ALOX12 (Arachidonate 12-Lipoxygenase) Homo sapiens

2007-03-01   Sreeparna Banerjee , Asli Erdog 

Department of Biology (SB), Department of Biotechnology (AE), Middle East Technical University, Ankara 06531 Turkey





With the exception of ALOX5, all human LOX genes, including ALOX12, are clustered on the short arm of chromosome 17 within a few megabases of each other. ALOX15, which has 86% sequence homology to ALOX12, is in closest proximity (17p13.2). Since chromosome 17 is known for gene duplications, the multiple LOX genes on the same chromosome may be as a result of such duplications.
Atlas Image
Diagram of the ALOX12 gene. Exons are represented by grey boxes (in scale) untranscribed sequences in black, with exon numbers on the bottom.


According to Entrez-Gene, ALOX12 gene maps to NC_000017.9 and spans a region of 16.1 kilo bases. According to Spidey (mRNA to genomic sequence alignment tool), ALOX15 has 14 exons, the sizes being 168, 202, 82, 123, 104, 161, 144, 210, 87, 170, 122, 101, 171 and 490 bp.


ALOX12 mRNA NM_000697 has 2335bp. Characterization of the 5 flanking region of the human ALOX12 in epidermoid carcinoma A431 cells indicated the presence of two Sp1 recognition motifs residing at -158 to -150 bp and -123 to -114 bp which are essential for gene expression.
The proposed mechanism of action is as follows: epidermal growth factor induces MAPK activation in cells, followed by the activation of JUN/AP1. The biosynthesis of c-Jun is thereby increased. Sp1 recruits HDAC1 together with c-Jun to the gene promoter. When Sp1 is deacetylated it interacts with acetylate histone 3, following which p300 is recruited to the gene promoter leading to the enhancement of the expression of 12(S)-lipoxygenase .


According to Entrez Gene the arachidonate 12-lipoxygenase pseudogene (ALOX12P2) (HGNC: 13742) is located on 17p13.1. This is the epidermal type 12-LOX (e-12LO) that was cloned using a murine e-LO12 probe. Humans express this functional pseudogene in the skin and hair follicles.



12S-lipoxygenases has three isoforms, named after their site of initial identification: platelet, leukocyte and epidermis. The leukocyte-type enzyme is expressed widely, while the platelet and epidermal enzymes are present in only a relatively limited number of cell types. Owing to the similarities in their genetic location, sequence and biological activities, leukocyte 12-LOX and 15-LOX-1 are often referred to as 12/15 lipoxygenase.


12-LOX protein consists of 662 amino acids, with a molecular weight of 75536 Da and contains non heme iron as a cofactor. According to the NCBI conserved domain search, the presence of a polycystin/lipoxygenase/alpha-toxin (PLAT) domain in the 12-LOX protein allows it access and enables it to catalyze enzymatic lipid peroxidation in complex biological structures via direct dioxygenation of phospholipids and cholesterol esters of biomembranes and plasma lipoproteins. The same conserved domain in 15-LOX-1 also enables it to oxidize complex lipids. Although cytosolic, both types of enzymes need this domain to access their sequestered membrane or micelle bound substrates.


The platelet type 12-LOX is expressed in the platelets and skin in humans. Based on structural and enzymatic properties, 15-LOX-1 is said to be a homolog of leukocyte type 12-LOX and are both expressed in mast cells, eosinophils, activated monocytes or dendritic cells, and bronchial epithelial cells.


All 12-LOX isoforms have been localized to the cytoplasm. In addition, the platelet-type 12S-lipoxygenase was found in both cytosol and microsomal fractions of epidermal cells of human skin.


12-LOX is a member of the inflammatory leukotriene biosynthesis pathway where, in presence of molecular oxygen, it converts arachidonic acid to 12-hydroxyeicosatetraenoic acid (12-HETE). The leukocyte type 12-LOX can, in addition, effectively oxygenate linoleic acid and phospholipids. This isoform can also generate significant amounts of the 15-LOX product in addition to 12-HETE.


C. familiaris: LOC479476 similar to arachidonate 12-lipoxygenase, P. troglodytes: ALOX12, R. norvegicus: Alox12 (predicted), M. musculus: Alox12 arachidonate 12-lipoxygenase (12/15LOX), D. rerio: wufb72a11.

