{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTRAF6 is a central adapter protein and E3 ubiquitin ligase that transduces signals from multiple innate immune receptors—including Toll‐like receptors, interleukin‑1 receptors, CD40, and IL‑17 receptors—by catalyzing Lys63‐linked polyubiquitination. This non‐degradative modification creates a platform for the recruitment and activation of downstream kinases such as TAK1 and IKK, leading to the activation of transcription factors NF‑κB, MAP kinases, and interferon regulatory factors. TRAF6 directly interacts with key adaptor molecules (e.g. MyD88, Pellino, TIFA, and Act1) and thereby orchestrates antiviral responses and cytokine production as well as the induction of interferon‑α via IRF7 activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its well‐established role in triggering canonical immune responses, TRAF6 participates in diverse non‐classical signaling pathways that respond to cellular stress, growth factors, and pathogen‐derived signals. For example, in TGF‑β receptor signaling, TRAF6 mediates Lys63‐linked ubiquitination events that activate JNK and p38—processes linked to apoptosis and epithelial–mesenchymal transition—while also regulating receptor cleavage associated with tumor invasion. TRAF6 is equally critical for osteoclastogenesis and Akt activation via membrane recruitment, and its activity is tightly regulated by both positive and negative modulators such as deubiquitinating enzymes (e.g. OTUB1/2, USP4), the scaffolding proteins p62 and NLRC3, and ubiquitin ligases like cIAPs. Moreover, TRAF6 function extends to redox‐dependent endosomal signaling, DNA damage responses, and RIG‑I/MAVS–dependent antiviral cascades, underscoring its multifaceted role in immune and stress signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTRAF6 also contributes to oncogenic processes and the modulation of immune cell functions. Dysregulation of TRAF6—often through altered expression of regulatory microRNAs (e.g. miR‑146a/b) or circular RNAs—can influence tumorigenesis by affecting cell survival, proliferation, migration, and invasion in cancers such as thyroid carcinoma, lung cancer, and hepatocellular carcinoma. In these contexts, TRAF6’s capacity to modulate NF‑κB and autophagy pathways is pivotal for both the maintenance of inflammatory circuits and the control of dendritic cell homeostasis. Such multifaceted roles have made TRAF6 a promising therapeutic target for modulating inflammatory responses and oncogenic signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "37", "end_ref": "42"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Christopher Hull, Graeme McLean, Fred Wong, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Thioredoxin and TRAF family proteins regulate reactive oxygen species-dependent activation of ASK1 through reciprocal modulation of the N-terminal homophilic interaction of ASK1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00227-07"}], "href": "https://doi.org/10.1128/MCB.00227-07"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17724081"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17724081"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Sinead E Keating, Geraldine M Maloney, Ellen M Moran, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IRAK-2 participates in multiple toll-like receptor signaling pathways to NFkappaB via activation of TRAF6 ubiquitination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M705266200"}], "href": "https://doi.org/10.1074/jbc.M705266200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17878161"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17878161"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Fei Huang, Cheng-Yuan Kao, Shinichiro Wachi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Requirement for both JAK-mediated PI3K signaling and ACT1/TRAF6/TAK1-dependent NF-kappaB activation by IL-17A in enhancing cytokine expression in human airway epithelial cells."}]}, {"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.179.10.6504"}], "href": "https://doi.org/10.4049/jimmunol.179.10.6504"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17982039"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17982039"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Krystian Jazdzewski, Elizabeth L Murray, Kaarle Franssila, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0802682105"}], "href": "https://doi.org/10.1073/pnas.0802682105"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18474871"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18474871"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Shunbin Ning, Alex D Campos, Bryant G Darnay, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRAF6 and the three C-terminal lysine sites on IRF7 are required for its ubiquitination-mediated activation by the tumor necrosis factor receptor family member latent membrane protein 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00785-08"}], "href": "https://doi.org/10.1128/MCB.00785-08"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18710948"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18710948"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Motozo Yamashita, Karoly Fatyol, Chaoyang Jin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2008.09.002"}], "href": "https://doi.org/10.1016/j.molcel.2008.09.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18922473"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18922473"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Qian Yin, Su-Chang Lin, Betty Lamothe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "E2 interaction and dimerization in the crystal structure of TRAF6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Struct Mol Biol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nsmb.1605"}], "href": "https://doi.org/10.1038/nsmb.1605"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19465916"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19465916"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Wei-Lei Yang, Jing Wang, Chia-Hsin Chan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The E3 ligase TRAF6 regulates Akt ubiquitination and activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1175065"}], "href": "https://doi.org/10.1126/science.1175065"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19713527"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19713527"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Caini Liu, Wen Qian, Youcun Qian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Act1, a U-box E3 ubiquitin ligase for IL-17 signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Signal (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scisignal.2000382"}], "href": "https://doi.org/10.1126/scisignal.2000382"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19825828"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19825828"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Shu Li, Hao Zheng, Ai-Ping Mao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of virus-triggered signaling by OTUB1- and OTUB2-mediated deubiquitination of TRAF3 and TRAF6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.074971"}], "href": "https://doi.org/10.1074/jbc.M109.074971"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19996094"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19996094"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Ai-Ping Mao, Shu Li, Bo Zhong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Virus-triggered ubiquitination of TRAF3/6 by cIAP1/2 is essential for induction of interferon-beta (IFN-beta) and cellular antiviral response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.071043"}], "href": "https://doi.org/10.1074/jbc.M109.071043"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20097753"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20097753"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Fabrice Yoboua, Alexis Martel, Annick Duval, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Respiratory syncytial virus-mediated NF-kappa B p65 phosphorylation at serine 536 is dependent on RIG-I, TRAF6, and IKK beta."