ALOX15 (Arachidonate 15-Lipoxygenase)

2006-06-01 Sreeparna Banerjee Affiliation

Department of Biology, Office: Z-16\\\/Lab: B-59, Middle East Technical University, 06531 Ankara, Turkey

Identity

HGNC

ALOX15

LOCATION

17p13.2

LOCUSID

246

ALIAS

12-LOX,15-LOX,15-LOX-1,LOG15

DNA/RNA

Note

With the exception of ALOX5, all human LOX genes, including ALOX15, are clustered on the short arm of chromosome 17 within a few megabases of each other. ALOX12, which has 86% sequence homology to ALOX15 is in closest proximity (17p13.1). Since chromosome 17 is known for gene duplications, the multiple LOX genes on the same chromosome may be as a result of such duplications.

ALOX15Fig. Diagram of the ALOX15 gene. Exons are represented by red boxes (in scale) untranscribed sequences in black, with exon numbers on the bottom. The arrows show the ATG and the stop codons respectively.

Description

ALOX15 gene spans a region of 10.7 kilo bases. and has 14 exons, the sizes being 149, 202, 82, 123, 104, 161, 144, 210, 87, 170, 122, 101, 108 and 859 bps.

Transcription

ALOX15 mRNA has 2702 bps.
TH2 cytokines IL-4 have been shown to transcriptionally upregulate 15-LOX-1 expression via phosphorylation of Signal Transducer and Activator of transcription (STAT) proteins, particularly STAT-1, STAT-3 and STAT-6 and their translocation to the nucleus. Acetylation of histones, which block STAT6 binding at the 15-LOX-1 promoter if they are present as nonacetylated proteins, enables promoter binding of phosphorylated and acetylated STAT6, which in turn may lead to transcriptional activation of the 15-LOX gene. NSAIDS have been reported to upregulate 15-LOX-1 expression through GATA-6. Ku70/ku80 lupus autoantigen transcription factors have also been reported to be induced by IL-4 and IL-13 in the upregulation of ALOX15. In addition, demethylation of the 5 CpG islands in the promoter region of ALOX15 has been shown to transcriptionally upregulate the gene.
ALOX15 mRNA is expressed in bone marrow, spleen, thymus, spinal cord, heart, skeletal muscle, liver, prostate, kidney and lung.

Pseudogene

The arachidonate 15-lipoxygenase pseudogene (ALOX15P) is located on 17p13.1.

Proteins

Note

Two different 15-Lipoxygenases exist, 15-LOX-1 (reticulocyte type) and 15-LOX-2 (epidermis type), differentiated by their tissue expression and a 40% homology at the amino acid level. 15-LOX-1 preferentially oxygenates linoleic acid into 13(S)-hydroxyoctadecadienoic acid (13(S)-HPODE) whereas 15-LOX-2 preferentially metabolizes arachidonic acid (AA) to 15S- hydroperoxyeicosatetraenoic acid (15-HETE) with poor activity with linoleic acid (LA).

Description

15-LOX-1 protein consists of 661 amino acids and is 74.7 kDa. It contains 1 gram atom of non-haem non-sulphur bound iron per mole of the enzyme. Conserved domain search, the presence of a polycystin/lipoxygenase/alpha-toxin (PLAT) domain in the 15-LOX-1 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 membrane binding domain of the rabbit reticulocyte 15-LOX are determined by a concerted action of the N-terminal beta-barrel and the C-terminal catalytic domain.

Expression

15-LOX-1 was first purified in rabbit reticulocytes and was subsequently found to be specifically expressed or induced in mast cells, eosinophils, activated monocytes or dendritic cells, and bronchial epithelial cells.

Localisation

Located in the cytoplasm.

Function

15-LOX-1 is a member of the inflammatory leukotriene biosynthesis pathway where, in presence of molecular oxygen, it converts arachidonic acid to(15-HETE). Also acts on C-12 of arachidonate forming products (12-HETE) at a ratio of 12:1 (15-HETE:12-HETE). Preferentially converts linoleic acid to 13(S)-HODE.

Homology

C. familiaris LOC4894581 similar to Arachidonate 15-lipoxygenase;
R. norvegicus: Alox15 arachidonate 12-lipoxygenase;
M. musculus: Alox15 arachidonate 15-lipoxygenase (12/15LOX);
A. thaliana: F12B7.11, F12B7_111 iron ion binding / lipoxygenase;

Mutations

Note

No mutations have been reported for ALOX15 that cause congenital anomalies. Single nucleotide polymorphism (SNP) studies have revealed that a C-to-T base exchange (-292C/T) enhances the transcriptional activity of the ALOX15 promoter in macrophages through the generation of a novel SPI1 transcription factor binding site. In addition, a G to A base exchange (-5229G/A) in the ALOX15 promoter region has been associated with low bone mineral density.

