{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNFATC2, a calcium/calcineurin‐dependent transcription factor, plays a pivotal role as a signaling nexus in diverse biological contexts. In endothelial cells, NFATC2 is activated downstream of basic fibroblast growth factor and modulates angiogenic processes by integrating stimulatory and inhibitory signals—including those mediated by c‐Jun N‐terminal kinases—to regulate apoptosis inhibitors such as c‐FLIP, thereby contributing to angiogenesis regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn malignant epithelial settings, NFATC2 contributes to the transcriptional control of genes such as cyclooxygenase‐2, indicating its involvement in tumor cell biology alongside other NFAT isoforms in colon carcinoma cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, NFATC2’s regulation of cytokine transcription is critical in immune-mediated diseases. Elevated nuclear accumulation of NFATC2 has been observed in T cells from patients with systemic lupus erythematosus, where it enhances the binding to promoters of key cytokines yet paradoxically associates with altered interleukin‐2 expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Similarly, in experimental colitis, NFATC2 drives mucosal T cell activation and cytokine production—its deficiency ameliorating inflammation by reducing IL‐6 and other proinflammatory mediators."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In a distinct context, NFATC2 has been shown to cooperate with heat shock factor 1 to induce the expression of proteins that promote the degradation of polyglutamine‐expanded proteins, thereby suppressing polyQ aggregation—a mechanism with implications in neurodegenerative diseases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Additionally, genetic studies reveal that an intronic variant in NFATC2 is associated with heightened expression and increased risk of asparaginase hypersensitivity, underscoring its clinical significance in immune response variability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in inflammation and proteostasis, NFATC2 also emerges as an oncogenic driver in certain contexts. Chromosomal translocations fusing EWSR1 to NFATC2 define a novel subset of small round cell sarcomas that are distinct from classic Ewing sarcoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Moreover, in lung cancer, NFATC2 regulates tumor‐initiating cell phenotypes by directly interacting with enhancer regions of SOX2 and, through this axis, upregulating ALDH1A1 to counteract oxidative stress induced by therapy, thereby facilitating resistance and aggressive behavior."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Tetiana A Zaichuk, Emelyn H Shroff, Rebekah Emmanuel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nuclear factor of activated T cells balances angiogenesis activation and inhibition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20040474"}], "href": "https://doi.org/10.1084/jem.20040474"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15184502"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15184502"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Javier Duque, Manuel Fresno, Miguel A Iñiguez "}, {"type": "b", "children": [{"type": "t", "text": "Expression and function of the nuclear factor of activated T cells in colon carcinoma cells: involvement in the regulation of cyclooxygenase-2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M413076200"}], "href": "https://doi.org/10.1074/jbc.M413076200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15632146"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15632146"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Vasileios C Kyttaris, Ying Wang, Yuang-Taung Juang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased levels of NF-ATc2 differentially regulate CD154 and IL-2 genes in T cells from patients with systemic lupus erythematosus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.178.3.1960"}], "href": "https://doi.org/10.4049/jimmunol.178.3.1960"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17237447"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17237447"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Benno Weigmann, Hans A Lehr, George Yancopoulos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The transcription factor NFATc2 controls IL-6-dependent T cell activation in experimental colitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20072484"}], "href": "https://doi.org/10.1084/jem.20072484"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18710929"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18710929"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Naoki Hayashida, Mitsuaki Fujimoto, Ke Tan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Heat shock factor 1 ameliorates proteotoxicity in cooperation with the transcription factor NFAT."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2010.225"}], "href": "https://doi.org/10.1038/emboj.2010.225"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20834230"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20834230"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Christian A Fernandez, Colton Smith, Wenjian Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide analysis links NFATC2 with asparaginase hypersensitivity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2015-02-628800"}], "href": "https://doi.org/10.1182/blood-2015-02-628800"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25987655"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25987655"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Christian Koelsche, Mark Kriegsmann, Felix K F Kommoss, et al. "}, {"type": "b", "children": [{"type": "t", "text": "DNA methylation profiling distinguishes Ewing-like sarcoma with EWSR1-NFATc2 fusion from Ewing sarcoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cancer Res Clin Oncol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00432-019-02895-2"}], "href": "https://doi.org/10.1007/s00432-019-02895-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30895378"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30895378"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Zhi-Jie Xiao, Jing Liu, Si-Qi Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NFATc2 enhances tumor-initiating phenotypes through the NFATc2/SOX2/ALDH axis in lung adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.26733"}], "href": "https://doi.org/10.7554/eLife.26733"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28737489"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28737489"}]}]}]}