryopoiesis. Pure populations of culture-derived (CD) megakaryocytes were obtained by culturing leukapheresis CD34+ cells in the presence of thrombopoietin. Using the calcium ionophor ionomycin and the calcineurin inhibitor cyclosporin A (CsA) in CD megakaryocytes as well as in various megakaryocytic cell lines, NFAT activation was found to be regulated in the same calcineurin-dependent and CsA-sensitive manner as is known from T lymphocytes. During the differentiation of CD34+ cells into megakaryocytes, the expression of NFATc2 protein was maintained at a high level, and progressive dephosphorylation of the protein in the course of the culture indicated activation of NFATc2 during the differentiation process. DSCR1 mRNA expression in CD34+ cells was low, but markedly upregulated during megakaryopoiesis. This upregulation was inhibited when differentiation was performed in the presence of CsA, an inhibitor of NFAT activation. In mature CD megakaryocytes as well as in all megakaryocytic cell lines tested, the expression of DSCR1 was further inducable by stimulating the cells with ionomycin and inhibited by treatment with CsA. To test the involvement of NFAT in the transcriptional regulation of the DSCR1 gene in megakaryocytes, CMK cell lines stably overexpressing either NFATc2 or the specific peptide inhibitor of NFAT activation, VIVIT, were generated by retroviral transduction. Overexpression of NFATc2 potently augmented, while VIVIT suppressed DSCR1 promoter transcriptional activity, confirming transcriptional regulation of DSCR1 expression by NFAT. These results establish DSCR1 as a transcriptional target gene for NFAT in megakaryocytes. The upregulation of DSCR1 expression during megakaryopoiesis suggests a possible implication of DSCR1 in megakaryocytic differentiation and should encourage further investigation into the reciprocal roles of DSCR1 and NFAT in the development of megakaryoblastic leukemia in DS.
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Jabr, Rita I., Andrew J. Wilson, Marilyn H. Riddervold, Alex H. Jenkins, Brian A. Perrino, and Lucie H. Clapp. "Nuclear translocation of calcineurin Aβ but not calcineurin Aα by platelet-derived growth factor in rat aortic smooth muscle." American Journal of Physiology-Cell Physiology 292, no. 6 (June 2007): C2213—C2225. http://dx.doi.org/10.1152/ajpcell.00139.2005.
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Calcineurin regulates the proliferation of many cell types through activation of the nuclear factor of activated T cells (NFAT). Two main isoforms of the calcineurin catalytic subunit [calcineurin A (CnA)α and CnAβ] have been identified, although their expression and function are largely unknown in smooth muscle. Western blot analysis and confocal imaging were performed in freshly isolated and cultured rat aortic myocytes to identify these CnA isoforms and elucidate the effect of PDGF on their cellular distribution and interaction with NFAT isoforms. CnAα and CnAβ isoforms displayed differential cellular distribution, with CnAα being evenly distributed between the nucleus and cytosol and CnAβ being restricted to the cytosol. In contrast with the rat brain, we found no evidence for particulate/membrane localization of calcineurin. PDGF caused significant nuclear translocation of CnAβ and induced smooth muscle cell proliferation, with both effects being abrogated by the calcineurin inhibitor cyclosporin A, the novel NFAT inhibitors A-285222 and inhibitor of NFAT-calcineurin association-6, and the adenylyl cyclase activator forskolin. PDGF also caused cyclosporin A-sensitive translocation of NFATc3, with no apparent effect on either CnAα or NFATc1 distribution. Moreover, ∼87% of nuclear CnAβ was found to colocalize with NFATc3, consistent with the finding that CnAβ bound more avidly than CnAα to a glutathione S-transferase-NFATc3 fusion protein. Based on their differential distribution in aortic muscle, our results suggest that CnAα and CnAβ are likely to have different cellular functions. However, CnAβ appears to be specifically activated by PDGF, and we postulate that calcineurin-dependent nuclear translocation of NFATc3 is involved in smooth muscle proliferation induced by this mitogen.
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Swoap, Steven J., R. Bridge Hunter, Eric J. Stevenson, Heather Mitchell Felton, Nilesh V. Kansagra, Joshua M. Lang, Karyn A. Esser, and Susan C. Kandarian. "The calcineurin-NFAT pathway and muscle fiber-type gene expression." American Journal of Physiology-Cell Physiology 279, no. 4 (October 1, 2000): C915—C924. http://dx.doi.org/10.1152/ajpcell.2000.279.4.c915.
