Atlas of Genetics and Cytogenetics in Oncology and Haematology
ALOX5 (Arachidonate 5-Lipoxygenase).
| Identity |
| Other names | 5-LO |
| EC 1.13.11.34 | |
| leukotriene A4 synthase | |
| 5LPG | |
| LOG5 | |
| Hugo | ALOX5 |
| Location | 10q11.2 |
| Local_order | Genes flanking ALOX5, in centromere to telomere direction on 10q11, are: |
| DNA/RNA |
 | |
| Diagram of the ALOX5 gene. Exons are represented by purple boxes (in scale). Exons 1 to 14 are from the 5' to 3¹ direction. | |
| Description | ALOX5 gene spans a region of 71,88 kb and has 14 exons, the sizes being 192, 199, 82, 123, 107, 173, 147, 204, 87, 179, 122, 101, 171 and 606 bps. ALOX5 gene has 5 CpG islands and 3' end of the gene for cellular modulator of immune recognition (c-MIR). |
| Transcription | ALOX5 gene promoter (H. sapiens) lacks the TATA box and has eight GC-boxes within 180 bp from the major transcription initiation site (at-65 in relation to ATG), five of which are in tandem (-176 to - 147). Consensus-binding sites for the transcription factor serum protein 1 (SP1), and early growth-response protein 1(EGR-1) exists in this region. A Vitamin D receptor binding site has been located in a positive regulatory region (-779 to -229) of the ALOX5 promoter. Several other consensus-binding sites for transcription factors such as GATA, glucocorticoid receptors and NFKB also exist. DNA methylation and histone deacetylase are also strongly involved in ALOX5 expression. |
| Pseudogene | No pseudogenes have been reported for ALOX5. |
| Protein |
| Note | The ALOX5 gene encodes a member of the lipoxygenase gene family, 5-LOX, which catalyzes the synthesis of leukotrienes (LT) from arachidonic acid. Leukotrienes are responsible for a series of inflammatory and allergic conditions. 5-LOX is also unique in requiring the 5-LOX activating protein (FLAP), a nuclear trans-membrane protein that plays an essential role in the transfer of arachidonic acid to 5-LOX. FLAP can also bind to MK-886, a compound that blocks LT biosynthesis. |
| Description | 5-LOX is a 77.9 kDa protein consisting of 673 amino acids. The enzyme requires calcium, iron and ATP as cofactors. The enzyme activity is also stimulated by the presence of microsomal membranes and trace amounts of lipid hydroperoxides. The protein has a catalytic domain and a regulatory domain. The regulatory domain, which controls leukotriene synthesis and binds calcium, nucleotides and phospholipids also has a PLAT (Polycystin-1, Lipoxygenase, alpha-Toxin) domain. |
| Expression | 5-LOX protein is expressed in bone marrow derived cells such as monocytes/macrophages, mast cells, B-lymphocytes, polymorphonuclear leukocytes, dendritic cells and foam cells of human atherosclerotic tissues, as well as spleen, thymus brain, spinal cord, skeletal muscle, pancreas, prostate, kidney and lung in humans. |
| Localisation | Subcellular location of 5-LOX protein is the cytoplasm or nucleoplasm. 5-LOX is largely cytosolic in resting peritoneal macrophages, monocytes, neutrophils, monocytes and eosinophils. By contrast, alveolar macrophages and mast cells contain cytosolic and intranuclear fractions of the enzyme. Leukotriene synthesis capacity is determined by a calcium independent nuclear import of 5-lipoxygenase. Three nuclear localization sequence (NLS) exist, Leu-111 to Asp-121; Asp-156 to Asp-166 and Val-514 to Leu-535. |
| Function | 5-LOX, a monomeric enzyme, catalyzes the conversion of arachidonic acid to 5(S)-hydroperoxy-6-trans-8, 11, 14-cis-eicosatetraenoic acid (5(S)-HETE), and further dehydration to the allylic epoxide 5(S)-trans-7,9-trans-11,14-cis-eicosatetrenoic acid (leukotriene A4). The LTA4 intermediate is then converted to LTB4 by LTA4 hydrolase. LTB4 attracts leukocytes and are important for the inflammatory response. 5-LOX migrates to the nuclear membrane upon cellular activation leading to LTB4 biosynthesis. This function depends on calcium dependent binding of the N-terminal C2 domain of 5-LOX to phospholipids resulting in the release of fatty acid substrates for enzyme action. Phosphorylation of 5-LOX on Ser-271 by MAPK-activating protein (MAPKAP) kinase 2, Ser-663 by extracellular signal-regulated kinases (ERK-2) and Ser-523 by protein kinase A (PKA) catalytic subunit has been shown to stimulate 5-LOX activity. In addition, overexpression of 5-LOX was shown to promote senescence-like growth arrest in human and mouse embryo fibroblasts via a p53/p21-dependent pathway, by regulating reactive oxygen species production, independent of telomerase activity. Thus, a senescence-like growth arrest may be of significance in the pathogenesis of 5-LOX-associated disorders. |
