{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMKRN2 is an evolutionarily conserved member of the makorin ring finger protein family. Early studies identified the gene as overlapping the RAF1 locus in an antisense orientation, suggesting potential regulatory roles via mRNA interactions and duplex formation that have been conserved for hundreds of millions of years. In addition, research in Parkinson’s disease has underscored the broader relevance of RNA‐regulatory mechanisms, including those mediated by RNA-binding proteins, in neurodegenerative contexts."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of hematopoiesis, MKRN2 is ubiquitously expressed in normal hematopoietic cells and is found at elevated levels in primary leukemia samples. Functional studies using cord blood CD34+ progenitors and leukemic cell lines indicate that MKRN2 supports cellular proliferation and helps maintain early stem/progenitor populations, implying a role in normal and malignant blood cell development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMKRN2 also plays a pivotal role in dampening inflammatory signaling. It functions as a RING finger ubiquitin E3 ligase that binds to the NF‐κB p65 subunit, promoting its polyubiquitination and proteasome‐dependent degradation. In doing so, MKRN2—acting alone and in synergy with other nuclear ligases such as PDLIM2—serves as a negative regulator of NF‐κB–mediated inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn various cancer models, MKRN2 exhibits context‐dependent roles. In non–small cell lung cancer its E3 ligase activity has been implicated in disease progression, whereas in neuroblastoma, knockdown of MKRN2 promotes proliferation and migration through the modulation of RNA-binding proteins like IGF2BP3 and subsequent effects on targets such as CD44 and PDPN. Moreover, overexpression of MKRN2 in ovarian cancer cells suppresses tumor-associated behaviors by curtailing proliferation and migration while enhancing apoptosis. Alterations in the makorin family, including MKRN2, have also been observed in aggressive malignancies such as renal clear cell carcinoma, reinforcing its relevance in cancer biology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the setting of viral infections, MKRN2 has been identified as an important host factor for influenza A virus. It associates with viral mRNAs and appears to facilitate their nuclear export—potentially via interaction with the RNA export mediator GLE1—thus preventing their nuclear retention and degradation by the RNA exosome."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "T A Gray, K Azama, K Whitmore, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phylogenetic conservation of the makorin-2 gene, encoding a multiple zinc-finger protein, antisense to the RAF1 proto-oncogene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genomics (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1006/geno.2001.6627"}], "href": "https://doi.org/10.1006/geno.2001.6627"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11597136"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11597136"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Qiao Wang, Chun-Lei Han, Kai-Liang Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Integrated analysis of exosomal lncRNA and mRNA expression profiles reveals the involvement of lnc-MKRN2-42:1 in the pathogenesis of Parkinson's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "CNS Neurosci Ther (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cns.13277"}], "href": "https://doi.org/10.1111/cns.13277"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31814304"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31814304"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "King Yiu Lee, Kathy Yuen Yee Chan, Kam Sze Tsang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ubiquitous expression of MAKORIN-2 in normal and malignant hematopoietic cells and its growth promoting activity."}]}, {"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.0092706"}], "href": "https://doi.org/10.1371/journal.pone.0092706"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24675897"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24675897"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Chanyoung Shin, Yuma Ito, Shota Ichikawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MKRN2 is a novel ubiquitin E3 ligase for the p65 subunit of NF-κB and negatively regulates inflammatory responses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep46097"}], "href": "https://doi.org/10.1038/srep46097"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28378844"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28378844"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jun Jiang, Yitong Xu, Hongjiu Ren, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MKRN2 inhibits migration and invasion of non-small-cell lung cancer by negatively regulating the PI3K/Akt pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Clin Cancer Res (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13046-018-0855-7"}], "href": "https://doi.org/10.1186/s13046-018-0855-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30103781"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30103781"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Caiwei Jia, Hongli Tang, Yun Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ubiquitination of IGF2BP3 by E3 ligase MKRN2 regulates the proliferation and migration of human neuroblastoma SHSY5Y cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2020.05.112"}], "href": "https://doi.org/10.1016/j.bbrc.2020.05.112"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32560817"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32560817"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yun Yang, Yanyan Luo, Shuting Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MKRN1/2 serve as tumor suppressors in renal clear cell carcinoma by regulating the expression of p53."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Biomark (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3233/CBM-210559"}], "href": "https://doi.org/10.3233/CBM-210559"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36938725"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36938725"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "F Z Jiang, Q J Xia, L Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[Overexpression of MKRN2 Inhibits the Growth of Ovarian Cancer Cells]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol (Mosk) (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.31857/S0026898423040109, EDN: QLPEZQ"}], "href": "https://doi.org/10.31857/S0026898423040109, EDN: QLPEZQ"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37528788"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37528788"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Stefano Bonazza, Hannah Leigh Coutts, Swathi Sukumar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identifying cellular RNA-binding proteins during infection uncovers a role for MKRN2 in influenza mRNA trafficking."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Pathog (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.ppat.1012231"}], "href": "https://doi.org/10.1371/journal.ppat.1012231"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38753876"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38753876"}]}]}]}