{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMyotrophin (also known as V-1) is a multifunctional protein whose roles span from modulating transcription factor activity to regulating cytoskeletal dynamics. In cardiac and neuronal cells, myotrophin accumulates in the cytoplasm and, upon sustained stimulation of nuclear factor‑kappaB (NF‑κB), translocates into the nucleus where it preferentially interacts with p65 and c‑Rel. Through its binding, myotrophin promotes the formation of repressive homodimers (p50‑p50 and p65‑p65) at the expense of the canonical transactivating p50‑p65 heterodimers, thereby attenuating NF‑κB–mediated gene expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in NF‑κB signaling, myotrophin is implicated in cardiac hypertrophy. Variations in its 3′‑untranslated region—in particular, a variant within the binding site for let‑7/miR‑98—affect its translational efficiency. Studies have shown that the allele facilitating microRNA binding down‑regulates myotrophin protein levels, a modulation that is thought to influence myocardial hypertrophy, even though a clear clinical association has not been established in large patient cohorts."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA further layer of complexity in myotrophin biology is provided by the expression of a cryptic antigen, MPD6, encoded by an open reading frame located in the 3′‑UTR of its mRNA. This unconventional antigen is translated via an internal ribosome entry site that is up‑regulated in response to interferon‑alpha, thereby eliciting immunogenic IgG responses in various myeloproliferative and neoplastic diseases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, retinoic acid—specifically the 9‑cis isomer—has been shown to down‑regulate myotrophin expression while increasing levels of miR‑375 in several cell types such as pancreatic β‑cells, adipocytes, and certain breast cancer models, suggesting a hormone‑mediated regulatory pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMyotrophin also plays a pivotal role in actin dynamics by directly binding to and inhibiting the heterodimeric actin capping protein (CP), a key regulator of filament assembly. Structural analyses reveal that myotrophin, a 13 kDa ankyrin‑repeat protein, maintains a similar conformation whether free or CP‑bound, with only subtle side‑chain rearrangements needed to block CP’s interaction with actin, thereby modulating cytoskeletal dynamics."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, while investigations into cholangiocarcinoma primary drug resistance have not directly expanded on the function of myotrophin, the broad spectrum of its regulatory activities—from NF‑κB modulation and translational control to interaction with cytoskeletal machinery—underscores its potential significance as a therapeutic target in various pathological conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Pascal Knuefermann, Peter Chen, Arunima Misra, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Myotrophin/V-1, a protein up-regulated in the failing human heart and in postnatal cerebellum, converts NFkappa B p50-p65 heterodimers to p50-p50 and p65-p65 homodimers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M202937200"}], "href": "https://doi.org/10.1074/jbc.M202937200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11971907"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11971907"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Chunli Wang, Yongqiang Sha, Sixiang Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Lysyl oxidase suppresses the inflammatory response in anterior cruciate ligament fibroblasts and promotes tissue regeneration by targeting myotrophin via the nuclear factor-kappa B pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Tissue Eng Regen Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/term.3077"}], "href": "https://doi.org/10.1002/term.3077"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32483895"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32483895"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yuyao Wang, Jingzhou Chen, Weihua Song, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Human Myotrophin Variant Attenuates MicroRNA-Let-7 Binding Ability but Not Risk of Left Ventricular Hypertrophy in Human Essential Hypertension."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0135526"}], "href": "https://doi.org/10.1371/journal.pone.0135526"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26274321"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26274321"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Zeyu Xiong, Enli Liu, Yan Yan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An unconventional antigen translated by a novel internal ribosome entry site elicits antitumor humoral immune reactions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.177.7.4907"}], "href": "https://doi.org/10.4049/jimmunol.177.7.4907"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16982933"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16982933"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Mariarita Perri, Maria Cristina Caroleo, Nannan Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "9-cis Retinoic acid modulates myotrophin expression and its miR in physiological and pathophysiological cell models."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2017.03.022"}], "href": "https://doi.org/10.1016/j.yexcr.2017.03.022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28300567"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28300567"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Britney Johnson, Patrick McConnell, Alex G Kozlov, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Allosteric Coupling of CARMIL and V-1 Binding to Capping Protein Revealed by Hydrogen-Deuterium Exchange."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2018.04.096"}], "href": "https://doi.org/10.1016/j.celrep.2018.04.096"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29847807"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29847807"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Shuichi Takeda, Ryotaro Koike, Takayuki Nagae, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Crystal structure of human V-1 in the apo form."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Crystallogr F Struct Biol Commun (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1107/S2053230X20016829"}], "href": "https://doi.org/10.1107/S2053230X20016829"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33439151"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33439151"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Yuting Wang, Wen Zhang, Lin Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The ATO/miRNA-885-5p/MTPN axis induces reversal of drug-resistance in cholangiocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Oncol (Dordr) (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s13402-021-00610-3"}], "href": "https://doi.org/10.1007/s13402-021-00610-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34170484"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34170484"}]}]}]}