{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ALOX15B, the gene encoding 15‐lipoxygenase‐2 (15‐LOX‐2), is emerging as a multifunctional regulator in diverse human tissues. In the normal prostate and breast epithelium, 15‐LOX‐2 is abundantly expressed and functions as a tumor suppressor by inducing cell cycle arrest, reducing pro‐angiogenic factor expression, and promoting cell senescence; conversely, its loss in prostate, breast and esophageal cancers correlates with malignant progression and poorer clinical outcome ["}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "]. In breast cancer, reduced ALOX15B expression is linked to advanced tumor stage and metastasis ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "]. In contrast, in atherosclerotic lesions and macrophages, ALOX15B is frequently upregulated; its enzymatic products contribute to the synthesis of bioactive lipid mediators that modulate cholesterol metabolism, immune cell recruitment, and thrombus formation, with higher ALOX15B transcript levels in carotid plaques associating with cerebrovascular symptoms and enhanced platelet aggregation ["}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "]. In lung and other epithelial contexts, induction of ALOX15B by bioactive compounds promotes apoptosis through peroxisome proliferator‐activated receptor (PPAR)–dependent pathways ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "]. Detailed biophysical studies indicate that 15‐LOX‐2 adopts a “tail‐first” substrate binding mode when oxygenating arachidonic acid, and its catalytic efficiency is modulated allosterically by lipid effectors, thereby altering product distribution toward bioactive 15‐hydroxy derivatives ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "]. Transcriptionally, the 15‐LOX‐2 gene is regulated by Sp family members, with Sp1 acting as an activator and Sp3 as a repressor in normal prostate cells, and its expression can also be influenced by tumor suppressors such as p53 and annexin A7, suggesting context‐dependent feedback in cancer cells ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "]. Additionally, in vascular smooth muscle and chondrocytes, 15‐LOX‐2–derived lipid mediators contribute to the modulation of MAPK signaling and PPARγ activation, thereby attenuating inflammatory responses and matrix metalloproteinase expression ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "]. Finally, in human macrophages, loss of ALOX15B activity disrupts intracellular cholesterol homeostasis and diminishes the secretion of chemokines essential for T‐cell recruitment, underlining its role in immune regulation ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "]. Collectively, these studies suggest that ALOX15B exerts pleiotropic functions through its lipid‐oxygenating activity and non–catalytic roles that impact cell proliferation, differentiation, inflammatory responses, and thrombosis in a tissue‐ and context‐dependent manner.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Linda C Hsi, Leigh C Wilson, Thomas E Eling "}, {"type": "b", "children": [{"type": "t", "text": "Opposing effects of 15-lipoxygenase-1 and -2 metabolites on MAPK signaling in prostate. Alteration in peroxisome proliferator-activated receptor gamma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M203522200"}], "href": "https://doi.org/10.1074/jbc.M203522200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12189136"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12189136"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Shaohua Tang, Bobby Bhatia, Carlos J Maldonado, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evidence that arachidonate 15-lipoxygenase 2 is a negative cell cycle regulator in normal prostate epithelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111936200"}], "href": "https://doi.org/10.1074/jbc.M111936200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11839751"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11839751"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Bobby Bhatia, Carlos J Maldonado, Shaohua Tang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Subcellular localization and tumor-suppressive functions of 15-lipoxygenase 2 (15-LOX2) and its splice variants."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M301920200"}], "href": "https://doi.org/10.1074/jbc.M301920200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12704195"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12704195"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yong Tang, Man-Tzu Wang, Yakun Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Downregulation of vascular endothelial growth factor and induction of tumor dormancy by 15-lipoxygenase-2 in prostate cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.24118"}], "href": "https://doi.org/10.1002/ijc.24118"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19089921"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19089921"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Wen G Jiang, Gareth Watkins, Anthony Douglas-Jones, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Prostaglandins Leukot Essent Fatty Acids (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.plefa.2006.01.009"}], "href": "https://doi.org/10.1016/j.plefa.2006.01.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16556493"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16556493"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Karl Gertow, Elena Nobili, Lasse Folkersen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "12- and 15-lipoxygenases in human carotid atherosclerotic lesions: associations with cerebrovascular symptoms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Atherosclerosis (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.atherosclerosis.2011.01.015"}], "href": "https://doi.org/10.1016/j.atherosclerosis.2011.01.