{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nLincRNA‐p21 has emerged as a pivotal regulator of gene expression and cell fate. Several studies demonstrate that, under p53 control, this long intergenic noncoding RNA primarily acts in cis to stimulate the transcription of the neighboring Cdkn1a (p21) gene. By recruiting cofactors such as hnRNP‐K and leveraging intrinsic enhancer elements within its locus, lincRNA‐p21 helps enforce cell cycle arrest and maintain genomic integrity. In vascular smooth muscle cells, for instance, a p53–lincRNA‐p21 axis modulates the miR‑17‑5p/SIRT7 pathway to curb excessive proliferation implicated in atherosclerosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n \nIn addition to its cis‑acting transcriptional roles, lincRNA‐p21 functions as a molecular scaffold and competing endogenous RNA (ceRNA). By associating with chromatin modifiers such as SETDB1 and DNMT1, it helps establish repressive histone and DNA methylation marks that impair somatic cell reprogramming. Its ability to sequester microRNAs—including miR‑30 and miR‑221—further influences apoptotic pathways and differentiation in diverse contexts such as liver fibrosis, neuronal injury in diabetes, and macrophage polarization within the tumor microenvironment."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": "\n \nFurthermore, lincRNA‐p21 enhances the functional capacity of mesenchymal stem cells and plays a protective role under conditions of cellular stress. It promotes MSC migration and survival—partly via activation of the Wnt/β‑catenin pathway—and can be secreted in exosomes to confer anti‐apoptotic benefits in models of acute lung injury. In the brain endothelium, it contributes to blood–brain barrier integrity by preventing the autophagy‐dependent degradation of junction proteins through PI3K/AKT/mTOR signaling. These multifaceted roles suggest that altered lincRNA‐p21 expression may impact cardiovascular remodeling, ischemia/reperfusion injury, and other pathologies associated with vascular and cardiac dysfunction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nadya Dimitrova, Jesse R Zamudio, Robyn M Jong, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "In Vivo Characterization of Linc-p21 Reveals Functional cis-Regulatory DNA Elements."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2016.07.050"}], "href": "https://doi.org/10.1016/j.celrep.2016.07.050"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27524623"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27524623"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Haojie Wang, Fei He, Bing Liang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "p53-Dependent LincRNA-p21 Protects Against Proliferation and Anti-apoptosis of Vascular Smooth Muscle Cells in Atherosclerosis by Upregulating SIRT7 via MicroRNA-17-5p."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cardiovasc Transl Res (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12265-020-10074-9"}], "href": "https://doi.org/10.1007/s12265-020-10074-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33169349"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33169349"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Riki Furuhata, Mai Imasaka, Michihiko Sugimoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LincRNA-p21 exon 1 expression correlates with Cdkn1a expression in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Cells (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/gtc.12906"}], "href": "https://doi.org/10.1111/gtc.12906"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34808017"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34808017"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Xichen Bao, Haitao Wu, Xihua Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The p53-induced lincRNA-p21 derails somatic cell reprogramming by sustaining H3K9me3 and CpG methylation at pluripotency gene promoters."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cr.2014.165"}], "href": "https://doi.org/10.1038/cr.2014.165"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25512341"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25512341"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Xiaolong Tu, Yuanyuan Zhang, Xiuxiu Zheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TGF-β-induced hepatocyte lincRNA-p21 contributes to liver fibrosis in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-017-03175-0"}], "href": "https://doi.org/10.1038/s41598-017-03175-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28592847"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28592847"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Qin Sun, Qing-Cui Zeng, Yan-Qiu Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Long intergenic noncoding RNA p21 suppresses the apoptosis of hippocampus neurons in streptozotocin-diabetic mice by sponging microRNA-221 through upregulation of FOS."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Physiol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcp.28714"}], "href": "https://doi.org/10.1002/jcp.28714"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31081202"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31081202"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Lining Zhou, Yu Tian, Fang Guo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LincRNA-p21 knockdown reversed tumor-associated macrophages function by promoting MDM2 to antagonize* p53 activation and alleviate breast cancer development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Immunol Immunother (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00262-020-02511-0"}], "href": "https://doi.org/10.1007/s00262-020-02511-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32062693"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32062693"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Gengze Wu, Jin Cai, Yu Han, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LincRNA-p21 regulates neointima formation, vascular smooth muscle cell proliferation, apoptosis, and atherosclerosis by enhancing p53 activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.114.011675"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.114.011675"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25156994"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25156994"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Wenzheng Xia, Lei Zhuang, Meng Hou "}, {"type": "b", "children": [{"type": "t", "text": "Role of lincRNA‑p21 in the protective effect of macrophage inhibition factor against hypoxia/serum deprivation‑induced apoptosis in mesenchymal stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Med (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijmm.2018.3767"}], "href": "https://doi.org/10.3892/ijmm.2018.3767"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30015822"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30015822"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Shan-Shan Meng, Xiu-Ping Xu, Wei Chang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LincRNA-p21 promotes mesenchymal stem cell migration capacity and survival through hypoxic preconditioning."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cell Res Ther (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13287-018-1031-x"}], "href": "https://doi.org/10.1186/s13287-018-1031-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30359325"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30359325"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Xintong Sui, Wei Liu, Zhi Liu "}, {"type": "b", "children": [{"type": "t", "text": "Exosomal lncRNA-p21 derived from mesenchymal stem cells protects epithelial cells during LPS-induced acute lung injury by sponging miR-181."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Biochim Biophys Sin (Shanghai) (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/abbs/gmab043"}], "href": "https://doi.org/10.1093/abbs/gmab043"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33891698"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33891698"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Yun-Hua Zhao, Yu Liang, Kang-Ji Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endothelial lincRNA-p21 alleviates cerebral ischemia/reperfusion injury by maintaining blood-brain barrier integrity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cereb Blood Flow Metab (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/0271678X241248907"}], "href": "https://doi.org/10.1177/0271678X241248907"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38661094"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38661094"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Yi Wang, Mingming Zhang, Rong Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Therapeutic Inhibition of "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "LincRNA-p21"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Protects Against Cardiac Hypertrophy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.123.323356"}], "href": "https://doi.org/10.1161/CIRCRESAHA.123.323356"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38864216"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38864216"}]}]}]}