Atlas of Genetics and Cytogenetics in Oncology and Haematology
ALOX15 (Arachidonate 15-Lipoxygenase)
| Identity |
| Other names | 15-LOX |
| EC 1.13.11.33 | |
| arachidonate omega 6-lipoxygenase | |
| LOG15 | |
| HGNC (Hugo) | ALOX15 |
| LocusID (NCBI) | 246 |
| Location | 17p13.2 |
| Location_base_pair | Starts at 4534214 and ends at 4544960 bp from pter ( according to hg19-Feb_2009) [Mapping] |
| Local_order | Genes flanking ALOX15 in centromere to telomere direction on 17p13 are: |
| Note | Arachidonate 15-Lipoxygenase (15-LOX-1) is one of several LOX isoforms that oxygenates polyunsaturated fatty acids as well as complex substrates such as biomembranes. Its expression is associated with the development of inflammatory diseases such as atherosclerosis, asthma, cancer and osteoporosis. |
| 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 and IL-13 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 5¹ 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. |
| Protein |
| 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 | 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 | 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 | 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 | 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 | 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. |
| External links |
| Bibliography |
| Discovery of a second 15S-lipoxygenase in humans. |
| Brash AR, Boeglin WE, Chang MS |
| Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (12) : 6148-6152. |
| PMID 9177185 |
| Expression of 15-lipoxygenase-1 in human colorectal cancer. |
| Ikawa H, Kamitani H, Calvo BF, Foley JF, Eling TE |
| Cancer research. 1999 ; 59 (2) : 360-366. |
| PMID 9927047 |
| 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, Badr KF |
| Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (8) : 4378-4383. |
| PMID 10200270 |
| Acetylation by histone acetyltransferase CREB-binding protein/p300 of STAT6 is required for transcriptional activation of the 15-lipoxygenase-1 gene. |
| Shankaranarayanan P, Chaitidis P, Kºhn H, Nigam S |
| The Journal of biological chemistry. 2001 ; 276 (46) : 42753-42760. |
| PMID 11509556 |
| Nonsteroidal anti-inflammatory drugs induce apoptosis in esophageal cancer cells by restoring 15-lipoxygenase-1 expression. |
| Shureiqi I, Xu X, Chen D, Lotan R, Morris JS, Fischer SM, Lippman SM |
| Cancer research. 2001 ; 61 (12) : 4879-4884. |
| PMID 11406566 |
| 15-lipoxygenase: a Janus enzyme? |
| Chanez P, Bonnans C, Chavis C, Vachier I |
| American journal of respiratory cell and molecular biology. 2002 ; 27 (6) : 655-658. |
| PMID 12444024 |
| 15-lipoxygenase-1 overexpression in prostate adenocarcinoma. |
| Kelavkar U, Cohen C, Eling T, Badr K |
| Advances in experimental medicine and biology. 2002 ; 507 : 133-145. |
| PMID 12664577 |
| KU 70/80 lupus autoantigen is the transcription factor induced by interleukins (IL)-13 and -4 leading to induction of 15-lipoxygenase (15-LO) in human cells. |
| Kelavkar U, Wang S, Badr K |
| Advances in experimental medicine and biology. 2002 ; 507 : 469-481. |
| PMID 12664628 |
| GATA-6 transcriptional regulation of 15-lipoxygenase-1 during NSAID-induced apoptosis in colorectal cancer cells. |
| Shureiqi I, Jiang W, Fischer SM, Xu X, Chen D, Lee JJ, Lotan R, Lippman SM |
| Cancer research. 2002 ; 62 (4) : 1178-1183. |
| PMID 11861401 |
| The N-terminal domain of the reticulocyte-type 15-lipoxygenase is not essential for enzymatic activity but contains determinants for membrane binding. |
| Walther M, Anton M, Wiedmann M, Fletterick R, Kuhn H |
| The Journal of biological chemistry. 2002 ; 277 (30) : 27360-27366. |
| PMID 12004065 |
| 15-hydroxy-eicosatetraenoic acid arrests growth of colorectal cancer cells via a peroxisome proliferator-activated receptor gamma-dependent pathway. |
| Chen GG, Xu H, Lee JF, Subramaniam M, Leung KL, Wang SH, Chan UP, Spelsberg TC |
| International journal of cancer. Journal international du cancer. 2003 ; 107 (5) : 837-843. |
| PMID 14566836 |
| 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, Nigam S |