| Homology | C. familiaris: LOC477753, similar to Arachidonate 5-lipoxygenase R. norvegicus: ALOX5, arachidonate 5-lipoxygenase M. musculus: ALOX5, arachidonate 5-lipoxygenase A. thaliana: AT3G22400 iron ion binding / lipoxygenase O. sativa: OSJNBb0017F17.2, putative lipoxygenase |
| Mutations |
| Note | A family of mutations in the G+C-rich transcription factor binding region of ALOX5 has been identified in which several Sp1 and Egr-1 binding motifs are altered in the region of 176 to 147 bp upstream from the ATG translation start site. These mutations alter transcription factor binding and may play a role in 5-LOX gene expression in vivo. A haplotype containing polymorphisms in a negative regulatory region of the ALOX5 promoter (G-1752A and G-1699A) may influence colon cancer risk in Caucasians. In addition, the genetic variant of tandem repeat (GGGCGG; Sp1-binding motif) in ALOX5 promoter in group of Korean aspirin intolerant asthma patients has been associated with the severity of airway hyper-responsiveness. |
| Implicated in |
| Entity | Esophageal cancer |
| Disease | Immunohistochemistry analyses of 5-LOX expression in 161 esophageal tissue indicated that the enzyme was expressed in 79% (127/161) of cancer tissues but in only 13% (4/32) of normal esophageal mucosa. 5-LOX was also expressed in 8 esophageal cancer cell lines examined. In addition, 5-LOX inhibitors AA861 and REV5901 increased cell viability and apoptosis in the esophageal cancer cell lines. |
| Entity | Pancreatic cancer |
| Disease | 5-LOX expression is upregulated human pancreatic cancer cells. The 5-LOX metabolite 5(S)-HETE was shown to stimulate proliferation, as well as the proliferation of the mitogenic intracellular tyrosine kinases, MEK/ERK and PI3 kinase/AKT. |
| Entity | Colorectal cancer |
| Disease | Exposure to cigarette smoke extract (CSE) was shown to enhance 5-LOX protein expression in the inflammation-associated colonic adenomas. The effects of CSE on colon cancer cells were mediated by 5-LOX DNA demethylation. In addition, an up-regulation of matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF), key angiogenic factors for tumorigenesis, were also observed. These effects were reversed by treating the colon cancer cells with dual 5-LOX and COX-2 inhibitors. |
| Entity | Atherosclerosis |
| Disease | 5-LOX, known to generate proinflammatory LTs, is highly expressed in the arterial walls of atherosclerotic patients, with the number of enzyme expressing lesion leukocytes increasing during disease progression. All constituents of the 5-LOX pathway are significantly expressed in human diseased arteries, thereby supporting a model of atherogenesis, whereby 5-LOX pathway dependent inflammatory circuits composed of leukocytes, smooth muscle cells and endothelial cells evolve within blood vessels during late stages of lesion development. |
| Entity | Asthma |
| Disease | LTs and their receptors play an important role in the pathogenesis of asthma. Th2 cytokines, interleukins-4 and -13 can upregulate cysteinyl leukotriene 1 receptor expression. In addition, cysteinyl LTs favour an allergic phenotype by upregulating type 2 cytokine expression and decreasing type 1 cytokine expression. Polymorphisms of the 5-LOX promoter have also been associated with the development of asthma. |
| Entity | Immune response and tissue homeostasis |