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To test for a role of the calcineurin-NFAT (nuclear factor of activated T cells) pathway in the regulation of fiber type-specific gene expression, slow and fast muscle-specific promoters were examined in C2C12 myotubes and in slow and fast muscle in the presence of calcineurin or NFAT2 expression plasmids. Overexpression of active calcineurin in myotubes induced both fast and slow muscle-specific promoters but not non-muscle-specific reporters. Overexpression of NFAT2 in myotubes did not activate muscle-specific promoters, although it strongly activated an NFAT reporter. Thus overexpression of active calcineurin activates transcription of muscle-specific promoters in vitro but likely not via the NFAT2 transcription factor. Slow myosin light chain 2 (MLC2) and fast sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA1) reporter genes injected into rat soleus (slow) and extensor digitorum longus (EDL) (fast) muscles were not activated by coinjection of activated calcineurin or NFAT2 expression plasmids. However, an NFAT reporter was strongly activated by overexpression of NFAT2 in both muscle types. Calcineurin and NFAT protein expression and binding activity to NFAT oligonucleotides were different in slow vs. fast muscle. Taken together, these results indicate that neither calcineurin nor NFAT appear to have dominant roles in the induction and/or maintenance of slow or fast fiber type in adult skeletal muscle. Furthermore, different pathways may be involved in muscle-specific gene expression in vitro vs. in vivo.
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Vaeth, Martin, Carina A. Bäuerlein, Tobias Pusch, Janina Findeis, Martin Chopra, Anja Mottok, Andreas Rosenwald, Andreas Beilhack, and Friederike Berberich-Siebelt. "Selective NFAT targeting in T cells ameliorates GvHD while maintaining antitumor activity." Proceedings of the National Academy of Sciences 112, no. 4 (January 12, 2015): 1125–30. http://dx.doi.org/10.1073/pnas.1409290112.
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Graft-versus-host disease (GvHD) is a life-threatening immunological complication after allogenic hematopoietic stem cell transplantation (allo-HCT). The intrinsic graft-versus-leukemia (GvL) effect, however, is the desirable curative benefit. Patients with acute GvHD are treated with cyclosporine A (CsA) or tacrolimus (FK506), which not only often causes severe adverse effects, but also interferes with the anticipated GvL. Both drugs inhibit calcineurin, thus at first suppressing activation of the nuclear factor of activated T cells (NFAT). Therefore, we explored the specific contribution of individual NFAT factors in donor T cells in animal models of GvHD and GvL. Ablation of NFAT1, NFAT2, or a combination of both resulted in ameliorated GvHD, due to reduced proliferation, target tissue homing, and impaired effector function of allogenic donor T cells. In contrast, the frequency of Foxp3+ regulatory T (Treg) cells was increased and NFAT-deficient Tregs were fully protective in GvHD. CD8+ T-cell recall response and, importantly, the beneficial antitumor activity were largely preserved in NFAT-deficient effector T cells. Thus, specific inhibition of NFAT opens an avenue for an advanced therapy of GvHD maintaining protective GvL.
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Hadi, Arindah, M. Roelianto, Ari Subiyanto, and Tamara Yuanita. "EKSPRESI Nuclear Factor of Activated T cells c-1 (NFATc-1) DAN OSTEOKALSIN PADA KERUSAKAN TULANG PERIAPIKAL AKIBAT INDUKSI BAKTERI Enterococcus faecalis." Conservative Dentistry Journal 7, no. 2 (December 5, 2019): 138. http://dx.doi.org/10.20473/cdj.v7i2.2017.138-144.
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Background. The main etiology of endodontic treatment failure is caused by bacteries that stay in the root canal. E.faecalis is a bactery that is found as an etiology of endodontic treatment failure. Cell wall of this bacteria is containing Lipoteichoic acid (LTA). LTA can penetrate into the periradicular tissue, act as endotoxin in host and cause periradicular inflammation then lead to bone destruction. Bone destruction occurs due to the inflammation process that is mediated by immune system. The important cell in the process of bone destruction is osteoclast. Bone destruction is marked by the form of osteoclast that is called osteoclastogenesis. NFATc-1 and osteocalcin play important things in osteoclastogenesis. Purpose. The aim of this study is to know about the expression of NFATc-1 and osteocalcin during the periapical bone destruction due to induction of E.faecalis. Method. This study used laboratory experimental with the post test only control group design. A total of 54 male rats were randomly divided into 2 main groups, which each main group had 3 subgroups. Group A (control) : every tooth was induced only by sterile BHIb. Group A had 3 subgroups (A Control day 3, 10, and 21), group B : every tooth was induced by 10 μl BHI-b E.faecalis ATCC212(106 CFU), it was contained 3 sub groups (B day 3,10, and 21). The animals were sacrificed based on their days scheduled group and prepared for histological examination of periapical bone, then we did the immunohistochemistry followed by calculation on the light microscope. Result. The analysis revealed that the expression of NFATc-1 and osteoclast increased significantly in group B when E.faecalis was induced. Conclusion. From this study we know that the expression of NFATc-1 and osteocalcin are increasing during the periapical bone destruction that induced by E.faecalis.