| Journal of immunology (Baltimore, Md. : 1950). 2003 ; 170 (2) : 887-894. |
| PMID 12517954 |
| Interleukin-13 induction of 15-lipoxygenase gene expression requires p38 mitogen-activated protein kinase-mediated serine 727 phosphorylation of Stat1 and Stat3. |
| Xu B, Bhattacharjee A, Roy B, Xu HM, Anthony D, Frank DA, Feldman GM, Cathcart MK |
| Molecular and cellular biology. 2003 ; 23 (11) : 3918-3928. |
| PMID 12748293 |
| Transcriptional regulation of 15-lipoxygenase expression by promoter methylation. |
| Liu C, Xu D, Sjberg J, Forsell P, Bjrkholm M, Claesson HE |
| Experimental cell research. 2004 ; 297 (1) : 61-67. |
| PMID 15194425 |
| 15-Lipoxygenase-1 has anti-tumorigenic effects in colorectal cancer. |
| Nixon JB, Kim KS, Lamb PW, Bottone FG, Eling TE |
| Prostaglandins, leukotrienes, and essential fatty acids. 2004 ; 70 (1) : 7-15. |
| PMID 14643174 |
| 15-LOX-1 inhibits p21 (Cip/WAF 1) expression by enhancing MEK-ERK 1/2 signaling in colon carcinoma cells. |
| Yoshinaga M, Buchanan FG, DuBois RN |
| Prostaglandins & other lipid mediators. 2004 ; 73 (1-2) : 111-122. |
| PMID 15165036 |
| 15S-Lipoxygenase-2 mediates arachidonic acid-stimulated adhesion of human breast carcinoma cells through the activation of TAK1, MKK6, and p38 MAPK. |
| Nony PA, Kennett SB, Glasgow WC, Olden K, Roberts JD |
| The Journal of biological chemistry. 2005 ; 280 (36) : 31413-31419. |
| PMID 16000313 |
| The role of lipoxygenase-isoforms in atherogenesis. |
| Kºhn H, Rmisch I, Belkner J |
| Molecular nutrition & food research. 2005 ; 49 (11) : 1014-1029. |
| PMID 16270276 |
| The critical role of 15-lipoxygenase-1 in colorectal epithelial cell terminal differentiation and tumorigenesis. |
| Shureiqi I, Wu Y, Chen D, Yang XL, Guan B, Morris JS, Yang P, Newman RA, Broaddus R, Hamilton SR, Lynch P, Levin B, Fischer SM, Lippman SM |
| Cancer research. 2005 ; 65 (24) : 11486-11492. |
| PMID 16357157 |
| Association of a single nucleotide polymorphism in the lipoxygenase ALOX15 5'-flanking region (-5229G/A) with bone mineral density. |
| Urano T, Shiraki M, Fujita M, Hosoi T, Orimo H, Ouchi Y, Inoue S |
| Journal of bone and mineral metabolism. 2005 ; 23 (3) : 226-230. |
| PMID 15838625 |
| Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer. |
| Jiang WG, Watkins G, Douglas-Jones A, Mansel RE |
| Prostaglandins, leukotrienes, and essential fatty acids. 2006 ; 74 (4) : 235-245. |
| PMID 16556493 |
| The yin and yang of 15-lipoxygenase-1 and delta-desaturases: dietary omega-6 linoleic acid metabolic pathway in prostate. |
| Kelavkar U, Lin Y, Landsittel D, Chandran U, Dhir R |
| Journal of carcinogenesis. 2006 ; 5 : page 9. |
| PMID 16566819 |
| Inflammation and immune regulation by 12/15-lipoxygenases. |
| Kºhn H, O'Donnell VB |
| Progress in lipid research. 2006 ; 45 (4) : 334-356. |
| PMID 16678271 |
| Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity. |
| Zuo X, Wu Y, Morris JS, Stimmel JB, Leesnitzer LM, Fischer SM, Lippman SM, Shureiqi I |
| Oncogene. 2006 ; 25 (8) : 1225-1241. |
| PMID 16288226 |
| Functional polymorphism in ALOX15 results in increased allele-specific transcription in macrophages through binding of the transcription factor SPI1. |
| Wittwer J, Marti-Jaun J, Hersberger M |
| Human mutation. 2006 ; 27 (1) : 78-87. |
| PMID 16320347 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 06-2006 | Sreeparna Banerjee |
| Department of Biology, Office: Z-16/Lab: B-59, Middle East Technical University, 06531 Ankara, Turkey |
| Citation |
| This paper should be referenced as such : |
| Banerjee S . ALOX15 (Arachidonate 15-Lipoxygenase). Atlas Genet Cytogenet Oncol Haematol. June 2006 . |
| URL : http://AtlasGeneticsOncology.org/Genes/ALOX15ID42986ch17p13.html |
The various updated versions of this paper are referenced and archived by INIST as such : |
| http://documents.irevues.inist.fr/bitstream/2042/38346/1/06-2006-ALOX15ID42986ch17p13.pdf [ Bibliographic record ] |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed Feb 26 10:10:51 CET 2014 |
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