Genomes and Genes
arachidonate 15 lipoxygenase
Summary: An enzyme that catalyzes the oxidation of arachidonic acid to yield 15-hydroperoxyarachidonate (15-HPETE) which is rapidly converted to 15-hydroxy-5,8,11,13-eicosatetraenoate (15-HETE). The 15-hydroperoxides are preferentially formed in NEUTROPHILS and LYMPHOCYTES.
- Andersson E, Schain F, Svedling M, Claesson H, Forsell P. Interaction of human 15-lipoxygenase-1 with phosphatidylinositol bisphosphates results in increased enzyme activity. Biochim Biophys Acta. 2006;1761:1498-505 pubmed..Taken together, this report demonstrates that human 15-LO-1 binds to PI(4.5)P(2) and PI(3.4)P(2) and that these phospholipids stimulate enzyme activity in the presence of calcium in a vesicle based assay. ..
- Tang Y, Wang M, Chen Y, Yang D, Che M, Honn K, et al. Downregulation of vascular endothelial growth factor and induction of tumor dormancy by 15-lipoxygenase-2 in prostate cancer. Int J Cancer. 2009;124:1545-51 pubmed publisher..Loss of 15-LOX-2 functionalities, therefore, represents a key step for prostate cancer cells to exit from dormancy and embark on malignant progression in vivo. ..
- Brash A, Boeglin W, Chang M. Discovery of a second 15S-lipoxygenase in humans. Proc Natl Acad Sci U S A. 1997;94:6148-52 pubmed..The different catalytic activities and tissue distribution suggest a distinct function for the new enzyme compared with the previously reported human 15S-lipoxygenase. ..
- Hatley M, Srinivasan S, Reilly K, Bolick D, Hedrick C. Increased production of 12/15 lipoxygenase eicosanoids accelerates monocyte/endothelial interactions in diabetic db/db mice. J Biol Chem. 2003;278:25369-75 pubmed..Modulation of the 12/15LO pathway in the vessel wall may provide therapeutic benefit for early vascular inflammatory events in diabetes. ..
- Serhan C, Jain A, Marleau S, Clish C, Kantarci A, Behbehani B, et al. Reduced inflammation and tissue damage in transgenic rabbits overexpressing 15-lipoxygenase and endogenous anti-inflammatory lipid mediators. J Immunol. 2003;171:6856-65 pubmed..Moreover, they suggest that LXs can be targets for novel approaches to diseases, e.g., periodontitis and arthritis, where inflammation and bone destruction are features. ..
- Wittwer J, Hersberger M. The two faces of the 15-lipoxygenase in atherosclerosis. Prostaglandins Leukot Essent Fatty Acids. 2007;77:67-77 pubmed..This will now allow large studies to investigate an association of 15-LOX with coronary artery disease and to answer the question whether 15-LOX is pro- or anti-atherogenic in humans. ..
- Seiler A, Schneider M, Forster H, Roth S, Wirth E, Culmsee C, et al. Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 2008;8:237-48 pubmed publisher..Since oxidative stress is common in the etiology of many human disorders, the identified pathway reveals promising targets for future therapies. ..
- Gonzalez A, Roberts R, Massion P, Olson S, Shyr Y, Shappell S. 15-Lipoxygenase-2 expression in benign and neoplastic lung: an immunohistochemical study and correlation with tumor grade and proliferation. Hum Pathol. 2004;35:840-9 pubmed..0001). These findings suggest a possible role of 15-LOX-2 in regulating secretory differentiation and proliferation in benign lung and NSCLCs, particularly adenocarcinomas. ..
- Harada S, Sugiyama E, Takebe S, Taki H, Shinoda K, Mohamed S, et al. Cooperative induction of 15-lipoxygenase in rheumatoid synovial cells by IL-4 and proinflammatory cytokines. Clin Exp Rheumatol. 2003;21:753-8 pubmed..Since 15-LOX metabolites have potent anti-inflammatory actions, our data suggest that IL-4 might downregulate rheumatoid inflammation via the induction of 15-LOX and its metabolites. ..
- Hsi L, Wilson L, Eling T. Opposing effects of 15-lipoxygenase-1 and -2 metabolites on MAPK signaling in prostate. Alteration in peroxisome proliferator-activated receptor gamma. J Biol Chem. 2002;277:40549-56 pubmed..These results provide a plausible mechanism to explain the apparent opposing effects 15-LOX-1 and 15-LOX-2 play in prostate cancer. ..
