{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNR0B1 (also known as DAX‐1) is an atypical orphan nuclear receptor that principally functions as a transcriptional repressor to modulate key developmental and endocrine processes. It plays a central role in adreno–gonadal development and steroidogenesis by antagonizing the activity of transcriptional activators such as steroidogenic factor‑1 (SF‑1) and the estrogen and androgen receptors. Mutations in NR0B1 lead to X‑linked adrenal hypoplasia congenita, hypogonadotropic hypogonadism, and a spectrum of disorders in reproductive function—including defects in spermatogenesis and aberrant sex determination—and investigations have also highlighted the importance of alternatively spliced isoforms in fine‑tuning its repressor activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn oncogenic contexts, NR0B1 has emerged as a critical mediator of transformation. In Ewing’s sarcoma, for example, aberrant activation of NR0B1 by the EWS/FLI fusion oncoprotein is essential for maintaining the malignant phenotype. Moreover, deregulated NR0B1 expression contributes to tumorigenesis in a range of cancers—including breast, lung, and cervical carcinomas—through its interplay with diverse nuclear receptors and signaling pathways that control cell proliferation and survival."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the mechanistic level, NR0B1 exerts its regulatory functions by directly interacting with multiple co-regulators and nuclear receptors. It displays the capacity to form homodimers and binds to partners such as RNF31 and SOX6, thereby influencing not only transcriptional repression but also processes such as pre‑mRNA splicing. In metabolic tissues like the liver, NR0B1 modulates gluconeogenesis, lipogenesis, and even the cellular response to hepatotoxic stress by interfacing with HNF4α, LXRα, and the glucocorticoid receptor. In addition, its inhibitory action on PPARγ activity underscores a role in adipocyte differentiation, while in neural cells NR0B1 contributes to retinoic acid‑induced nitric oxide synthase expression. Such multifaceted interactions—including those mediated by alternatively spliced isoforms—underscore the complexity of NR0B1’s regulatory repertoire in maintaining cellular homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "39"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "J C Achermann, J J Meeks, J L Jameson "}, {"type": "b", "children": [{"type": "t", "text": "Phenotypic spectrum of mutations in DAX-1 and SF-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Endocrinol (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0303-7207(01)00619-0"}], "href": "https://doi.org/10.1016/s0303-7207(01"}, {"type": "t", "text": "00619-0) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11738790"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11738790"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Y H Zhang, B L Huang, K Anyane-Yeboa, et al. 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