{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPAGE4 is an intrinsically disordered cancer/testis antigen that exhibits unique biophysical properties and dynamic conformational behavior. Early studies demonstrated that its protein sequence lacks stable secondary structure and displays anomalous migration on size‐exclusion and SDS–PAGE analyses, features typical of intrinsically disordered proteins. Bioinformatic predictions further revealed a nuclear localization signal and high likelihood for DNA binding, while spectroscopic analyses confirmed its disordered nature. Functionally, PAGE4 interacts with the transcription factor c‑Jun—potentiating c‑Jun transactivation—and this interaction is modulated by site‐specific phosphorylation events that induce conformational shifts in defined regions of the protein."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in transcriptional regulation, PAGE4 significantly modulates several key oncogenic signaling pathways in prostate tissue. In prostate epithelial cells, up‐regulation of PAGE4 is associated with attenuation of androgen receptor (AR) signaling, as it interferes with AR nuclear translocation and diminishes AR protein stabilization. In parallel, PAGE4 acts as a tissue‐specific inhibitor of Tankyrase 1 by functioning as an optimal substrate decoy, thereby repressing canonical Wnt/β‑catenin signaling. Moreover, under oxidative stress conditions—as encountered in benign prostatic hyperplasia—the protein promotes cell survival by activating p‑ERK1/2 while simultaneously inhibiting p‑JNK1/2 pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe expression of PAGE4 is carefully orchestrated in a spatiotemporal manner, underscoring its context-dependent functions during development and disease progression. Originally identified in reproductive tissues, PAGE4 is notably upregulated in the fetal prostate and in preneoplastic lesions, where its anti-apoptotic and stress-response functions appear to confer protective advantages. In contrast, its expression diminishes in advanced and metastatic prostate cancer. Importantly, in the stromal compartment, elevated PAGE4 levels are linked to reduced epithelial cell migration and invasion as well as dampened pro-inflammatory and transforming growth factor signaling—findings that highlight its potential as both a prognostic biomarker and a therapeutic target in prostate disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yu Zeng, Yanan He, Fan Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The cancer/testis antigen prostate-associated gene 4 (PAGE4) is a highly intrinsically disordered protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.210765"}], "href": "https://doi.org/10.1074/jbc.M110.210765"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21357425"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21357425"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Krithika Rajagopalan, Ruoyi Qiu, Steven M Mooney, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Stress-response protein prostate-associated gene 4, interacts with c-Jun and potentiates its transactivation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbadis.2013.11.014"}], "href": "https://doi.org/10.1016/j.bbadis.2013.11.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24263171"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24263171"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Steven M Mooney, Ruoyi Qiu, John J Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cancer/testis antigen PAGE4, a regulator of c-Jun transactivation, is phosphorylated by homeodomain-interacting protein kinase 1, a component of the stress-response pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi500013w"}], "href": "https://doi.org/10.1021/bi500013w"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24559171"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24559171"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yanan He, Yihong Chen, Steven M Mooney, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phosphorylation-induced Conformational Ensemble Switching in an Intrinsically Disordered Cancer/Testis Antigen."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M115.658583"}], "href": "https://doi.org/10.1074/jbc.M115.658583"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26242913"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26242913"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Natalie Sampson, Christian Ruiz, Christoph Zenzmaier, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PAGE4 positivity is associated with attenuated AR signaling and predicts patient survival in hormone-naive prostate cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajpath.2012.06.040"}], "href": "https://doi.org/10.1016/j.ajpath.2012.06.040"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22885105"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22885105"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Sajjan Koirala, Jonathon Klein, Yumei Zheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tissue-Specific Regulation of the Wnt/β-Catenin Pathway by PAGE4 Inhibition of Tankyrase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2020.107922"}], "href": "https://doi.org/10.1016/j.celrep.2020.107922"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32698014"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32698014"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yan Li, Jianmin Liu, Daoquan Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Prostate-Associated Gene 4 (PAGE4) Could Play a Role in the Development of Benign Prostatic Hyperplasia under Oxidative Stress."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oxid Med Cell Longev (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2022/7041739"}], "href": "https://doi.org/10.1155/2022/7041739"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35633887"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35633887"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Carlo Iavarone, Curt Wolfgang, Vasantha Kumar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PAGE4 is a cytoplasmic protein that is expressed in normal prostate and in prostate cancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer Ther (2002)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12489849"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12489849"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Shui Fu, Tao Liu, Chengcheng Lv, et al. 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