Details for: ALOX12

Gene ID: 239

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: ALOX12

Ensembl ID: ENSG00000108839

Description: arachidonate 12-lipoxygenase, 12S type

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 3.64
    rCSI 3.28%
    PRS 99.69
  • megakaryocyte CL0000556
    CSI 3.26
    rCSI 14.16%
    PRS 99.14
  • ependymal cell CL0000065
    CSI 3.26
    rCSI 6.62%
    PRS 97.91
  • promyelocyte CL0000836
    CSI 3.22
    rCSI 4.65%
    PRS 99.66
  • platelet CL0000233
    CSI 2.89
    rCSI 11.98%
    PRS 98.8
  • basal cell of epidermis CL0002187
    CSI 2.33
    rCSI 4.13%
    PRS 93.68

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
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    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
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  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [ALOX12](/details-gene/239) (arachidonate 12-lipoxygenase) is a protein-coding gene located on chromosome 17p13.1 that encodes an enzyme crucial for lipid metabolism. As a lipoxygenase, its primary function is to catalyze the oxygenation of arachidonic acid, initiating the synthesis of a variety of bioactive lipid mediators, including hepoxilins and lipoxins ([Link](https://doi.org/10.1042/bj2960127)). **Overall**, expression data reveals that [ALOX12](/details-gene/239) is a significant gene in the hematopoietic system, with particularly high significance in cells of the megakaryocytic lineage, such as [megakaryocyte-erythroid progenitor cell](/details-cell/CL0000050), [megakaryocyte](/details-cell/CL0000556), and mature [platelet](/details-cell/CL0000233). It also shows prominent expression in epidermal cells and [ependymal cell](/details-cell/CL0000065)s, suggesting diverse roles in hemostasis, skin barrier function, and potentially the central nervous system. Its clinical relevance is noted under OMIM entry [152391](https://omim.org/entry/152391). ## Cellular Roles and Expression Landscape The expression pattern of [ALOX12](/details-gene/239) highlights its specialized roles in distinct cellular contexts. **Overall**, its highest significance is observed within the platelet production pathway. It is a key marker for [megakaryocyte-erythroid progenitor cell](/details-cell/CL0000050) (CSI: 3.64), [megakaryocyte](/details-cell/CL0000556) (CSI: 3.26), and their anucleated progeny, [platelet](/details-cell/CL0000233) (CSI: 2.89). This strong association with megakaryopoiesis is consistent with its established role in producing metabolites that modulate platelet aggregation. Beyond hematopoiesis, [ALOX12](/details-gene/239) demonstrates a significant role in epithelial tissues, particularly in the [basal cell of epidermis](/details-cell/CL0002187) (CSI: 2.33). This is supported by its functional involvement in the establishment of the skin barrier and evidence suggesting its overexpression in the germinal layer of keratinocytes in psoriasis ([Link](https://doi.org/10.1152/ajpcell.1994.266.1.c243)). The gene's high significance in [promyelocyte](/details-cell/CL0000836) (CSI: 3.22) suggests a broader role in myeloid cell differentiation. Furthermore, its notable expression in [ependymal cell](/details-cell/CL0000065) (CSI: 3.26), which line the cerebral ventricles, suggests a potential, though less characterized, function in the central nervous system. ## Pathways and Molecular Function [ALOX12](/details-gene/239) is an enzyme with [arachidonate 12(s)-lipoxygenase activity](/details-go/GO:0004052) that primarily functions within the [Lipoxygenase pathway](/details-go/GO:0019372). Its activity is central to the metabolism of unsaturated fatty acids, including the [Arachidonate metabolic process](/details-go/GO:0019369) and the [Linoleic acid metabolic process](/details-go/GO:0043651). The enzyme's function is integral to several key Reactome pathways, including [Arachidonate metabolism](/details-reactome/R-HSA-2142753) and the broader [Metabolism of lipids](/details-reactome/R-HSA-556833). It plays a critical role in the synthesis of specific signaling lipids. These include the [Biosynthesis of lipoxins (lx)](/details-reactome/R-HSA-2142700) and the [Synthesis of hepoxilins (hx) and trioxilins (trx)](/details-reactome/R-HSA-2142696), which are involved in the resolution of inflammation and cellular signaling. This is further elaborated by its role in the [Biosynthesis of specialized proresolving mediators (spms)](/details-reactome/R-HSA-9018678). The biological outcomes of these pathways are reflected in its associated GO terms. For instance, its high expression in platelets is directly linked to the [Negative regulation of platelet aggregation](/details-go/GO:0090331). Similarly, its expression in epidermal cells corresponds to its function in the [Establishment of skin barrier](/details-go/GO:0061436). The enzyme, which requires [Iron ion binding](/details-go/GO:0005506) for its catalytic activity, primarily localizes to the [cytoplasm](/details-go/GO:0005737) and [cytosol](/details-go/GO:0005829). ## Research Directions The diverse expression profile and enzymatic function of [ALOX12](/details-gene/239) suggest it plays a critical role in both physiological and pathological processes, pointing to several avenues for future research. ### Testable Hypotheses 1. **Role in Inflammatory Skin Disease:** Based on its high expression in [basal cell of epidermis](/details-cell/CL0002187), its function in [Establishment of skin barrier](/details-go/GO:0061436), and prior research linking it to psoriasis ([Link](https://doi.org/10.1152/ajpcell.1994.266.1.c243)), we hypothesize that overexpression of [ALOX12](/details-gene/239) in keratinocytes contributes to the hyperproliferative and pro-inflammatory phenotype of psoriasis by generating lipid mediators that disrupt normal differentiation and promote immune cell infiltration. 2. **Contribution to Tumor Angiogenesis:** Given previous reports that platelet-type 12-lipoxygenase stimulates angiogenesis in prostate cancer ([Link](https://pubmed.ncbi.nlm.nih.gov/9751607/)), we hypothesize that tumor cells expressing [ALOX12](/details-gene/239) secrete 12-HETE and other metabolites into the tumor microenvironment, which act as paracrine signals to promote endothelial cell proliferation, migration, and vessel formation, thereby fueling tumor growth. 3. **Regulation of Hemostasis and Thrombosis:** The profound expression of [ALOX12](/details-gene/239) across the megakaryocytic lineage suggests a central role in platelet function. We hypothesize that genetic or pharmacological modulation of [ALOX12](/details-gene/239) activity directly alters the risk of thrombosis, where inhibition would reduce platelet reactivity and hyperactivity would predispose individuals to thrombotic events through altered production of pro- or anti-aggregatory eicosanoids. ### Key Experimental Approach To test the hypothesis regarding its role in psoriasis (Hypothesis 1), a compelling experiment would be to use a conditional knockout mouse model. A mouse line with a floxed *Alox12* allele could be crossed with a line expressing Cre recombinase under a keratinocyte-specific promoter (e.g., KRT14-Cre). These mice and their wild-type littermates would then be subjected to an imiquimod-induced model of psoriasis. The therapeutic effect of [ALOX12](/details-gene/239) deletion would be assessed by measuring disease parameters such as ear thickness, scaling, and erythema. Skin biopsies would be analyzed via histology for epidermal thickness, RNA-seq to determine changes in inflammatory and differentiation gene expression signatures, and lipidomics to confirm the absence of [ALOX12](/details-gene/239)-derived metabolites. ### Therapeutic Potential As an enzyme, [ALOX12](/details-gene/239) is a highly druggable target. Its association with cancer progression and inflammatory skin disorders suggests it is a promising candidate for therapeutic **inhibition**. The development of potent and specific small-molecule inhibitors of [ALOX12](/details-gene/239) could offer a novel treatment strategy for certain prostate cancers by targeting tumor angiogenesis. Similarly, topical inhibitors could be developed to treat inflammatory skin conditions like psoriasis, potentially reducing keratinocyte hyperproliferation and inflammation with fewer systemic side effects. However, any systemic inhibition would need to be carefully evaluated for its impact on platelet function and overall hemostasis.

