{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPersephin (PSPN) is a member of the glial cell line‑derived neurotrophic factor (GDNF) family that, in certain contexts, contributes to cell survival and proliferation. In oral squamous cell carcinoma (OSCC), PSPN is markedly up‑regulated compared with normal oral keratinocytes, and its inhibition leads to decreased cellular proliferation accompanied by G1 phase cell cycle arrest mediated by increased expression of cyclin‑dependent kinase inhibitors. These results suggest that PSPN may be a key regulator of OSCC progression—possibly via activation of RET and downstream mitogen‑activated protein kinase pathways—and that its overexpression holds promise as a diagnostic marker in this malignancy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "Disparate studies of neurotrophic factor signaling have further highlighted PSPN’s role as a ligand in neuronal systems. Reporter‑gene assays revealed that PSPN acts as a novel ligand for the GFRα1/RET receptor complex, an interaction with therapeutic implications for rescue of dopaminergic neurons in Parkinson’s disease. In addition, investigations using the homologous mouse systems show that while PSPN induces RET phosphorylation via GFRα4, it does so without effectively recruiting RET into lipid rafts—a contrast to the conventional GFRα1‑mediated signaling—nonetheless promoting neurite outgrowth and neuronal survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "Complementary immunohistochemical studies in human postmortem brain tissue have documented the expression and subcellular distribution of PSPN throughout the hippocampus, suggesting its involvement in both developmental organization and the maintenance of mature neurons. Moreover, given that RET is a major susceptibility gene in Hirschsprung disease, and considering the pivotal role that RET ligands play in the development of the enteric nervous system, PSPN, alongside other GDNF family members, is being considered as a candidate gene contributing to disease pathogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Takao Baba, Yosuke Sakamoto, Atsushi Kasamatsu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Persephin: A potential key component in human oral cancer progression through the RET receptor tyrosine kinase-mitogen-activated protein kinase signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Carcinog (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/mc.22127"}], "href": "https://doi.org/10.1002/mc.22127"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24375483"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24375483"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yulia A Sidorova, Kert Mätlik, Mikhail Paveliev, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Persephin signaling through GFRalpha1: the potential for the treatment of Parkinson's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Neurosci (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mcn.2010.03.009"}], "href": "https://doi.org/10.1016/j.mcn.2010.03.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20350599"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20350599"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jianmin Yang, Maria Lindahl, Päivi Lindholm, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PSPN/GFRalpha4 has a significantly weaker capacity than GDNF/GFRalpha1 to recruit RET to rafts, but promotes neuronal survival and neurite outgrowth."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2004.06.007"}], "href": "https://doi.org/10.1016/j.febslet.2004.06.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15225646"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15225646"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Marina Quartu, Maria Pina Serra, Annalisa Manca, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neurturin, persephin, and artemin in the human pre- and full-term newborn and adult hippocampus and fascia dentata."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain Res (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.brainres.2005.02.007"}], "href": "https://doi.org/10.1016/j.brainres.2005.02.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15829225"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15829225"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Raquel M Fernandez, Macarena Ruiz-Ferrer, Manuel Lopez-Alonso, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polymorphisms in the genes encoding the 4 RET ligands, GDNF, NTN, ARTN, PSPN, and susceptibility to Hirschsprung disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Pediatr Surg (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jpedsurg.2008.05.018"}], "href": "https://doi.org/10.1016/j.jpedsurg.2008.05.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18970938"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18970938"}]}]}]}