- Kuhn H, O Donnell V. Inflammation and immune regulation by 12/15-lipoxygenases. Prog Lipid Res. 2006;45:334-56 pubmed..This review will summarize the biochemistry and tissue expression of 12/15-LOX and will describe the current knowledge regarding its immunobiology and regulation of inflammation. ..
- Spanbroek R, Hildner M, Kohler A, Muller A, Zintl F, Kuhn H, et al. IL-4 determines eicosanoid formation in dendritic cells by down-regulation of 5-lipoxygenase and up-regulation of 15-lipoxygenase 1 expression. Proc Natl Acad Sci U S A. 2001;98:5152-7 pubmed..These actions of IL-4/IL-13 reveal a paradigm of eicosanoid formation consisting of the inhibition of one and the stimulation of another LO in a single leukocyte lineage. ..
- Tang S, Bhatia B, Maldonado C, Yang P, Newman R, Liu J, et al. Evidence that arachidonate 15-lipoxygenase 2 is a negative cell cycle regulator in normal prostate epithelial cells. J Biol Chem. 2002;277:16189-201 pubmed..Taken together, these results suggest that 15-LOX2 could be a suppressor of prostate cancer development, which functions by restricting cell cycle progression. ..
- Nassar G, Morrow J, Roberts L, Lakkis F, Badr K. Induction of 15-lipoxygenase by interleukin-13 in human blood monocytes. J Biol Chem. 1994;269:27631-4 pubmed..The contrasting effects of interferon-gamma and IL-13 on 15-LO induction demonstrate mechanisms by which T-lymphocyte subsets may modulate macrophage/monocyte function in inflammation or atherosclerosis. ..
- Dwarakanath R, Sahar S, Lanting L, Wang N, Stemerman M, Natarajan R, et al. Viral vector-mediated 12/15-lipoxygenase overexpression in vascular smooth muscle cells enhances inflammatory gene expression and migration. J Vasc Res. 2008;45:132-42 pubmed..Enhanced proatherogenic responses in VSMCs triggered by increased 12/15-LO levels under pathological conditions may contribute to vascular dysfunction. ..
- Andersson C, Claesson H, Rydell Törmänen K, Swedmark S, Hällgren A, Erjefalt J. Mice lacking 12/15-lipoxygenase have attenuated airway allergic inflammation and remodeling. Am J Respir Cell Mol Biol. 2008;39:648-56 pubmed publisher..Hence, pharmacologic targeting of the human 15-LO-1 may represent an attractive therapeutic strategy to control inflammation and remodeling in asthma. ..
- Roy B, Cathcart M. Induction of 15-lipoxygenase expression by IL-13 requires tyrosine phosphorylation of Jak2 and Tyk2 in human monocytes. J Biol Chem. 1998;273:32023-9 pubmed..This occurs as an early and essential signal transduction event for the IL-13-mediated induction of 15-LO expression. These data represent the first characterization of upstream kinases involved in the induced expression of 15-LO. ..
- Middleton M, Rubinstein T, Pure E. Cellular and molecular mechanisms of the selective regulation of IL-12 production by 12/15-lipoxygenase. J Immunol. 2006;176:265-74 pubmed..Taken together, these findings reveal a highly selective pathway to IL-12 production that may prove a useful target in chronic inflammation while sparing the acute response to infection. ..
- Hashimoto A, Hayashi I, Murakami Y, Sato Y, Kitasato H, Matsushita R, et al. Antiinflammatory mediator lipoxin A4 and its receptor in synovitis of patients with rheumatoid arthritis. J Rheumatol. 2007;34:2144-53 pubmed..These findings could lead to the development of new therapy for inflammatory arthritis such as RA. ..
- Tang X, Holmes B, Nithipatikom K, Hillard C, Kuhn H, Campbell W. Reticulocyte 15-lipoxygenase-I is important in acetylcholine-induced endothelium-dependent vasorelaxation in rabbit aorta. Arterioscler Thromb Vasc Biol. 2006;26:78-84 pubmed..15-LO-I is expressed in rabbit aortic endothelium and is important in endothelium-dependent regulation of vascular tone. ..
- Zhao L, Funk C. Lipoxygenase pathways in atherogenesis. Trends Cardiovasc Med. 2004;14:191-5 pubmed..Development of novel pharmacologic tools to dissect the individual enzymes and receptors in the LO pathways should improve understanding of the individual components in the inflammatory aspects of atherosclerosis disease progression. ..