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He, Rui-Lan, Zhi-Juan Wu, Xiao-Ru Liu, Long-Xin Gui, Rui-Xing Wang, and Mo-Jun Lin. "Calcineurin/NFAT Signaling Modulates Pulmonary Artery Smooth Muscle Cell Proliferation, Migration and Apoptosis in Monocrotaline-Induced Pulmonary Arterial Hypertension Rats." Cellular Physiology and Biochemistry 49, no. 1 (2018): 172–89. http://dx.doi.org/10.1159/000492852.
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Background/Aims: Pulmonary arterial hypertension (PAH) is a severe and debilitating disease characterized by remodeling of the pulmonary vessels, which is driven by excessive proliferation and migration and apoptosis resistance in pulmonary artery smooth muscle cells (PASMCs). The calcineurin (CaN)/nuclear factor of activated T-cells (NFAT) signaling pathway is the most important downstream signaling pathway of store-operated Ca2+ entry (SOCE), which is increased in PAH. CaN/NFAT has been reported to contribute to abnormal proliferation in chronic hypoxia (CH)-induced PAH. However, the effect of CaN/NFAT signaling on PASMC proliferation, migration and apoptosis in monocrotaline (MCT)-induced PAH remains unclear. Methods: PAH rats were established by a single intraperitoneal injection of MCT for 21 days. PASMCs were isolated and cultured in normal and MCT-induced PAH Sprague-Dawley rat. PASMCs were treated with CsA targeting CaN and siRNA targeting NFATc2-4 gene respectively by liposome. We investigated the expression of calcineurin/NFAT signaling by immunofluorescence, qRT-PCR and Western blotting methods. Cell proliferation was monitored using MTS reagent or by assessing proliferating cell nuclear antigen (PCNA) expression. Cell apoptosis was evaluated with an Annexin V - FITC/propidium iodide (PI) apoptosis kit by flow cytometry. PASMC migration was assessed with a Transwell chamber. Results: MCT successfully induced PAH and pulmonary vascular remodeling in rats. CaN phosphatase activity and nuclear translocation of NFATc2-4 were increased in PASMCs derived from MCT-treated rats. In addition, CaNBβ/NFATc2-4 expression was amplified at the mRNA and protein levels. PASMC proliferation and migration were markedly inhibited in a dosedependent manner by cyclosporin A (CsA). Furthermore, siRNA targeting NFATc2 and NFATc4 attenuated the excessive proliferation and migration and apoptosis resistance in PASMCs derived from both CON and MCT-treated rats, while NFATc3 knockdown specifically affected MCT-PASMCs. Conclusion: Our results demonstrate that CaN/NFAT signaling is activated and involved in the modulation of PASMC proliferation, migration and apoptosis in MCT-induced PAH.
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Woodrow, M., N. A. Clipstone, and D. Cantrell. "p21ras and calcineurin synergize to regulate the nuclear factor of activated T cells." Journal of Experimental Medicine 178, no. 5 (November 1, 1993): 1517–22. http://dx.doi.org/10.1084/jem.178.5.1517.
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In T lymphocytes, triggering of the T cell receptor (TCR) induces several signaling cascades which ultimately synergize to induce the activity of the nuclear factor of activated T cells (NFAT), a DNA binding complex critical to the inducibility and T cell specificity of the T cell growth factor interleukin 2. One immediate consequence of T cell activation via the TCR is an increase in cytosolic calcium. Calcium signals are important for NFAT induction, and recent studies have identified calcineurin, a calcium-calmodulin dependent serine-threonine phosphatase, as a prominent component of the calcium signaling pathway in T cells. A second important molecule in TCR signal transduction is the guanine nucleotide binding protein, p21ras, which is coupled to the TCR by a protein tyrosine kinase dependent mechanism. The experiments presented here show that expression by transfection of mutationally activated calcineurin or activated p21ras alone is insufficient for NFAT transactivation. However, coexpression of the activated calcineurin with activated p21ras could mimic TCR signals in NFAT induction. These data identify calcineurin and p21ras as cooperative partners in T cell activation.