{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRegucalcin (RGN), also known as senescence marker protein‐30 (SMP30), is a unique calcium‐binding protein that lacks the typical EF‐hand motif. It plays a central role in maintaining intracellular Ca²⁺ homeostasis and in regulating numerous Ca²⁺‐dependent enzymes, including membrane Ca²⁺ pumps. Structural studies have revealed that it possesses a specialized substrate‐binding pocket that is critical for its function in L–ascorbic acid (vitamin C) biosynthesis. Collectively, these features underscore its importance as a master regulator of cellular homeostasis in diverse tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to these homeostatic functions, regucalcin exerts potent growth‐suppressive and tumor–protective actions. Experimental studies have shown that its overexpression in various cell types leads to G₁ and G₂/M phase cell cycle arrest through modulation of key regulators such as p21, p53, and retinoblastoma protein, while concurrently downregulating oncogenic drivers like c–fos, c–myc and components of the Ras/Akt/MAP kinase pathways. In contrast, its suppressed expression is a common feature in multiple human malignancies—including hepatocellular, breast, prostate, pancreatic, colorectal, lung, and renal cancers—and is frequently associated with poor clinical outcome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its oncostatic effects, regucalcin is a crucial cytoprotective molecule that mitigates oxidative stress and modulates metabolic processes. Overexpression studies in hepatoma cells have demonstrated that increased RGN levels reduce reactive oxygen species (ROS) formation and lipid peroxidation, thereby protecting cells from apoptotic injury. Furthermore, RGN influences insulin signaling, lipid metabolism, and energy homeostasis—functions that are relevant not only for normal metabolic balance but also in conditions such as nonalcoholic fatty liver disease and diabetic nephropathy. Its role in regulating the biosynthesis of vitamin C via modulation of L–gulonolactone oxidase further supports its protective impact on cellular redox status."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRegucalcin also fulfills tissue–specific roles that extend its biological impact. In the reproductive system, for example, it is expressed in testicular cells—where its androgen–dependent regulation suggests a role in spermatogenesis—while in the brain it contributes to the regulation of neuronal Ca²⁺ signaling and may influence age–related cognitive changes. In ocular tissues, altered RGN expression has been linked to lens epithelial cell apoptosis and cataract formation. Such tissue–restricted actions, together with its frequent downregulation in a variety of cancers, point to its potential as both a diagnostic marker and therapeutic target in age–related as well as neoplastic disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Akihito Ishigami, Setsuko Handa, Naoki Maruyama, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Structural basis of the γ-lactone-ring formation in ascorbic acid biosynthesis by the senescence marker protein-30/gluconolactonase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0053706"}], "href": "https://doi.org/10.1371/journal.pone.0053706"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23349732"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23349732"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Masayoshi Yamaguchi, Yuko Daimon "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of regucalcin suppresses cell proliferation in cloned rat hepatoma H4-II-E cells: involvement of intracellular signaling factors and cell cycle-related genes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biochem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcb.20490"}], "href": "https://doi.org/10.1002/jcb.20490"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15962315"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15962315"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Cláudio Maia, Cecília Santos, Fernando Schmitt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regucalcin is under-expressed in human breast and prostate cancers: Effect of sex steroid hormones."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biochem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcb.22158"}], "href": "https://doi.org/10.1002/jcb.22158"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19347872"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19347872"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Sheng-Chang Zhang, Ming-Kang Liang, Guang-Lin Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of SMP30 gene expression influences the biological characteristics of human Hep G2 cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Asian Pac J Cancer Prev (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7314/apjcp.2014.15.3.1193"}], "href": "https://doi.org/10.7314/apjcp.2014.15.3.1193"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24606440"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24606440"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Ricardo Marques, Cátia V Vaz, Cláudio J Maia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Histopathological and in vivo evidence of regucalcin as a protective molecule in mammary gland carcinogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2014.08.007"}], "href": "https://doi.org/10.1016/j.yexcr.2014.08.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25128811"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25128811"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Masayoshi Yamaguchi, Tomiyasu Murata "}, {"type": "b", "children": [{"type": "t", "text": "Suppressive effects of exogenous regucalcin on the proliferation of human pancreatic cancer MIA PaCa-2 cells in vitro."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Med (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijmm.2015.2164"}], "href": "https://doi.org/10.3892/ijmm.2015.2164"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25847529"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25847529"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Kari N Nejak-Bowen, Gang Zeng, Xinping Tan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Beta-catenin regulates vitamin C biosynthesis and cell survival in murine liver."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.047258"}], "href": "https://doi.org/10.1074/jbc.M109.047258"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19690176"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19690176"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Setsuko Handa, Naoki Maruyama, Akihito Ishigami "}, {"type": "b", "children": [{"type": "t", "text": "Over-expression of Senescence Marker Protein-30 decreases reactive oxygen species in human hepatic carcinoma Hep G2 cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biol Pharm Bull (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1248/bpb.32.1645"}], "href": "https://doi.org/10.1248/bpb.32.1645"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19801822"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19801822"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Hyohun Park, Akihito Ishigami, Toshihide Shima, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hepatic senescence marker protein-30 is involved in the progression of nonalcoholic fatty liver disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Gastroenterol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00535-009-0154-3"}], "href": "https://doi.org/10.1007/s00535-009-0154-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19946731"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19946731"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Masayoshi Yamaguchi, Tomiyasu Murata "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of regucalcin in lipid metabolism and diabetes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Metabolism (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.metabol.2013.01.023"}], "href": "https://doi.org/10.1016/j.metabol.2013.01.023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23453039"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23453039"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Sandra S Laurentino, Sara Correia, José Eduardo Cavaco, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regucalcin, a calcium-binding protein with a role in male reproduction?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Hum Reprod (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/molehr/gar075"}], "href": "https://doi.org/10.1093/molehr/gar075"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22121208"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22121208"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Masayoshi Yamaguchi "}, {"type": "b", "children": [{"type": "t", "text": "Role of regucalcin in brain calcium signaling: involvement in aging."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Integr Biol (Camb) (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1039/c2ib20042b"}], "href": "https://doi.org/10.1039/c2ib20042b"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22652898"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22652898"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Cátia V Vaz, Daniel B Rodrigues, Sílvia Socorro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Effect of extracellular calcium on regucalcin expression and cell viability in neoplastic and non-neoplastic human prostate cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbamcr.2015.07.006"}], "href": "https://doi.org/10.1016/j.bbamcr.2015.07.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26171977"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26171977"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Dan Zhou, Dan Yin, Fang Xiao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expressions of Senescence-Associated β-Galactosidase and Senescence Marker Protein-30 are Associated with Lens Epithelial Cell Apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Med Sci Monit (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.12659/msm.895596"}], "href": "https://doi.org/10.12659/msm.895596"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26619319"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26619319"}]}]}]}