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21316676"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21316676"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Sophia J A Wuest, Margot Crucet, Claudio Gemperle, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression and regulation of 12/15-lipoxygenases in human primary macrophages."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Atherosclerosis (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.atherosclerosis.2012.07.022"}], "href": "https://doi.org/10.1016/j.atherosclerosis.2012.07.022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22980500"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22980500"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "S E Clements, T Techanukul, J E Lai-Cheong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in AEC syndrome skin reveal a role for p63 in basement membrane adhesion, skin barrier integrity and hair follicle biology."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Dermatol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1365-2133.2012.10888.x"}], "href": "https://doi.org/10.1111/j.1365-2133.2012.10888.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22329826"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22329826"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Jenny T Mao, Wen-Xian Nie, I-Hsien Tsu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "White tea extract induces apoptosis in non-small cell lung cancer cells: the role of peroxisome proliferator-activated receptor-{gamma} and 15-lipoxygenases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Prev Res (Phila) (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1940-6207.CAPR-09-0264"}], "href": "https://doi.org/10.1158/1940-6207.CAPR-09-0264"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20668019"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20668019"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Aaron T Wecksler, Victor Kenyon, Natalie K Garcia, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Kinetic and structural investigations of the allosteric site in human epithelial 15-lipoxygenase-2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi9009242"}], "href": "https://doi.org/10.1021/bi9009242"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19645454"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19645454"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Reynier Suardíaz, Pablo G Jambrina, Laura Masgrau, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Understanding the Mechanism of the Hydrogen Abstraction from Arachidonic Acid Catalyzed by the Human Enzyme 15-Lipoxygenase-2. A Quantum Mechanics/Molecular Mechanics Free Energy Simulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Chem Theory Comput (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/acs.jctc.5b01236"}], "href": "https://doi.org/10.1021/acs.jctc.5b01236"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26918937"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26918937"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Shaohua Tang, Bobby Bhatia, Jianjun Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evidence that Sp1 positively and Sp3 negatively regulate and androgen does not directly regulate functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) gene expression in normal human prostate epithelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1207913"}], "href": "https://doi.org/10.1038/sj.onc.1207913"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15247906"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15247906"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Yelizaveta Torosyan, Albert Dobi, Shanmugam Naga, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Distinct effects of annexin A7 and p53 on arachidonate lipoxygenation in prostate cancer cells involve 5-lipoxygenase transcription."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-06-1574"}], "href": "https://doi.org/10.1158/0008-5472.CAN-06-1574"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17018618"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17018618"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Xiufeng Yu, Tingting Li, Xia Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Modulation of Pulmonary Vascular Remodeling in Hypoxia: Role of 15-LOX-2/15-HETE-MAPKs Pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Physiol Biochem (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1159/000374015"}], "href": "https://doi.org/10.1159/000374015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25895668"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25895668"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Nadir Chabane, Nadia Zayed, Mohamed Benderdour, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human articular chondrocytes express 15-lipoxygenase-1 and -2: potential role in osteoarthritis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arthritis Res Ther (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/ar2652"}], "href": "https://doi.org/10.1186/ar2652"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19296842"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19296842"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Ryan G Snodgrass, Ekaterina Zezina, Dmitry Namgaladze, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A Novel Function for 15-Lipoxygenases in Cholesterol Homeostasis and CCL17 Production in Human Macrophages."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Immunol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fimmu.2018.01906"}], "href": "https://doi.org/10.3389/fimmu.2018.01906"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30197642"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30197642"}]}]}]}