- Klein R, Allard J, Avnur Z, Nikolcheva T, Rotstein D, Carlos A, et al. Regulation of bone mass in mice by the lipoxygenase gene Alox15. Science. 2004;303:229-32 pubmed..These results suggest that drugs targeting the 12/15-lipoxygenase pathway merit investigation as a therapy for osteoporosis. ..
- Shappell S, Olson S, Hannah S, Manning S, Roberts R, Masumori N, et al. Elevated expression of 12/15-lipoxygenase and cyclooxygenase-2 in a transgenic mouse model of prostate carcinoma. Cancer Res. 2003;63:2256-67 pubmed
- Cyrus T, Witztum J, Rader D, Tangirala R, Fazio S, Linton M, et al. Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice. J Clin Invest. 1999;103:1597-604 pubmed..The combined data indicate a role for 12/15-lipoxygenase in the pathogenesis of atherosclerosis and suggest that inhibition of this enzyme may decrease disease progression. ..
- George J, Afek A, Shaish A, Levkovitz H, Bloom N, Cyrus T, et al. 12/15-Lipoxygenase gene disruption attenuates atherogenesis in LDL receptor-deficient mice. Circulation. 2001;104:1646-50 pubmed..12/15-LO plays a dominant role in promoting atherogenesis in LDL-R(-/-) mice. ..
- Tang D, Bhatia B, Tang S, Schneider Broussard R. 15-lipoxygenase 2 (15-LOX2) is a functional tumor suppressor that regulates human prostate epithelial cell differentiation, senescence, and growth (size). Prostaglandins Other Lipid Mediat. 2007;82:135-46 pubmed..Here we summarize these new findings to provide a concise view of the potential biological functions of 15-LOX2 in NHP cells and of its deregulation in PCa development. ..
- Subbarayan V, Krieg P, Hsi L, Kim J, Yang P, Sabichi A, et al. 15-Lipoxygenase-2 gene regulation by its product 15-(S)-hydroxyeicosatetraenoic acid through a negative feedback mechanism that involves peroxisome proliferator-activated receptor gamma. Oncogene. 2006;25:6015-25 pubmed..These data suggest that crosstalk mechanisms exist between the 15-LOX-2 gene and PPARgamma to counterbalance expression and help explain the inverse relationship of these genes in normal versus cancer cells. ..
- Bolick D, Srinivasan S, Whetzel A, Fuller L, Hedrick C. 12/15 lipoxygenase mediates monocyte adhesion to aortic endothelium in apolipoprotein E-deficient mice through activation of RhoA and NF-kappaB. Arterioscler Thromb Vasc Biol. 2006;26:1260-6 pubmed..Induction of ICAM-1 on aortic endothelium stimulates monocyte:endothelial adhesion in vivo in apoEKO mice. ..
- Kilty I, Logan A, Vickers P. Differential characteristics of human 15-lipoxygenase isozymes and a novel splice variant of 15S-lipoxygenase. Eur J Biochem. 1999;266:83-93 pubmed..These results demonstrate that there are substantial differences in the enzyme characteristics and regulation of the 15-LO isozymes which may reflect differing roles for the proteins in vivo. ..
- Bhatia B, Maldonado C, Tang S, Chandra D, Klein R, Chopra D, et al. Subcellular localization and tumor-suppressive functions of 15-lipoxygenase 2 (15-LOX2) and its splice variants. J Biol Chem. 2003;278:25091-100 pubmed..Together, these results suggest that both 15-LOX2 and 15-LOX2sv-b suppress prostate tumor development, and the tumor-suppressive functions apparently do not necessarily depend on AA-metabolizing activity and nuclear localization. ..
- Ichikawa S, Koller D, Johnson M, Lai D, Xuei X, Edenberg H, et al. Human ALOX12, but not ALOX15, is associated with BMD in white men and women. J Bone Miner Res. 2006;21:556-64 pubmed..0083), whereas the second most common haplotype was associated with high spine BMD in women (p = 0.0081). Polymorphisms in the ALOX12 gene may contribute to normal variation in spine BMD. ..
