Genomes and Genes
arachidonate 12 lipoxygenase
Summary: An enzyme that catalyzes the oxidation of arachidonic acid to yield 12-hydroperoxyarachidonate (12-HPETE) which is itself rapidly converted by a peroxidase to 12-hydroxy-5,8,10,14-eicosatetraenoate (12-HETE). The 12-hydroperoxides are preferentially formed in PLATELETS.
- Canals S, Casarejos M, de Bernardo S, Rodríguez Martín E, Mena M. Nitric oxide triggers the toxicity due to glutathione depletion in midbrain cultures through 12-lipoxygenase. J Biol Chem. 2003;278:21542-9 pubmed..The potentiating effect of NO over such a signaling pathway may be of relevance as part of the cascade of events leading to and sustaining nerve cell death. ..
- van Leyen K, Kim H, Lee S, Jin G, Arai K, Lo E. Baicalein and 12/15-lipoxygenase in the ischemic brain. Stroke. 2006;37:3014-8 pubmed..In contrast, the 12/15-LOX knockout mice are not further protected by baicalein. Baicalein protects against ischemia/reperfusion injury by inhibiting the 12/15-lipoxygenase pathway to neuronal cell death. ..
- Maskrey B, Bermudez Fajardo A, Morgan A, Stewart Jones E, Dioszeghy V, Taylor G, et al. Activated platelets and monocytes generate four hydroxyphosphatidylethanolamines via lipoxygenase. J Biol Chem. 2007;282:20151-63 pubmed..2), did not reveal PE esters, indicating that this modification is restricted to the LOX pathway. In summary, we show formation of PE-esterified HETEs in immune cells that may contribute to LOX signaling in inflammation. ..
- 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. ..
- 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. ..
- 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. ..
- Chen M, Yang Z, Smith K, Carter J, Nadler J. Activation of 12-lipoxygenase in proinflammatory cytokine-mediated beta cell toxicity. Diabetologia. 2005;48:486-95 pubmed
- Li S, Dwarakanath R, Cai Q, Lanting L, Natarajan R. Effects of silencing leukocyte-type 12/15-lipoxygenase using short interfering RNAs. J Lipid Res. 2005;46:220-9 pubmed..Our results illustrate the functional relevance of 12/15-LO activation in macrophages and VSMCs and its relationship to oxidant stress and inflammation. ..
- Gong Z, Hebert J, Bostick R, Deng Z, Hurley T, Dixon D, et al. Common polymorphisms in 5-lipoxygenase and 12-lipoxygenase genes and the risk of incident, sporadic colorectal adenoma. Cancer. 2007;109:849-57 pubmed..Further studies will be needed to confirm these findings. Cancer 2007 (c) 2007 American Cancer Society. ..
- Jin G, Arai K, Murata Y, Wang S, Stins M, Lo E, et al. Protecting against cerebrovascular injury: contributions of 12/15-lipoxygenase to edema formation after transient focal ischemia. Stroke. 2008;39:2538-43 pubmed publisher..12/15-LOX inhibitors may thus be effective as both neuroprotectants and vasculoprotectants. ..
- 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. ..
- McDuffie M, Maybee N, Keller S, Stevens B, Garmey J, Morris M, et al. Nonobese diabetic (NOD) mice congenic for a targeted deletion of 12/15-lipoxygenase are protected from autoimmune diabetes. Diabetes. 2008;57:199-208 pubmed..These results suggest an important role for 12/15-LO in conferring susceptibility to autoimmune diabetes in NOD mice through its effects on macrophage recruitment or activation. ..
- Wen Y, Gu J, Vandenhoff G, Liu X, Nadler J. Role of 12/15-lipoxygenase in the expression of MCP-1 in mouse macrophages. Am J Physiol Heart Circ Physiol. 2008;294:H1933-8 pubmed publisher..These results suggest a potentially important mechanism linking 12/15-LO activation to MCP-1 expression that induces inflammatory cell infiltration. ..
- Chen X, Kurre U, Jenkins N, Copeland N, Funk C. cDNA cloning, expression, mutagenesis of C-terminal isoleucine, genomic structure, and chromosomal localizations of murine 12-lipoxygenases. J Biol Chem. 1994;269:13979-87 pubmed..Antibodies prepared against the two forms of 12-lipoxygenase revealed the differential distribution of the two enzymes throughout the mouse. ..
- 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. ..
- Pratico D, Zhukareva V, Yao Y, Uryu K, Funk C, Lawson J, et al. 12/15-lipoxygenase is increased in Alzheimer's disease: possible involvement in brain oxidative stress. Am J Pathol. 2004;164:1655-62 pubmed..These data show that the 12/15-LOX metabolic pathway is increased and correlates with an oxidative imbalance in the AD brain, implying that this enzyme might contribute to the pathogenesis of this neurodegenerative disorder. ..
