{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUBE4B is a multifunctional ubiquitin ligase that can act both as an E3 enzyme and an E4 chain assembly factor. Detailed structural studies have revealed that its unique monomeric U‐box domain facilitates binding to specific E2 conjugating enzymes, while specialized domains such as the MPAC region undergo phosphorylation and apoptotic cleavage to modulate its activity (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Moreover, UBE4B interacts with key regulatory proteins; it enhances polyubiquitination and subsequent degradation of tumor suppressor p53 by forming complexes with Hdm2, decreases p53‐mediated transactivation and apoptosis, and is itself regulated by microRNAs such as miR-1301. In addition, UBE4B regulates proteins involved in neuronal differentiation—notably by ubiquitinating FEZ1 to modulate neurite extension—and stabilizes factors like ΔNp63α, which influences cellular responses to DNA‐damaging agents."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn multiple cancer settings, aberrant UBE4B expression contributes to tumorigenesis by regulating the stability and trafficking of proteins that control cell survival and proliferation. In hepatocellular carcinoma, for example, genomic studies have implicated the 1p36.22 locus—including UBE4B—as a susceptibility region, and overexpression of UBE4B is associated with increased cell proliferation, migration, and a poor clinical outcome."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In neuroblastoma, loss-of-function mutations and low expression have pointed to a tumor-suppressive role, yet in other contexts UBE4B cooperates with partners such as ITCH to promote the polyubiquitination of apoptotic regulators like Ku70 and c-FLIPL, thereby modulating responses to targeted therapies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "16"}]}, {"type": "t", "text": " In addition, a circular RNA derived from the UBE4B locus encodes a protein variant capable of stimulating MAPK/ERK signaling in esophageal squamous carcinoma, further underscoring how UBE4B-related pathways impact oncogenic circuits."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the nervous system, UBE4B plays critical roles in both development and neurodegeneration. Alternative splicing generates muscle- and neuron-specific isoforms that are expressed during myogenesis and may fine-tune interactions with key factors such as the AAA-type ATPase VCP/p97."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " Furthermore, by partnering with chaperone-associated ligases like CHIP, UBE4B enhances the ubiquitination and autophagy-mediated degradation of hyperphosphorylated Tau protein, suggesting that modulation of its activity could hold therapeutic promise in Alzheimer’s disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " The multifaceted roles of UBE4B—in orchestrating protein turnover, regulating signal transduction, and determining cell fate—illustrate its importance as a nodal point in cellular homeostasis and disease pathogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}, {"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Fumihiko Okumura, Shigetsugu Hatakeyama, Masaki Matsumoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional regulation of FEZ1 by the U-box-type ubiquitin ligase E4B contributes to neuritogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M402916200"}], "href": "https://doi.org/10.1074/jbc.M402916200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15466860"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15466860"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Sarah Spinette, James A Mahoney, Antony Rosen "}, {"type": "b", "children": [{"type": "t", "text": "The MPAC domain is a novel mitotically regulated domain, removed by apoptotic protease cleavage during cell death."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2006.06.194"}], "href": "https://doi.org/10.1016/j.bbrc.2006.06.194"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16870146"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16870146"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Aditi Chatterjee, Sunil Upadhyay, Xiaofei Chang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "U-box-type ubiquitin E4 ligase, UFD2a attenuates cisplatin mediated degradation of DeltaNp63alpha."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Cycle (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/cc.7.9.5795"}], "href": "https://doi.org/10.4161/cc.7.9.5795"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18418053"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18418053"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Robert C Benirschke, James R Thompson, Yves Nominé, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular basis for the association of human E4B U box ubiquitin ligase with E2-conjugating enzymes UbcH5c and Ubc4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Structure (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.str.2010.04.017"}], "href": "https://doi.org/10.1016/j.str.2010.04.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20696396"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20696396"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Hong Wu, Scott L Pomeroy, Manuel Ferreira, et al. "}, {"type": "b", "children": [{"type": "t", "text": "UBE4B promotes Hdm2-mediated degradation of the tumor suppressor p53."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm.2283"}], "href": "https://doi.org/10.1038/nm.2283"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21317885"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21317885"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ying Zhang, Yanrong Lv, Yongyang Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation of p53 level by UBE4B in breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0090154"}], "href": "https://doi.org/10.1371/journal.pone.0090154"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24587254"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24587254"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Cheng Du, Hong Wu, Roger P Leng "}, {"type": "b", "children": [{"type": "t", "text": "UBE4B targets phosphorylated p53 at serines 15 and 392 for degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.6555"}], "href": "https://doi.org/10.18632/oncotarget.6555"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26673821"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26673821"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Benfan