- Shappell S, Boeglin W, Olson S, Kasper S, Brash A. 15-lipoxygenase-2 (15-LOX-2) is expressed in benign prostatic epithelium and reduced in prostate adenocarcinoma. Am J Pathol. 1999;155:235-45 pubmed..15-LOX-2 is a novel human lipoxygenase with a limited tissue distribution that is strongly expressed in benign prostate glandular epithelium and lost to a variable degree in the majority of prostate adenocarcinomas. ..
- Levy B, Clish C, Schmidt B, Gronert K, Serhan C. Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol. 2001;2:612-9 pubmed
- Cyrus T, Pratico D, Zhao L, Witztum J, Rader D, Rokach J, et al. Absence of 12/15-lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein e-deficient mice. Circulation. 2001;103:2277-82 pubmed..Strong positive correlations exist between lesion size, isoprostane levels, and MDA-LDL autoantibodies, providing in vivo evidence for an enzymatic (12/15-LO) component to lipid peroxidation and atherogenesis. ..
- Zhu H, Takahashi Y, Xu W, Kawajiri H, Murakami T, Yamamoto M, et al. Low density lipoprotein receptor-related protein-mediated membrane translocation of 12/15-lipoxygenase is required for oxidation of low density lipoprotein by macrophages. J Biol Chem. 2003;278:13350-5 pubmed..We propose that cholesterol ester selectively transferred from the LDL particle to the plasma membrane via LRP is oxygenated by 12/15-lipoxygenase translocated to this membrane. ..
- Wen Y, Gu J, Chakrabarti S, Aylor K, Marshall J, Takahashi Y, et al. The role of 12/15-lipoxygenase in the expression of interleukin-6 and tumor necrosis factor-alpha in macrophages. Endocrinology. 2007;148:1313-22 pubmed..These results suggest a potentially important mechanism linking 12/15-LO activation to chronic inflammation and atherosclerosis. ..
- Feltenmark S, Gautam N, Brunnström A, Griffiths W, Backman L, Edenius C, et al. Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells. Proc Natl Acad Sci U S A. 2008;105:680-5 pubmed publisher..Taken together, this article describes the formation of proinflammatory EXs, in particular in human eosinophils but also in human mast cells and nasal polyps. ..
- Wang D, Chen S, Feng Y, Yang Q, Campbell B, Tang X, et al. Reduced expression of 15-lipoxygenase 2 in human head and neck carcinomas. Tumour Biol. 2006;27:261-73 pubmed..Our results demonstrate that 15-LOX-2 expression is significantly reduced and this reduction may promote proliferation in human head and neck carcinoma. 15-LOX-2 may be a possible biomarker in human head and neck malignancy. ..
- Liu C, Xu D, Sjoberg J, Forsell P, Bjorkholm M, Claesson H. Transcriptional regulation of 15-lipoxygenase expression by promoter methylation. Exp Cell Res. 2004;297:61-7 pubmed..Taken together, demethylation of the 15-LO promoter is a prerequisite for the gene transactivation, which contributes to tissue- and cell-type-specific regulation of 15-LO expression. ..
- Schweiger D, Furstenberger G, Krieg P. Inducible expression of 15-lipoxygenase-2 and 8-lipoxygenase inhibits cell growth via common signaling pathways. J Lipid Res. 2007;48:553-64 pubmed..Our data suggest that 15-LOX-2 and 8-LOX, although displaying different positional specificity, may use common signaling pathways to induce growth inhibition in premalignant epithelial cells. ..
- Lee Y, Kuhn H, Kaiser S, Hennig B, Daugherty A, Toborek M. Interleukin 4 induces transcription of the 15-lipoxygenase I gene in human endothelial cells. J Lipid Res. 2001;42:783-91 pubmed..The lack of active 15-LO-I protein in the presence of functional 15-LO-I mRNA suggests additional regulatory elements of 15-LO expression at posttranscriptional levels. ..
- Shappell S, Gupta R, Manning S, Whitehead R, Boeglin W, Schneider C, et al. 15S-Hydroxyeicosatetraenoic acid activates peroxisome proliferator-activated receptor gamma and inhibits proliferation in PC3 prostate carcinoma cells. Cancer Res. 2001;61:497-503 pubmed
- Bhatia B, Tang S, Yang P, Doll A, Aumüeller G, Newman R, et al. Cell-autonomous induction of functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) contributes to replicative senescence of human prostate progenitor cells. Oncogene. 2005;24:3583-95 pubmed..Together, these data suggest that 15-LOX2 may represent an endogenous prostate senescence gene and its tumor-suppressing functions might be associated with its ability to induce cell senescence. ..