- 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. ..
- 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. ..
- Tan W, Wu J, Zhang X, Guo Y, Liu J, Sun T, et al. Associations of functional polymorphisms in cyclooxygenase-2 and platelet 12-lipoxygenase with risk of occurrence and advanced disease status of colorectal cancer. Carcinogenesis. 2007;28:1197-201 pubmed..38, 95% CI = 1.09-1.74). Together, these observations indicate that inherited polymorphisms in arachidonic acid-metabolizing enzymes may confer susceptibility to CRC. ..
- Nie D, Nemeth J, Qiao Y, Zacharek A, Li L, Hanna K, et al. Increased metastatic potential in human prostate carcinoma cells by overexpression of arachidonate 12-lipoxygenase. Clin Exp Metastasis. 2003;20:657-63 pubmed..Taken together, our data suggest that an increase in 12-LOX expression enhances the metastatic potential of human prostate cancer cells. ..
- Khanna S, Roy S, Slivka A, Craft T, Chaki S, Rink C, et al. Neuroprotective properties of the natural vitamin E alpha-tocotrienol. Stroke. 2005;36:2258-64 pubmed..Such protection was associated with lower c-Src activation and 12-Lox phosphorylation at the stroke site. The natural vitamin E, TCT, acts on key molecular checkpoints to protect against glutamate- and stroke-induced neurodegeneration. ..
- Mohammad A, Abdel H, Abdel W, Ahmed A, Wael T, Eiman G. Expression of cyclooxygenase-2 and 12-lipoxygenase in human breast cancer and their relationship with HER-2/neu and hormonal receptors: impact on prognosis and therapy. Indian J Cancer. 2006;43:163-8 pubmed..Furthermore, there is an inverse association between cox-2 expression and hormonal receptor status. This observation may drive us to the possible role of those two enzymes in determining the plan of therapy of breast cancer patients. ..
- 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. ..
- 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...
- Yoshimoto T, Yamamoto Y, Arakawa T, Suzuki H, Yamamoto S, Yokoyama C, et al. Molecular cloning and expression of human arachidonate 12-lipoxygenase. Biochem Biophys Res Commun. 1990;172:1230-5 pubmed..The cytosol of Escherichia coli transformed with a recombinant pUC19 plasmid oxygenated the position 12 of arachidonic acid. ..
- Wang H, Li J, Follett P, Zhang Y, Cotanche D, Jensen F, et al. 12-Lipoxygenase plays a key role in cell death caused by glutathione depletion and arachidonic acid in rat oligodendrocytes. Eur J Neurosci. 2004;20:2049-58 pubmed..These results suggest that 12-LOX activation plays a key role in oxidative stress-induced OL death. ..
- Lebeau A, Terro F, Rostene W, Pelaprat D. Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by beta-amyloid peptide. Cell Death Differ. 2004;11:875-84 pubmed..These data indicate that blockade of 12-LOX expression disrupts a c-Jun-dependent apoptosis pathway, and suggest that 12-LOX may represent a new target for the treatment of AD. ..
- Yoshimura R, Matsuyama M, Tsuchida K, Kawahito Y, Sano H, Nakatani T. Expression of lipoxygenase in human bladder carcinoma and growth inhibition by its inhibitors. J Urol. 2003;170:1994-9 pubmed..Results suggest that lipoxygenase inhibitors may mediate potent antiproliferative effects against bladder cancer cells. Thus, lipoxygenase may become a new target in the treatment of bladder tumors. ..
- Jiang W, Douglas Jones A, Mansel R. Levels of expression of lipoxygenases and cyclooxygenase-2 in human breast cancer. Prostaglandins Leukot Essent Fatty Acids. 2003;69:275-81 pubmed
- Patricia M, Natarajan R, Dooley A, Hernandez F, Gu J, Berliner J, et al. Adenoviral delivery of a leukocyte-type 12 lipoxygenase ribozyme inhibits effects of glucose and platelet-derived growth factor in vascular endothelial and smooth muscle cells. Circ Res. 2001;88:659-65 pubmed..They document an important role for the 12LO pathway in regulating inflammatory changes in endothelial cells and smooth muscle cells. ..