Genular Protein ID: 2812426038

Symbol: LOX12_HUMAN

Name: Lipoxin synthase 12-LO

UniProtKB Accession Codes:

P18054 O95569 Q6ISF8 Q9UQM4

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEBI 74 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugCentral 1 EC 3 EMBL 10 EMDB 4 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 25 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 9 KEGG 1 MANE-Select 1 MIM 5 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 5 PDBsum 5 PIR 1 PRINTS 2 PRO 1 PROSITE 4 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 6 RefSeq 1 Rhea 44 SABIO-RK 1 SMART 1 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 SwissLipids 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 2244907

Title: Molecular cloning and expression of human arachidonate 12-lipoxygenase.

PubMed ID: 2244907

DOI: 10.1016/0006-291x(90)91580-l

PubMed ID: 2377602

Title: Molecular cloning, primary structure, and expression of the human platelet/erythroleukemia cell 12-lipoxygenase.

PubMed ID: 2377602

DOI: 10.1073/pnas.87.15.5638

PubMed ID: 2217179

Title: Cloning of the cDNA for human 12-lipoxygenase.

PubMed ID: 2217179

DOI: 10.1073/pnas.87.19.7477

PubMed ID: 16625196

Title: DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage.

PubMed ID: 16625196

DOI: 10.1038/nature04689

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 1447217

Title: Structure and chromosomal localization of human arachidonate 12-lipoxygenase gene.

PubMed ID: 1447217

DOI: 10.1016/s0021-9258(18)35835-6

PubMed ID: 1570320

Title: Characterization of human 12-lipoxygenase genes.