Wang, Hong Wu, Chengsen Chai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-1301 suppresses tumor cell migration and invasion by targeting the p53/UBE4B pathway in multiple human cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Lett (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.canlet.2017.04.038"}], "href": "https://doi.org/10.1016/j.canlet.2017.04.038"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28483517"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28483517"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Hongxing Zhang, Yun Zhai, Zhibin Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.638"}], "href": "https://doi.org/10.1038/ng.638"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20676096"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20676096"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Xiao-Fei Zhang, Qiu-Zhong Pan, Ke Pan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression and prognostic role of ubiquitination factor E4B in primary hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Carcinog (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/mc.22259"}], "href": "https://doi.org/10.1002/mc.22259"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25557723"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25557723"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Cecilia Krona, Katarina Ejeskär, Frida Abel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Screening for gene mutations in a 500 kb neuroblastoma tumor suppressor candidate region in chromosome 1p; mutation and stage-specific expression in UBE4B/UFD2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1206324"}], "href": "https://doi.org/10.1038/sj.onc.1206324"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12700669"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12700669"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Peter E Zage, Natalie Sirisaengtaksin, Yin Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "UBE4B levels are correlated with clinical outcomes in neuroblastoma patients and with altered neuroblastoma cell proliferation and sensitivity to epidermal growth factor receptor inhibitors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cncr.27785"}], "href": "https://doi.org/10.1002/cncr.27785"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22990745"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22990745"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Natalie Sirisaengtaksin, Monica Gireud, Qing Yan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "UBE4B protein couples ubiquitination and sorting machineries to enable epidermal growth factor receptor (EGFR) degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.495671"}], "href": "https://doi.org/10.1074/jbc.M113.495671"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24344129"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24344129"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Kimiya Memarzadeh, David J Savage, Andrew J Bean "}, {"type": "b", "children": [{"type": "t", "text": "Low UBE4B expression increases sensitivity of chemoresistant neuroblastoma cells to EGFR and STAT5 inhibition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Biol Ther (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15384047.2019.1647049"}], "href": "https://doi.org/10.1080/15384047.2019.1647049"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31475882"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31475882"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Song Wu, Linlin Xie, Shaofei Cheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "UBE4B promotes the development of lung adenocarcinoma by enhancing proliferation, migration and glycolysis via PP2A/AKT signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pathol Res Pract (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.prp.2022.153762"}], "href": "https://doi.org/10.1016/j.prp.2022.153762"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35220170"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35220170"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Hyungmin Kim, Soon-Young Jung, Hye Hyeon Yun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "UBE4B regulates p27 expression in A549 NSCLC cells through regulating the interaction of HuR and the p27 5' UTR."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2024.149484"}], "href": "https://doi.org/10.1016/j.bbrc.2024.149484"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38211530"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38211530"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Yingcheng Lyu, Binghua Tan, Lin Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel protein encoded by circUBE4B promotes progression of esophageal squamous cell carcinoma by augmenting MAPK/ERK signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-023-05865-2"}], "href": "https://doi.org/10.1038/s41419-023-05865-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37264022"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37264022"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Andrew L Mammen, James A Mahoney, Amanda St Germain, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel conserved isoform of the ubiquitin ligase UFD2a/UBE4B is expressed exclusively in mature striated muscle cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0028861"}], "href": "https://doi.org/10.1371/journal.pone.0028861"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22174917"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22174917"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Manivannan Subramanian, Seung Jae Hyeon, Tanuza Das, et al. "}, {"type": "b", "children": [{"type": "t", "text": "UBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-021-23597-9"}], "href": "https://doi.org/10.1038/s41467-021-23597-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34078905"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34078905"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Christophe Le Clorennec, Divya Subramonian, Yuchen Huo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "UBE4B interacts with the ITCH E3 ubiquitin ligase to induce Ku70 and c-FLIPL polyubiquitination and enhanced neuroblastoma apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-023-06252-7"}], "href": "https://doi.org/10.1038/s41419-023-06252-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37957138"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37957138"}]}]}]}