{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSPAG5, whose protein product is also known as astrin, is a conserved mitotic spindle‐associated factor that plays critical roles in ensuring accurate cell division. It localizes to spindle microtubules and kinetochores where it helps to stabilize kinetochore–microtubule attachments, regulate separase activation, and thereby maintain proper chromosome segregation and genomic stability. SPAG5 interacts with multiple regulatory proteins—including components of the NuMA complex and mitotic kinases such as Aurora‐A and GSK3β—ensuring timely spindle assembly and checkpoint silencing during mitosis. These functions were initially revealed by studies showing its phosphorylation by p34(cdc2) and its participation in the astrin–SKAP complex that helps in spindle organization and centrosome integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOverexpression of SPAG5 has been demonstrated in a wide spectrum of human cancers—including prostate, cervical, bladder urothelial, triple‐negative breast, hepatocellular, non–small cell lung, gastric, ovarian, melanoma, colorectal cancers, and multiple myeloma—and generally correlates with aggressive clinical behavior and poor patient outcomes. In these tumors, elevated SPAG5 levels promote cellular proliferation, migration, invasion, and resistance to apoptosis. Its upregulation, therefore, serves not only as a marker of rampant cellular division but also as an independent prognostic indicator in several malignancies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in cell division and tumor proliferation, SPAG5 modulates several key intracellular signaling pathways that drive oncogenesis. It has been shown to act upstream of cascades such as the AKT/mTOR and Wnt/β‐catenin pathways, partly via regulation by microRNAs (for example, miR‑1179, miR‑367‑3p, and miR‑133a‑3p) as well as through effects on FOXM1, Survivin, and ADAM17/NOTCH1 networks. These interactions not only amplify its tumor‐promoting effects but also suggest potential avenues for targeted therapy—approaches including the modulation of specific miRNAs or the use of natural compounds such as curcumin to suppress SPAG5 activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its oncogenic and cell‐cycle regulatory functions, SPAG5 has been implicated in other pathophysiological contexts. Aberrant expression of SPAG5 has been observed in developmental disorders—for example, in men with Down’s syndrome presenting with cryptorchidism—and in conditions such as diabetic nephropathy and atherosclerosis, where its impact on autophagy or structural integrity of cellular complexes may contribute to disease progression. These studies broaden the significance of SPAG5 as a multifaceted regulator whose dysregulation can perturb both normal development and chronic disease processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "37", "end_ref": "40"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "M S Chang, C J Huang, M L Chen, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Silencing of astrin induces the p53-dependent apoptosis by suppression of HPV18 E6 expression and sensitizes cells to paclitaxel treatment in HeLa cells."}]}, {"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.2006.02.166"}], "href": "https://doi.org/10.1016/j.bbrc.2006.02.166"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16546135"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16546135"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Tai-Shan Cheng, Yun-Ling Hsiao, Ching-Chih Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "hNinein is required for targeting spindle-associated protein Astrin to the centrosome during the S and G2 phases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2007.02.023"}], "href": "https://doi.org/10.1016/j.yexcr.2007.02.023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17383637"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17383637"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Kerstin H Thein, Julia Kleylein-Sohn, Erich A Nigg, et al. 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