- Matsuyama M, Yoshimura R, Mitsuhashi M, Hase T, Tsuchida K, Takemoto Y, et al. Expression of lipoxygenase in human prostate cancer and growth reduction by its inhibitors. Int J Oncol. 2004;24:821-7 pubmed..LOX is induced in prostate cancer, and our results suggest that LOX inhibitors may mediate potent antiproliferative effects against prostate cancer cells. Thus, LOX may become a new target in treatment of prostate cancer. ..
- Kandouz M, Nie D, Pidgeon G, Krishnamoorthy S, Maddipati K, Honn K. Platelet-type 12-lipoxygenase activates NF-kappaB in prostate cancer cells. Prostaglandins Other Lipid Mediat. 2003;71:189-204 pubmed
- Nunemaker C, Chen M, Pei H, Kimble S, Keller S, Carter J, et al. 12-Lipoxygenase-knockout mice are resistant to inflammatory effects of obesity induced by Western diet. Am J Physiol Endocrinol Metab. 2008;295:E1065-75 pubmed publisher..Inhibiting 12-LO may provide a new therapeutic approach to prevent inflammation-mediated metabolic consequences of excess fat intake. ..
- Bleich D, Chen S, Zipser B, Sun D, Funk C, Nadler J. Resistance to type 1 diabetes induction in 12-lipoxygenase knockout mice. J Clin Invest. 1999;103:1431-6 pubmed..In summary, elimination of leukocyte 12-LO in mice ameliorates low dose streptozotocin-induced diabetes by increasing islet resistance to cytokines and decreasing macrophage production of nitric oxide. ..
- 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. ..
- Kong E, Huang Y, Sanderson J, Chan K, Yu S, Yu C. Baicalein and Wogonin inhibit collagen deposition in SHR and WKY cardiac fibroblast cultures. BMB Rep. 2010;43:297-303 pubmed..Our results show that both Baicalein and Wogonin can suppress collagen deposition in AngII-stimulated SHR and WKY cardiac fibroblasts...
- Hung J, Wang Y, Chang W. Sp1 deacetylation induced by phorbol ester recruits p300 to activate 12(S)-lipoxygenase gene transcription. Mol Cell Biol. 2006;26:1770-85 pubmed..p300 is then recruited to the gene promoter through the interaction with deacetylated Sp1 to acetylate histone 3, leading to the enhancement of the expression of 12(S)-lipoxygenase. ..
- TURMAN M, Kingsley P, Rouzer C, Cravatt B, Marnett L. Oxidative metabolism of a fatty acid amide hydrolase-regulated lipid, arachidonoyltaurine. Biochemistry. 2008;47:3917-25 pubmed publisher..Over prolonged incubations, RPMs also generated small amounts of diHETE-T. Oxidative metabolism of polyunsaturated N-acyltaurines may represent a pathway for the generation or termination of novel signaling molecules. ..
- Johannesson M, Backman L, Claesson H, Forsell P. Cloning, purification and characterization of non-human primate 12/15-lipoxygenases. Prostaglandins Leukot Essent Fatty Acids. 2010;82:121-9 pubmed publisher..Taken together, the switch during evolution from a 12-lipoxygenating enzyme in lower primates to a 15-lipoxygenating enzyme in higher primates and man might be of importance for the biological function of this enzyme. ..
- Reddy M, Adler S, Kim Y, Lanting L, Rossi J, Kang S, et al. Interaction of MAPK and 12-lipoxygenase pathways in growth and matrix protein expression in mesangial cells. Am J Physiol Renal Physiol. 2002;283:F985-94 pubmed..ANG II effects may be mediated by the LO pathway. These results suggest a novel interaction between LO and p38(MAPK) activation in MC matrix synthesis associated with renal complications. ..
- Sundler R, Emilsson A, Wijkander J. A glycerol ether induces mobilization and 12-lipoxygenation of arachidonic acid in macrophages. Synergistic effect on mobilization and induction of leukotriene C formation by activators of protein kinase C. Agents Actions. 1990;29:247-53 pubmed..When macrophages were exposed to both a kinase C activator and the glycerol triether, the mobilization of arachidonic acid was synergistically enhanced and formation of leukotriene C was induced. ..
- Merched A, Ko K, Gotlinger K, Serhan C, Chan L. Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators. FASEB J. 2008;22:3595-606 pubmed publisher..Taken together, these findings suggest that a failure of local endogenous resolution mechanisms may underlie the unremitting inflammation that fuels atherosclerosis. ..
- Nigam S, Kumar G, Sutherland M, Schewe T, Ikawa H, Yamasaki Y, et al. Metabolic suppression of platelet-type 12-lipoxygenase in human uterine cervix with invasive carcinoma. Int J Cancer. 1999;82:827-31 pubmed..Furthermore, the data suggest an anti-carcinogenic action of 12-lipoxygenase in human cervix, in contrast to its reported pro-carcinogenic action in breast cancer. ..