Implicated in

Entity name
Inflammation and cancer
End product of arachidonic acid metabolism by the platelet-type 12-LOX 12(S)-Hydroxy eicosatetraenoic acid (12(S)-HETE) is shown to induce invasion, motility, and angiogenesis and protect tumour cells from apoptosis. Great many biological activities of 12(S)-HETE appear to be partly mediated by the activation of NFkappaB. NF-kappaB is a family of five DNA binding proteins that regulate the expression of a variety of genes involved in host immune responses and inflammation. A direct relationship between platelet-type 12-LOX overexpression and NF-kappaB activation is reported in prostate cancer cells.
Entity name
Polymorphisms associated with diseases
Aberrant arachidonic acid metabolism by 12-lipoxygenase (12-LOX) is implicated in carcinogenesis. Genetic polymorphisms 12-LOX is therefore thought to influence its function and/or expression and may modify the risk for colorectal adenoma. One of the single nucleotide polymorphisms (SNPs) reported in the 12-LOX gene located in exon 6 resulting in an Arg to Gln substitution at amino acid 261 of 12-LOX is in a highly conserved region of the lipoxygenase domain. Data from a community-based, case-control study of incident, sporadic colorectal adenoma that included 162 cases and 211 controls have shown an inverse association between the Arg261Gln polymorphism in 12-LOX and colorectal adenoma (OR, 0.63; 95% CI, 0.40-1.00). A significant interaction also is observed between the 12-LOX polymorphism (Arg261Gln) and the use of nonsteroidal anti-inflammatory drugs. Another study argues that Gln261Arg in ALOX12 does not appear to be associated with colon cancer risk.
Studies have shown higher urinary excretion of the arachidonic acid-derived metabolite 12-(S)hydroxyeicosatetraenoic acid (12(S)-HETE) in essential hypertension. For analysis of the association of polymorphisms in ALOX12 with hypertension and urinary levels of 12(S)-HETE, a study with 200 patients with essential hypertension and 166 matched controls is performed and as a result, the distribution of genotypes of the R261Q (Arg to Gln) polymorphism is found to be significantly different between patients and controls. These results indicate that a nonsynonymous polymorphism in ALOX12 is associated to essential hypertension and to urinary levels of 12(S)-HETE.
Peak BMD is a major determinant of osteoporosis which is a complex disease with both genetic and environmental risk factors. In a population - and family - based association study of ALOX15 and ALOX12, SNPs distributed across the two genes are genotyped. Moderate evidence of association is found between spine BMD and six SNPs in the ALOX12 gene in both men and women. These data conclude that polymorphisms in the ALOX12 gene may contribute to normal variation in spine BMD.
Entity name
Alzheimers disease
Alzheimers disease (AD) is a chronic neurodegenerative disorder that impairs cognition and behavior. Although the initiating molecular events are not known, increasing evidence suggests that 12/15-LOX is a major source of oxidative stress which could play a functional role in pathogenesis. Quantitative Western blot analysis confirmed by immunohistochemical studies demonstrate that in affected frontal and temporal regions of AD brains, the amount of 12/15-LOX is higher compared to controls. Also metabolic products of 12/15-LOX are markedly elevated in AD brains compared to controls.
Entity name
Bladder cancer
12-LOX expression is shown to be induced in bladder cancer tissues by an immunohistochemistry analysis. Also lipoxygenase inhibitors cause marked inhibition of bladder cancer cells in a concentration and time dependent manner. Cells treated with lipoxygenase inhibitors show chromatin condensation, cellular shrinkage, small membrane bound bodies (apoptotic bodies) and cytoplasmic condensation.
Entity name
Testicular cancer
12-LOX is only slightly expressed in normal testis tissues, however, 12-LOX expression is found to be significant in testicular cancer tissues by immunohistochemistry studies. Specific LOX inhibitors have also been shown to inhibit the growth of testicular cancer in cell lines.
Entity name
Prostate cancer
Research focusing on mechanisms of action of 12-lipoxygenase in prostate cancer cells revealed that overexpression of 12-lipoxygenase in PC-3 cells results in a 3-fold increase in VEGF protein level when compared with vector control cells and there is an increase in PI3-kinase activity in 12-LOX-transfected PC-3 cells.
The expression of 12-LOX is detected to be low in benign prostatic hyperplasia and normal prostate tissues, whereas marked expression of 12-lipoxygenase is detected in prostatic intraepithelial neoplasia and prostate cancer tissues. The LOX inhibitors cause marked cellular death through apoptosis in prostate cancer cells in a concentration and time-dependent manner.
Another effect of 12-LOX in prostate cancer cells is that increase in 12-LOX expression enhances the metastatic potential of human prostate cancer cells. 12-LOX transfected PC-3 cells show a significant change in cell adhesiveness, spreading, motility, and invasiveness.
Entity name
Breast cancer
Total cellular RNA extraction from 64 frozen tissue samples of breast carcinoma and their corresponding normal adjacent tissues is performed for expression analysis of cyclooxygenase-2 and 12-lipooxygenase using RT-PCR. 62.5% of carcinoma samples showed over-expression of 12-lipooxygenase as compared to normal breast tissues. Results also reveal that and 12-lipooxygenase mRNA expressions are associated with TNM staging in human breast cancer.
A second study indicates that levels of 12- lipoxygenases together with 5-lipoxygenase are also particularly high in tumours from patients who died of breast cancer. Therefore raised level of 12-lipoxygenase might have prognostic value in patients with breast cancer.


