{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Cytoplasmic polyadenylation element binding protein 4 (CPEB4) is an RNA‐binding protein that regulates mRNA translation through modulation of cytoplasmic polyadenylation and plays diverse roles in both normal physiology and disease. Genetic studies have implicated loci near CPEB4 in contributing to body fat distribution independent of overall adiposity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In several malignancies—including pancreatic ductal adenocarcinoma, glioblastoma, colorectal, non‐small cell lung, and cervical cancers—CPEB4 is overexpressed and acts as a critical translational activator that promotes tumor growth, invasion, metastasis, and pathological angiogenesis by selectively activating mRNAs (e.g., tissue plasminogen activator, VEGF, anti‐apoptotic factors) otherwise silent in normal tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "5"}]}, {"type": "t", "text": " In the nervous system, CPEB4 binds transcripts of high‐confidence autism spectrum disorder risk genes and maintains proper polyadenylation and expression of these mRNAs; imbalances in its transcript isoforms have been linked to ASD-related phenotypes and disease‐associated changes in protein levels."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Moreover, CPEB4 contributes to pathological angiogenesis in liver disease by mediating the cytoplasmic polyadenylation of VEGF mRNA after prior alternative processing events"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", and its binding to the 3′-UTR of PFKFB3 mRNA promotes glycolysis-driven activation of hepatic stellate cells, thereby facilitating liver fibrogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of erythropoiesis, CPEB4 is induced by key transcription factors and interacts with components of the translation initiation machinery (eIF3) to establish a negative feedback loop that is essential for proper terminal red blood cell differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In addition, CPEB4 is a direct transcriptional target of p53, indicating its integration into stress-responsive gene expression networks."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its oncogenic roles, CPEB4 also plays a part in the resolution of inflammation. In macrophages, it counterbalances the activity of mRNA-destabilizing factors to stabilize anti-inflammatory transcripts bearing cytoplasmic polyadenylation elements and AU-rich elements, thereby ensuring proper inflammatory resolution."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Conversely, in non-small cell lung cancer cells, CPEB4 promotes migration and invasion by modulating signaling pathways that include Akt and reactive oxygen species, underscoring its multifaceted role in tumor biology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Furthermore, in dermal fibroblasts and macrophages, increased CPEB4 expression is linked to activation of TAK1-, MAPK-, and Smad-dependent pathways that contribute to post-burn hypertrophic scarring."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, studies in neurological disorders have revealed that in temporal lobe epilepsy CPEB4 is upregulated in the hippocampus, and its loss exacerbates seizure severity and neurodegeneration, suggesting an adaptive, protective function in the brain."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Collectively, these findings illustrate that CPEB4 serves as a pivotal post-transcriptional regulator whose context-dependent actions—ranging from promoting oncogenic translation to mediating adaptive responses in neuronal and inflammatory settings—underline its potential as both a biomarker and therapeutic target.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Iris M Heid, Anne U Jackson, Joshua C Randall, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution."}]}, {"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.685"}], "href": "https://doi.org/10.1038/ng.685"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20935629"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20935629"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Elena Ortiz-Zapater, David Pineda, Neus Martínez-Bosch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Key contribution of CPEB4-mediated translational control to cancer progression."}]}, {"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.2540"}], "href": "https://doi.org/10.1038/nm.2540"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22138752"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22138752"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Xiaohua Zhong, Yipin Xiao, Chao Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-203-mediated posttranscriptional deregulation of CPEB4 contributes to colorectal cancer progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2015.09.008"}], "href": "https://doi.org/10.1016/j.bbrc.2015.09.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26361147"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26361147"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jing Hu, LiBin Zhang, Qiang Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Knockdown of CPEB4 expression suppresses cell migration and invasion via Akt pathway in non-small cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Biol Int (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cbin.10930"}], "href": "https://doi.org/10.1002/cbin.10930"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29286212"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29286212"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Qingyan Zhou, Yuan Xie, Li Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LncRNA EWSAT1 upregulates CPEB4 via miR-330-5p to promote cervical cancer development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biochem (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11010-020-03778-8"}], "href": "https://doi.org/10.1007/s11010-020-03778-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32556917"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32556917"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Alberto Parras, Héctor Anta, María Santos-Galindo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41586-018-0423-5"}], "href": "https://doi.org/10.1038/s41586-018-0423-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30111840"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30111840"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Vittorio Calderone, Javier Gallego, Gonzalo Fernandez-Miranda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sequential Functions of CPEB1 and CPEB4 Regulate Pathologic Expression of Vascular Endothelial Growth Factor and Angiogenesis in Chronic Liver Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2015.11.038"}], "href": "https://doi.org/10.1053/j.gastro.2015.11.038"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26627607"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26627607"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Marc Mejias, Javier Gallego, Salvador Naranjo-Suarez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CPEB4 Increases Expression of PFKFB3 to Induce Glycolysis and Activate Mouse and Human Hepatic Stellate Cells, Promoting Liver Fibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2020.03.008"}], "href": "https://doi.org/10.1053/j.gastro.2020.03.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32169429"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32169429"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Wenqian Hu, Bingbing Yuan, Harvey F Lodish "}, {"type": "b", "children": [{"type": "t", "text": "Cpeb4-mediated translational regulatory circuitry controls terminal erythroid differentiation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Cell (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.devcel.2014.07.008"}], "href": "https://doi.org/10.1016/j.devcel.2014.07.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25220394"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25220394"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "S Zaccara, T Tebaldi, C Pederiva, et al. "}, {"type": "b", "children": [{"type": "t", "text": "p53-directed translational control can shape and expand the universe of p53 target genes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Differ (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cdd.2014.79"}], "href": "https://doi.org/10.1038/cdd.2014.79"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24926617"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24926617"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Xu Zhang, Xiaoli Chen, Qiuying Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Translation repression via modulation of the cytoplasmic poly(A)-binding protein in the inflammatory response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.27786"}], "href": "https://doi.org/10.7554/eLife.27786"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28635594"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28635594"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Hui Song Cui, So Young Joo, Yoon Soo Cho, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CPEB1 or CPEB4 knockdown suppresses the TAK1 and Smad signalings in THP-1 macrophage-like cells and dermal fibroblasts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Biochem Biophys (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.abb.2020.108322"}], "href": "https://doi.org/10.1016/j.abb.2020.108322"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32113875"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32113875"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Alberto Parras, Laura de Diego-Garcia, Mariana Alves, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polyadenylation of mRNA as a novel regulatory mechanism of gene expression in temporal lobe epilepsy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awaa168"}], "href": "https://doi.org/10.1093/brain/awaa168"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32594159"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32594159"}]}]}]}