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Virol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/JVI.00142-10"}], "href": "https://doi.org/10.1128/JVI.00142-10"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20410276"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20410276"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Michael Hinz, Michael Stilmann, Seda Çöl Arslan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-κB activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2010.09.008"}], "href": "https://doi.org/10.1016/j.molcel.2010.09.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20932475"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20932475"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Yabing Mu, Reshma Sundar, Noopur Thakur, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms1332"}], "href": "https://doi.org/10.1038/ncomms1332"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21629263"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21629263"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Daniel T Starczynowski, William W Lockwood, Sophie Deléhouzée, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRAF6 is an amplified oncogene bridging the RAS and NF-κB pathways in human lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI58818"}], "href": "https://doi.org/10.1172/JCI58818"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21911935"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21911935"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Ning Xiao, Hui Li, Jian Luo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ubiquitin-specific protease 4 (USP4) targets TRAF2 and TRAF6 for deubiquitination and inhibits TNFα-induced cancer cell migration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20111358"}], "href": "https://doi.org/10.1042/BJ20111358"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22029577"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22029577"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Erika Zilahi, Tünde Tarr, Gábor Papp, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased microRNA-146a/b, TRAF6 gene and decreased IRAK1 gene expressions in the peripheral mononuclear cells of patients with Sjögren's syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunol Lett (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.imlet.2011.09.006"}], "href": "https://doi.org/10.1016/j.imlet.2011.09.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22033216"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22033216"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Monika Schneider, Albert G Zimmermann, Reid A Roberts, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The innate immune sensor NLRC3 attenuates Toll-like receptor signaling via modification of the signaling adaptor TRAF6 and transcription factor NF-κB."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni.2378"}], "href": "https://doi.org/10.1038/ni.2378"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22863753"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22863753"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Francesca Nazio, Flavie Strappazzon, Manuela Antonioli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb2708"}], "href": "https://doi.org/10.1038/ncb2708"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23524951"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23524951"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Siyu Wu, Li He, Yuye Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-146a facilitates replication of dengue virus by dampening interferon induction by targeting TRAF6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Infect (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jinf.2013.05.003"}], "href": "https://doi.org/10.1016/j.jinf.2013.05.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23685241"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23685241"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Prithiksha Ramkaran, Sajidah Khan, Alisa Phulukdaree, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-146a polymorphism influences levels of miR-146a, IRAK-1, and TRAF-6 in young patients with coronary artery disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Biochem Biophys (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12013-013-9704-7"}], "href": "https://doi.org/10.1007/s12013-013-9704-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23794009"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23794009"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Juan F Linares, Angeles Duran, Tomoko Yajima, et al. "}, {"type": "b", "children": [{"type": "t", "text": "K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2013.06.020"}], "href": "https://doi.org/10.1016/j.molcel.2013.06.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23911927"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23911927"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Pei-Shi Hung, Chung-Ji Liu, Chung-Shan Chou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-146a enhances the oncogenicity of oral carcinoma by concomitant targeting of the IRAK1, TRAF6 and NUMB genes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0079926"}], "href": "https://doi.org/10.1371/journal.pone.0079926"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24302991"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24302991"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Zhenzhen Zhan, Xuefeng Xie, Hao Cao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autophagy facilitates TLR4- and TLR3-triggered migration and invasion of lung cancer cells through the promotion of TRAF6 ubiquitination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Autophagy (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/auto.27162"}], "href": "https://doi.org/10.4161/auto.27162"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24321786"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24321786"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "Haein Park, Xin Huang, Changming Lu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-146a and microRNA-146b regulate human dendritic cell apoptosis and cytokine production by targeting TRAF6 and IRAK1 proteins."}]}, {"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.M114.591420"}], "href": "https://doi.org/10.1074/jbc.M114.591420"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25505246"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25505246"}]}, {"type": "r", "ref": 40, "children": [{"type": "t", "text": "Chao Li, Runchen Miao, Sushun Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Down-regulation of miR-146b-5p by long noncoding RNA MALAT1 in hepatocellular carcinoma promotes cancer growth and metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.15640"}], "href": "https://doi.org/10.18632/oncotarget.15640"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28404923"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28404923"}]}, {"type": "r", "ref": 41, "children": [{"type": "t", "text": "Yoon Min, Mi-Jeong Kim, Sena Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of TRAF6 ubiquitin-ligase activity by PRDX1 leads to inhibition of NFKB activation and autophagy activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Autophagy (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15548627.2018.1474995"}], "href": "https://doi.org/10.1080/15548627.2018.1474995"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29929436"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29929436"}]}, {"type": "r", "ref": 42, "children": [{"type": "t", "text": "Zhicheng Yao, Ruiyun Xu, Lin Yuan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Circ_0001955 facilitates hepatocellular carcinoma (HCC) tumorigenesis by sponging miR-516a-5p to release TRAF6 and MAPK11."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-019-2176-y"}], "href": "https://doi.org/10.1038/s41419-019-2176-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31822654"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31822654"}]}]}]}