Pubmed IDLast YearTitleAuthors
161227002005Transcription factor Sp1 functions as an anchor protein in gene transcription of human 12(S)-lipoxygenase.Chang WC et al
172362252007Common polymorphisms in 5-lipoxygenase and 12-lipoxygenase genes and the risk of incident, sporadic colorectal adenoma.Gong Z et al
153085832004Arachidonate lipoxygenase (ALOX) and cyclooxygenase (COX) polymorphisms and colon cancer risk.Goodman JE et al
164789972006Sp1 deacetylation induced by phorbol ester recruits p300 to activate 12(S)-lipoxygenase gene transcription.Hung JJ et al
165983762006Human ALOX12, but not ALOX15, is associated with BMD in white men and women.Ichikawa S et al
129071382003Levels of expression of lipoxygenases and cyclooxygenase-2 in human breast cancer.Jiang WG et al
145185612003Platelet-type 12-lipoxygenase activates NF-kappaB in prostate cancer cells.Kandouz M et al
91648491997Transcriptional activation of human 12-lipoxygenase gene promoter is mediated through Sp1 consensus sites in A431 cells.Liu YW et al
150108182004Expression of lipoxygenase in human prostate cancer and growth reduction by its inhibitors.Matsuyama M et al
126645782002Characterization of epidermal 12(S) and 12(R) lipoxygenases.McDonnell M et al
171926872006Expression 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.Mohammad AM et al
166387502006Mechanisms regulating tumor angiogenesis by 12-lipoxygenase in prostate cancer cells.Nie D et al
146697972003Increased metastatic potential in human prostate carcinoma cells by overexpression of arachidonate 12-lipoxygenase.Nie D et al
15111312200412/15-lipoxygenase is increased in Alzheimer's disease: possible involvement in brain oxidative stress.Praticò D et al
165144352006A coding polymorphism in the 12-lipoxygenase gene is associated to essential hypertension and urinary 12(S)-HETE.Quintana LF et al
96911811998Cloning of a human "epidermal-type" 12-lipoxygenase-related gene and chromosomal localization to 17p13.Sun D et al
82434621993Investigation of the oxygenation of phospholipids by the porcine leukocyte and human platelet arachidonate 12-lipoxygenases.Takahashi Y et al
171510912007Associations of functional polymorphisms in cyclooxygenase-2 and platelet 12-lipoxygenase with risk of occurrence and advanced disease status of colorectal cancer.Tan W et al
87775661995Arachidonate 12-lipoxygenase.Yoshimoto T et al
147675682004Relationship between lipoxygenase and human testicular cancer.Yoshimura R et al

Other Information

Locus ID:

NCBI: 239
MIM: 152391
HGNC: 429
Ensembl: ENSG00000108839


dbSNP: 239
ClinVar: 239
TCGA: ENSG00000108839


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Arachidonic acid metabolismKEGGko00590
Arachidonic acid metabolismKEGGhsa00590
Metabolic pathwaysKEGGhsa01100
Serotonergic synapseKEGGhsa04726
Inflammatory mediator regulation of TRP channelsKEGGhsa04750
Inflammatory mediator regulation of TRP channelsKEGGko04750
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Arachidonic acid metabolismREACTOMER-HSA-2142753
Synthesis of 12-eicosatetraenoic acid derivativesREACTOMER-HSA-2142712
Synthesis of Lipoxins (LX)REACTOMER-HSA-2142700
Synthesis of Hepoxilins (HX) and Trioxilins (TrX)REACTOMER-HSA-2142696
Antifolate resistanceKEGGko01523
Antifolate resistanceKEGGhsa01523

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA446108Colorectal NeoplasmsDiseaseClinicalAnnotationassociatedPD23778325


Pubmed IDYearTitleCitations
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
15111312200412/15-lipoxygenase is increased in Alzheimer's disease: possible involvement in brain oxidative stress.73
20089617201012-Lipoxygenase Products Reduce Insulin Secretion and {beta}-Cell Viability in Human Islets.53
261061572015Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A2-IIA.43
157295742005Activation of 12-lipoxygenase in proinflammatory cytokine-mediated beta cell toxicity.39
223233042012DNA hypomethylation at ALOX12 is associated with persistent wheezing in childhood.36
153085832004Arachidonate lipoxygenase (ALOX) and cyclooxygenase (COX) polymorphisms and colon cancer risk.34
171510912007Associations of functional polymorphisms in cyclooxygenase-2 and platelet 12-lipoxygenase with risk of occurrence and advanced disease status of colorectal cancer.33
171510912007Associations of functional polymorphisms in cyclooxygenase-2 and platelet 12-lipoxygenase with risk of occurrence and advanced disease status of colorectal cancer.33
186766802008Pathway-based evaluation of 380 candidate genes and lung cancer susceptibility suggests the importance of the cell cycle pathway.32


Sreeparna Banerjee ; Asli Erdog

ALOX12 (Arachidonate 12-Lipoxygenase) Homo sapiens

Atlas Genet Cytogenet Oncol Haematol. 2007-03-01

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