| Note | The products of the ALOX5 pathway, particularly LTs, are lipid messengers that act on the immune response system and tissue homeostasis. Their abnormal production can induce several diseases such as asthma, inflammation, atherosclerosis, basophilic leukaemia, oedema, exercise-induced asthma, anaphylaxis, psoriasis, bronchial spasms and allergic rhinitis. |
| Oncogenesis | Alterations in the 5-LOX pathway can result in the aberrant formation of its products, hydroxyeicosatetraenoic acids or leukotrienes. This can, in turn, increase cellular proliferation and survival and suppress apoptosis of human cells and thereby play a significant role in human carcinogenesis. |
| External links |
| Bibliography |
| Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. |
| In KH, Asano K, Beier D, Grobholz J, Finn PW, Silverman EK, Silverman ES, Collins T, Fischer AR, Keith TP, Serino K, Kim SW, De Sanctis GT, Yandava C, Pillari A, Rubin P, Kemp J, Israel E, Busse W, Ledford D, Murray JJ, Segal A, Tinkleman D, Drazen JM |
| The Journal of clinical investigation. 1997 ; 99 (5) : 1130-1137. |
| PMID 9062372 |
| Egr-1 and Sp1 interact functionally with the 5-lipoxygenase promoter and its naturally occurring mutants. |
| Silverman ES, Du J, De Sanctis GT, Rdmark O, Samuelsson B, Drazen JM, Collins T |
| American journal of respiratory cell and molecular biology. 1998 ; 19 (2) : 316-323. |
| PMID 9698605 |
| Mutations in the human 5-lipoxygenase gene. |
| In KH, Silverman ES, Asano K, Beier D, Fischer AR, Keith TP, Serino K, Yandava C, De Sanctis GT, Drazen JM |
| Clinical reviews in allergy & immunology. 1999 ; 17 (1-2) : 59-69. |
| PMID 10436859 |
| The discovery of the leukotrienes. |
| Samuelsson B |
| American journal of respiratory and critical care medicine. 2000 ; 161 (2 Pt 2) : S2-S6. |
| PMID 10673217 |
| Extracellular signal-regulated kinases phosphorylate 5-lipoxygenase and stimulate 5-lipoxygenase product formation in leukocytes. |
| Werz O, Bºrkert E, Fischer L, Szellas D, Dishart D, Samuelsson B, Rdmark O, Steinhilber D |
| The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2002 ; 16 (11) : 1441-1443. |
| PMID 12205041 |
| Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). |
| Werz O, Szellas D, Steinhilber D, Rdmark O |
| The Journal of biological chemistry. 2002 ; 277 (17) : 14793-14800. |
| PMID 11844797 |
| Extending the understanding of leukotrienes in asthma. |
| Coffey M, Peters-Golden M |
| Current opinion in allergy and clinical immunology. 2003 ; 3 (1) : 57-63. |
| PMID 12582316 |
| Multiple signal pathways are involved in the mitogenic effect of 5(S)-HETE in human pancreatic cancer. |
| Ding XZ, Tong WG, Adrian TE |
| Oncology. 2003 ; 65 (4) : 285-294. |
| PMID 14707447 |
| Trichostatin A and structurally related histone deacetylase inhibitors induce 5-lipoxygenase promoter activity. |
| Klan N, Seuter S, Schnur N, Jung M, Steinhilber D |
| Biological chemistry. 2003 ; 384 (5) : 777-785. |
| PMID 12817474 |
| Nuclear localization of 5-lipoxygenase as a determinant of leukotriene B4 synthetic capacity. |
| Luo M, Jones SM, Peters-Golden M, Brock TG |
| Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (21) : 12165-12170. |
| PMID 14530386 |
| 5-lipoxygenase and FLAP. |
| Peters-Golden M, Brock TG |
| Prostaglandins, leukotrienes, and essential fatty acids. 2003 ; 69 (2-3) : 99-109. |
| PMID 12895592 |
| Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. |
| Spanbroek R, Grabner R, Lotzer K, Hildner M, Urbach A, Ruhling K, Moos MP, Kaiser B, Cohnert TU, Wahlers T, Zieske A, Plenz G, Robenek H, Salbach P, Kuhn H, Radmark O, Samuelsson B, Habenicht AJ |
| Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (3) : 1238-1243. |
| PMID 12552108 |
| DNA methylation regulates 5-lipoxygenase promoter activity. |
| Uhl J, Klan N, Rose M, Entian KD, Werz O, Steinhilber D |
| Advances in experimental medicine and biology. 2003 ; 525 : 169-172. |
| PMID 12751760 |
| Arachidonate lipoxygenase (ALOX) and cyclooxygenase (COX) polymorphisms and colon cancer risk. |
| Goodman JE, Bowman ED, Chanock SJ, Alberg AJ, Harris CC |
| Carcinogenesis. 2004 ; 25 (12) : 2467-2472. |
| PMID 15308583 |
| Protein kinase A inhibits leukotriene synthesis by phosphorylation of 5-lipoxygenase on serine 523. |