- Shappell S, Keeney D, Zhang J, Page R, Olson S, Brash A. 15-Lipoxygenase-2 expression in benign and neoplastic sebaceous glands and other cutaneous adnexa. J Invest Dermatol. 2001;117:36-43 pubmed
- Shankaranarayanan P, Chaitidis P, Kuhn H, Nigam S. Acetylation by histone acetyltransferase CREB-binding protein/p300 of STAT6 is required for transcriptional activation of the 15-lipoxygenase-1 gene. J Biol Chem. 2001;276:42753-60 pubmed..After 9-11 h, when histones become acetylated, STAT6 binding sites may be demasked so that the phosphorylated and acetylated transcription factor can bind to activate gene transcription. ..
- Zhu D, Medhora M, Campbell W, Spitzbarth N, Baker J, Jacobs E. Chronic hypoxia activates lung 15-lipoxygenase, which catalyzes production of 15-HETE and enhances constriction in neonatal rabbit pulmonary arteries. Circ Res. 2003;92:992-1000 pubmed..Although a clear causal relationship remains to be demonstrated, these data suggest a previously unrecognized role for 15-LO in hypoxic vasoconstriction in neonatal mammals. ..
- Yang X, Wang L, Mihalic K, Xiao W, Chen T, Li P, et al. Interleukin (IL)-4 indirectly suppresses IL-2 production by human T lymphocytes via peroxisome proliferator-activated receptor gamma activated by macrophage-derived 12/15-lipoxygenase ligands. J Biol Chem. 2002;277:3973-8 pubmed..These data provide a mechanism whereby IL-4 may indirectly affect Thp function via PPARgamma activated by macrophage products of the 12/15-LO pathway. ..
- Nagelin M, Srinivasan S, Lee J, Nadler J, Hedrick C. 12/15-Lipoxygenase activity increases the degradation of macrophage ATP-binding cassette transporter G1. Arterioscler Thromb Vasc Biol. 2008;28:1811-9 pubmed publisher..The purpose of this study was to evaluate the effect of 12/15-lipoxygenase (12/15LO) in macrophage ABCG1 expression and function associated with cholesterol efflux...
- Dioszeghy V, Rosas M, Maskrey B, Colmont C, Topley N, Chaitidis P, et al. 12/15-Lipoxygenase regulates the inflammatory response to bacterial products in vivo. J Immunol. 2008;181:6514-24 pubmed..No changes in neutrophil or lymphocyte numbers were seen. In summary, endogenous 12/15-LOX defines the resident MPhi population and regulates both the recruitment of monocytes/Mphi and cytokine response to bacterial products in vivo. ..
- Huo Y, Zhao L, Hyman M, Shashkin P, Harry B, Burcin T, et al. Critical role of macrophage 12/15-lipoxygenase for atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2004;110:2024-31 pubmed..We conclude that macrophage 12/15-LO plays a dominant role in the development of atherosclerosis by promoting endothelial inflammation and foam cell formation. ..
- Bolick D, Orr A, Whetzel A, Srinivasan S, Hatley M, Schwartz M, et al. 12/15-lipoxygenase regulates intercellular adhesion molecule-1 expression and monocyte adhesion to endothelium through activation of RhoA and nuclear factor-kappaB. Arterioscler Thromb Vasc Biol. 2005;25:2301-7 pubmed..These findings identify a major signaling pathway in EC through which 12/15-LO contributes to vascular inflammation and atherosclerosis. ..
- Gronert K, Maheshwari N, Khan N, Hassan I, Dunn M, Laniado Schwartzman M. A role for the mouse 12/15-lipoxygenase pathway in promoting epithelial wound healing and host defense. J Biol Chem. 2005;280:15267-78 pubmed..Collectively, these results identify a novel action for the mouse 12/15-LOX (Alox15) and its products, LXA(4) and NPD1, in wound healing that is distinct from their well established anti-inflammatory properties. ..
- Katoh T, Lakkis F, Makita N, Badr K. Co-regulated expression of glomerular 12/15-lipoxygenase and interleukin-4 mRNAs in rat nephrotoxic nephritis. Kidney Int. 1994;46:341-9 pubmed..This represents the first demonstration of tandem regulated in vivo gene expression for a lymphokine (IL-4) and a lipoxygenase, both of which promote counter-inflammatory influences in immune complex-mediated injury. ..