Implicated in

Entity name

Prostate cancer

Note

Genechip study of the mRNA levels of key enzymes involved in the LA and AA pathways in 18 human donor (normal) prostates compared to 60 prostate tumours showed a lower level of 15-LOX-1 expression (the key enzyme in the LA pathway) in contrast to a higher 15-lipoxygenase-2 expression in donor (normal) prostates. On the other hand, significantly high levels of 15-LOX-1 and low levels of 15-LOX-2/ALOX15B were observed in prostate carcinoma tissues.

Entity name

Colorectal cancer

Note

The role of 15-LOX-1 in colorectal cancer is controversial with some researchers claiming a mitogenic role through up-regulation of the EGF signaling pathway as well as activation of ERK and down regulation of anti-inflammatory PPAR-gamma transcriptional activity. Its upregulation by mutant TP53 has been reported. On the other hand, in recent years others have shown that 15-LOX-1 expression is reduced in colorectal cancer and implicated 13(S)-HPODE in the pro-apoptotic functions of 15-LOX-1. 15-LOX-1 expression was shown to be down-regulated in colorectal adenomas (compared with non neoplastic epithelial mucosa) in 87% (13 of 15) of patients with familial adenomatous polyposis resulting in an escape from apoptosis. Ectopic restoration of 15-LOX-1 expression re-established apoptosis in Caco-2 colon cancer cells. A proapoptotic function ascribed to 15-LOX-1 and 15-LOX-2 in colon cancer is said to be through the activation of the anti-tumorigenic PPAR-gamma and down-regulation of the pro-tumorigenic PPAR-delta/beta. In addition, the apoptotic functions of NSAIDS are reported to be via an upregulation of 15-LOX-1.

Entity name

Breast cancer

Note

An immunoblot analysis of metastatic human breast carcinoma cells with antibodies to 15-LOX-1 and 15-LOX-2 indicated that it is the 15(S)-LOX-2 isoform that generates 15-HETE and activates specific growth factor receptor-related signalling pathways, thereby initiating signal transduction events resulting in enhanced cell adhesion to the extracellular matrix. However, a second study indicated that both 15-LOX-2 and 15-LOX-1 were expressed at significantly lower levels in metastatic tumours and in patients who died of breast cancer related causes. This reduction is correlated with the disease progression of breast cancer and a poor clinical outcome.

Entity name

Atherosclerosis

Disease

Atherosclerosis is a chronic proliferative disease of the arterial wall that is associated with aberrant immune reactions. A proatherogenic activity of 12/15LOX via oxidation of low density lipoproteins and formation of foam cells in various rodent atherosclerosis models has been shown. A similar extrapolation to humans has not been convincingly proven, particularly since significantly lower expression of 15-LOX-1 was detected in diseased and normal human arteries when compared to 5-LOX.

Entity name

Asthma

Disease

Patients with severe asthma with persistent airway eosinophils have been shown to manifest high levels of 15(S)-HETE in bronchoalveolar lavage (BALF), which may be associated with airway fibrosis. In addition, IL-4-induced apoptosis via upregulation of 15-LOX-1 and PPAR-gamma may contribute to severe loss of alveolar structures and infiltration of eosinophils, mononuclear phagocytes, etc., into the lung tissue of chronic asthma patients.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
9177185	1997	Discovery of a second 15S-lipoxygenase in humans.	Brash AR et al
12444024	2002	15-lipoxygenase: a Janus enzyme?	Chanez P et al
14566836	2003	15-hydroxy-eicosatetraenoic acid arrests growth of colorectal cancer cells via a peroxisome proliferator-activated receptor gamma-dependent pathway.	Chen GG et al
9927047	1999	Expression of 15-lipoxygenase-1 in human colorectal cancer.	Ikawa H et al
16556493	2006	Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer.	Jiang WG et al
16678271	2006	Inflammation and immune regulation by 12/15-lipoxygenases.	Kühn H et al
16566819	2006	The yin and yang of 15-lipoxygenase-1 and delta-desaturases: dietary omega-6 linoleic acid metabolic pathway in prostate.	Kelavkar U et al
10200270	1999	Effects of mutant p53 expression on human 15-lipoxygenase-promoter activity and murine 12/15-lipoxygenase gene expression: evidence that 15-lipoxygenase is a mutator gene.	Kelavkar UP et al
15194425	2004	Transcriptional regulation of 15-lipoxygenase expression by promoter methylation.	Liu C et al
14643174	2004	15-Lipoxygenase-1 has anti-tumorigenic effects in colorectal cancer.	Nixon JB et al
16000313	2005	15S-Lipoxygenase-2 mediates arachidonic acid-stimulated adhesion of human breast carcinoma cells through the activation of TAK1, MKK6, and p38 MAPK.	Nony PA et al
12517954	2003	IL-4 induces apoptosis in A549 lung adenocarcinoma cells: evidence for the pivotal role of 15-hydroxyeicosatetraenoic acid binding to activated peroxisome proliferator-activated receptor gamma transcription factor.	Shankaranarayanan P et al
16357157	2005	The critical role of 15-lipoxygenase-1 in colorectal epithelial cell terminal differentiation and tumorigenesis.	Shureiqi I et al
15838625	2005	Association of a single nucleotide polymorphism in the lipoxygenase ALOX15 5'-flanking region (-5229G/A) with bone mineral density.	Urano T et al
12004065	2002	The N-terminal domain of the reticulocyte-type 15-lipoxygenase is not essential for enzymatic activity but contains determinants for membrane binding.	Walther M et al
16320347	2006	Functional polymorphism in ALOX15 results in increased allele-specific transcription in macrophages through binding of the transcription factor SPI1.	Wittwer J et al
12748293	2003	Interleukin-13 induction of 15-lipoxygenase gene expression requires p38 mitogen-activated protein kinase-mediated serine 727 phosphorylation of Stat1 and Stat3.	Xu B et al
15165036	2004	15-LOX-1 inhibits p21 (Cip/WAF 1) expression by enhancing MEK-ERK 1/2 signaling in colon carcinoma cells.	Yoshinaga M et al
16288226	2006	Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity.	Zuo X et al