- Nardi M, Feinmark S, Hu L, Li Z, Karpatkin S. Complement-independent Ab-induced peroxide lysis of platelets requires 12-lipoxygenase and a platelet NADPH oxidase pathway. J Clin Invest. 2004;113:973-80 pubmed..A new Ab-mediated mechanism is described in which the platelet 12-LO product, 12(S)-HETE activates the NADPH oxidase pathway to generate ROS. ..
- Cevik O, Baykal A, Sener A. Platelets Proteomic Profiles of Acute Ischemic Stroke Patients. PLoS ONE. 2016;11:e0158287 pubmed publisher..Our data provides an insight into the proteins that are involved in the platelets' activation response during ischemic stroke. It could be argued that this study lays the foundation for future mechanistic studies. ..
- Sadok A, Bourgarel Rey V, Gattacceca F, Penel C, Lehmann M, Kovacic H. Nox1-dependent superoxide production controls colon adenocarcinoma cell migration. Biochim Biophys Acta. 2008;1783:23-33 pubmed..We conclude that Nox1 activation by arachidonic acid metabolism occurs through 12-lipoxygenase and protein kinase C delta, and controls cell migration by affecting integrin alpha 2 subunit turn-over. ..
- Tang L, Ding T, Pratico D. Additive anti-atherogenic effect of thromboxane receptor antagonism with 12/15lipoxygenase gene disruption in apolipoprotein E-deficient mice. Atherosclerosis. 2008;199:265-70 pubmed publisher..These results suggest that the 12/15LO- and TxA(2) receptor-mediated pro-atherogenic effects are two distinct pathways and represent two separate therapeutic targets for a better anti-atherogenic strategy. ..
- Guo Y, Zhang X, Tan W, Miao X, Sun T, Zhao D, et al. Platelet 12-lipoxygenase Arg261Gln polymorphism: functional characterization and association with risk of esophageal squamous cell carcinoma in combination with COX-2 polymorphisms. Pharmacogenet Genomics. 2007;17:197-205 pubmed..45, 95% CI=2.71-7.29). These observations suggest that inherited polymorphisms in arachidonic acid-metabolizing enzymes, which result in heightened gene expression or enzymatic activity, may confer host susceptibility to ESCC. ..
- Tanabe M, Kamitani H, Watanabe T, Radmark O. C-terminus of p47(phox) is required for interaction with leukocyte type rat 12-lipoxygenase. Protein Pept Lett. 2005;12:295-7 pubmed..These results indicate that C-terminus of p47(phox) is important for its interaction to rat 12-LO. ..
- Hagmann W, Gao X, Zacharek A, Wojciechowski L, Honn K. 12-Lipoxygenase in Lewis lung carcinoma cells: molecular identity, intracellular distribution of activity and protein, and Ca(2+)-dependent translocation from cytosol to membranes. Prostaglandins. 1995;49:49-62 pubmed..Thus, we suggest that 12-LOX in 3LL cells undergoes rapid translocation from cytosol to membrane in a Ca(2+)-dependent manner, but is no longer active or becomes inactivated at the membrane site. ..
- Chuang J, Wang Y, Yeh S, Liu Y, Chang W, Hung J. Phosphorylation by c-Jun NH2-terminal kinase 1 regulates the stability of transcription factor Sp1 during mitosis. Mol Biol Cell. 2008;19:1139-51 pubmed publisher..Together, our results indicate that JNK1 activation is necessary to phosphorylate Sp1 and to shield Sp1 from the ubiquitin-dependent degradation pathway during mitosis in tumor cell lines. ..
- Du S, McLaughlin B, Pal S, Aizenman E. In vitro neurotoxicity of methylisothiazolinone, a commonly used industrial and household biocide, proceeds via a zinc and extracellular signal-regulated kinase mitogen-activated protein kinase-dependent pathway. J Neurosci. 2002;22:7408-16 pubmed..Because of their widespread use, the neurotoxic consequences of both acute and chronic human exposure to these toxins need to be evaluated. ..
- Jankun J, Aleem A, Malgorzewicz S, Szkudlarek M, Zavodszky M, DeWitt D, et al. Synthetic curcuminoids modulate the arachidonic acid metabolism of human platelet 12-lipoxygenase and reduce sprout formation of human endothelial cells. Mol Cancer Ther. 2006;5:1371-82 pubmed..This universal event for all tested lipoxygenase inhibitors suggests that the inhibition of sprout formation was most likely due to the inhibition of human P-12-LOX but not other cancer-related pathways. ..