| Luo M, Jones SM, Phare SM, Coffey MJ, Peters-Golden M, Brock TG |
| The Journal of biological chemistry. 2004 ; 279 (40) : 41512-41520. |
| PMID 15280375 |
| Multiple nuclear localization sequences allow modulation of 5-lipoxygenase nuclear import. |
| Luo M, Pang CW, Gerken AE, Brock TG |
| Traffic (Copenhagen, Denmark). 2004 ; 5 (11) : 847-854. |
| PMID 15479450 |
| Contributory role of 5-lipoxygenase and its association with angiogenesis in the promotion of inflammation-associated colonic tumorigenesis by cigarette smoking. |
| Ye YN, Liu ES, Shin VY, Wu WK, Cho CH |
| Toxicology. 2004 ; 203 (1-3) : 179-188. |
| PMID 15363593 |
| Structural organization of the regulatory domain of human 5-lipoxygenase. |
| Allard JB, Brock TG |
| Current protein & peptide science. 2005 ; 6 (2) : 125-131. |
| PMID 15853649 |
| 5-Lipoxygenase regulates senescence-like growth arrest by promoting ROS-dependent p53 activation. |
| Catalano A, Rodilossi S, Caprari P, Coppola V, Procopio A |
| The EMBO journal. 2005 ; 24 (1) : 170-179. |
| PMID 15616590 |
| GC-rich sequences in the 5-lipoxygenase gene promoter are required for expression in Mono Mac 6 cells, characterization of a novel Sp1 binding site. |
| Dishart D, Schnur N, Klan N, Werz O, Steinhilber D, Samuelsson B, Rdmark O |
| Biochimica et biophysica acta. 2005 ; 1738 (1-3) : 37-47. |
| PMID 16413224 |
| Stress-induced nuclear export of 5-lipoxygenase. |
| Hanaka H, Shimizu T, Izumi T |
| Biochemical and biophysical research communications. 2005 ; 338 (1) : 111-116. |
| PMID 16165096 |
| Increased 5-lipoxygenase expression and induction of apoptosis by its inhibitors in esophageal cancer: a potential target for prevention. |
| Hoque A, Lippman SM, Wu TT, Xu Y, Liang ZD, Swisher S, Zhang H, Cao L, Ajani JA, Xu XC |
| Carcinogenesis. 2005 ; 26 (4) : 785-791. |
| PMID 15661803 |
| Polymorphism of tandem repeat in promoter of 5-lipoxygenase in ASA-intolerant asthma: a positive association with airway hyperresponsiveness. |
| Kim SH, Bae JS, Suh CH, Nahm DH, Holloway JW, Park HS |
| Allergy. 2005 ; 60 (6) : 760-765. |
| PMID 15876305 |
| The 5-lipoxygenase pathway in arterial wall biology and atherosclerosis. |
| Ltzer K, Funk CD, Habenicht AJ |
| Biochimica et biophysica acta. 2005 ; 1736 (1) : 30-37. |
| PMID 16081317 |
| Regulation of 5-lipoxygenase enzyme activity. |
| Rdmark O, Samuelsson B |
| Biochemical and biophysical research communications. 2005 ; 338 (1) : 102-110. |
| PMID 16122704 |
| Dual inhibition of 5-LOX and COX-2 suppresses colon cancer formation promoted by cigarette smoke. |
| Ye YN, Wu WK, Shin VY, Bruce IC, Wong BC, Cho CH |
| Carcinogenesis. 2005 ; 26 (4) : 827-834. |
| PMID 15637091 |
| 5-Lipoxygenase-activating protein homodimer in human neutrophils: evidence for a role in leukotriene biosynthesis. |
| Plante H, Picard S, Mancini J, Borgeat P |
| The Biochemical journal. 2006 ; 393 (Pt 1) : 211-218. |
| PMID 16144515 |
| Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. |
| Qiu H, Gabrielsen A, Agardh HE, Wan M, Wetterholm A, Wong CH, Hedin U, Swedenborg J, Hansson GK, Samuelsson B, Paulsson-Berne G, Haeggstrm JZ |
| Proceedings of the National Academy of Sciences of the United States of America. 2006 ; 103 (21) : 8161-8166. |
| PMID 16698924 |
| Analysis of the 5-lipoxygenase promoter and characterization of a vitamin D receptor binding site. |
| Sorg BL, Klan N, Seuter S, Dishart D, Rdmark O, Habenicht A, Carlberg C, Werz O, Steinhilber D |
| Biochimica et biophysica acta. 2006 ; 1761 (7) : 686-697. |
| PMID 16750418 |
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| Contributor(s) |
| Written | 07-2006 | Sreeparna Banerjee, Seda Tuncay |
| Citation |
| This paper should be referenced as such : |
| Banerjee S, Tuncay S . ALOX5 (Arachidonate 5-Lipoxygenase).. Atlas Genet Cytogenet Oncol Haematol. July 2006 . URL : http://AtlasGeneticsOncology.org/Genes/ALOX5ID42985ch10q11.html |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed Jul 2 08:21:49 2008 |
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