Other Information

Locus ID:

NCBI: 246
MIM: 152392
HGNC: 433
Ensembl: ENSG00000161905

Variants:

dbSNP: 246
ClinVar: 246
TCGA: ENSG00000161905
COSMIC: ALOX15

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000161905	ENST00000293761	P16050
ENSG00000161905	ENST00000570836	P16050
ENSG00000161905	ENST00000574640	P16050

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Arachidonic acid metabolism	KEGG	ko00590
Linoleic acid metabolism	KEGG	ko00591
Arachidonic acid metabolism	KEGG	hsa00590
Linoleic acid metabolism	KEGG	hsa00591
Metabolic pathways	KEGG	hsa01100
Serotonergic synapse	KEGG	hsa04726
Immune System	REACTOME	R-HSA-168256
Cytokine Signaling in Immune system	REACTOME	R-HSA-1280215
Signaling by Interleukins	REACTOME	R-HSA-449147
Metabolism	REACTOME	R-HSA-1430728
Metabolism of lipids and lipoproteins	REACTOME	R-HSA-556833
Arachidonic acid metabolism	REACTOME	R-HSA-2142753
Synthesis of Leukotrienes (LT) and Eoxins (EX)	REACTOME	R-HSA-2142691
Synthesis of 15-eicosatetraenoic acid derivatives	REACTOME	R-HSA-2142770
Synthesis of 12-eicosatetraenoic acid derivatives	REACTOME	R-HSA-2142712
Interleukin-4 and 13 signaling	REACTOME	R-HSA-6785807
Ferroptosis	KEGG	ko04216
Ferroptosis	KEGG	hsa04216

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
38641013	2024	Identifying ALOX15-initiated lipid peroxidation increases susceptibility to ferroptosis in asthma epithelial cells.	0
38685084	2024	Association between arachidonate lipoxygenase 15,c.-292 C > T gene polymorphism and non-cystic fibrosis bronchiectasis in children: a pilot study on the effects on airway lipoxin A4 and disease phenotype.	0
38641013	2024	Identifying ALOX15-initiated lipid peroxidation increases susceptibility to ferroptosis in asthma epithelial cells.	0
38685084	2024	Association between arachidonate lipoxygenase 15,c.-292 C > T gene polymorphism and non-cystic fibrosis bronchiectasis in children: a pilot study on the effects on airway lipoxin A4 and disease phenotype.	0
36529997	2023	Photothermal lipolysis accelerates ECM production via macrophage-derived ALOX15-mediated p38 MAPK activation in fibroblasts.	0
37673368	2023	CircRNA 06209 inhibits cataract development by sponging miR-6848-5p and regulating ALOX15 expression.	0
37716021	2023	15-lipoxygenase and cyclooxygenase expression profile and their related modulators in COVID-19 infection.	1
37849828	2023	A review on the relationship between Arachidonic acid 15-Lipoxygenase (ALOX15) and diabetes mellitus.	1
37874359	2023	Epigenetic regulation of 15-lipoxygenase-1 expression in human chondrocytes by promoter methylation.	0
36529997	2023	Photothermal lipolysis accelerates ECM production via macrophage-derived ALOX15-mediated p38 MAPK activation in fibroblasts.	0
37673368	2023	CircRNA 06209 inhibits cataract development by sponging miR-6848-5p and regulating ALOX15 expression.	0
37716021	2023	15-lipoxygenase and cyclooxygenase expression profile and their related modulators in COVID-19 infection.	1
37849828	2023	A review on the relationship between Arachidonic acid 15-Lipoxygenase (ALOX15) and diabetes mellitus.	1
37874359	2023	Epigenetic regulation of 15-lipoxygenase-1 expression in human chondrocytes by promoter methylation.	0
34762602	2022	15LO1 dictates glutathione redox changes in asthmatic airway epithelium to worsen type 2 inflammation.	37

Citation

Sreeparna Banerjee

ALOX15 (Arachidonate 15-Lipoxygenase)

Atlas Genet Cytogenet Oncol Haematol. 2006-06-01

Online version: http://atlasgeneticsoncology.org/gene/42986