PubMed ID: 1570320

DOI: 10.1073/pnas.89.9.3962

PubMed ID: 8304420

Title: Epidermis contains platelet-type 12-lipoxygenase that is overexpressed in germinal layer keratinocytes in psoriasis.

PubMed ID: 8304420

DOI: 10.1152/ajpcell.1994.266.1.c243

PubMed ID: 1851637

Title: Catalytic properties of human platelet 12-lipoxygenase as compared with the enzymes of other origins.

PubMed ID: 1851637

DOI: 10.1016/0005-2760(91)90128-5

PubMed ID: 8250832

Title: Lipoxin synthase activity of human platelet 12-lipoxygenase.

PubMed ID: 8250832

DOI: 10.1042/bj2960127

PubMed ID: 8319693

Title: Purification and characterization of recombinant histidine-tagged human platelet 12-lipoxygenase expressed in a baculovirus/insect cell system.

PubMed ID: 8319693

DOI: 10.1111/j.1432-1033.1993.tb17988.x

PubMed ID: 8500694

Title: Structure-function properties of human platelet 12-lipoxygenase: chimeric enzyme and in vitro mutagenesis studies.

PubMed ID: 8500694

DOI: 10.1096/fasebj.7.8.8500694

PubMed ID: 8912711

Title: 12-Lipoxygenase in A431 cells: genetic identity, modulation of expression, and intracellular localization.

PubMed ID: 8912711

DOI: 10.1006/excr.1996.0317

PubMed ID: 9751607

Title: Platelet-type 12-lipoxygenase in a human prostate carcinoma stimulates angiogenesis and tumor growth.

PubMed ID: 9751607

PubMed ID: 16638750

Title: Mechanisms regulating tumor angiogenesis by 12-lipoxygenase in prostate cancer cells.

PubMed ID: 16638750

DOI: 10.1074/jbc.m601887200

PubMed ID: 17493578

Title: Oxidative metabolism of lipoamino acids and vanilloids by lipoxygenases and cyclooxygenases.

PubMed ID: 17493578

DOI: 10.1016/j.abb.2007.04.007

PubMed ID: 18311922

Title: Oxidative metabolism of a fatty acid amide hydrolase-regulated lipid, arachidonoyltaurine.

PubMed ID: 18311922

DOI: 10.1021/bi702530z

PubMed ID: 18755188

Title: Reciprocal regulation of 12- and 15-lipoxygenases by UV-irradiation in human keratinocytes.

PubMed ID: 18755188

DOI: 10.1016/j.febslet.2008.08.017

PubMed ID: 22237009

Title: Up-regulation of 12(S)-lipoxygenase induces a migratory phenotype in colorectal cancer cells.

PubMed ID: 22237009

DOI: 10.1016/j.yexcr.2011.12.017

PubMed ID: 23578768

Title: 12S-Lipoxygenase is necessary for human vascular smooth muscle cell survival.

PubMed ID: 23578768

DOI: 10.1016/j.yexcr.2013.04.001

PubMed ID: 22984144

Title: Investigations of human platelet-type 12-lipoxygenase: role of lipoxygenase products in platelet activation.

PubMed ID: 22984144

DOI: 10.1194/jlr.m026385

PubMed ID: 23504711

Title: The novel 13S,14S-epoxy-maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H), and shifts macrophage phenotype.

PubMed ID: 23504711

DOI: 10.1096/fj.13-227728

PubMed ID: 24282679

Title: Functional characterization of genetic enzyme variations in human lipoxygenases.

PubMed ID: 24282679

DOI: 10.1016/j.redox.2013.11.001

PubMed ID: 25036362

Title: Maresin biosynthesis and identification of maresin 2, a new anti-inflammatory and pro-resolving mediator from human macrophages.

PubMed ID: 25036362

DOI: 10.1371/journal.pone.0102362

PubMed ID: 32404334

Title: 15-Lipoxygenase-1 biosynthesis of 7S,14S-diHDHA implicates 15-lipoxygenase-2 in biosynthesis of resolvin D5.

PubMed ID: 32404334

DOI: 10.1194/jlr.ra120000777

PubMed ID: 15308583

Title: Arachidonate lipoxygenase (ALOX) and cyclooxygenase (COX) polymorphisms and colon cancer risk.

PubMed ID: 15308583

DOI: 10.1093/carcin/bgh260

PubMed ID: 17151091

Title: Associations of functional polymorphisms in cyclooxygenase-2 and platelet 12-lipoxygenase with risk of occurrence and advanced disease status of colorectal cancer.

PubMed ID: 17151091

DOI: 10.1093/carcin/bgl242

PubMed ID: 17460548

Title: Platelet 12-lipoxygenase Arg261Gln polymorphism: functional characterization and association with risk of esophageal squamous cell carcinoma in combination with COX-2 polymorphisms.

PubMed ID: 17460548

DOI: 10.1097/fpc.0b013e328010bda1

Sequence Information:

  • Length: 663
  • Mass: 75694
  • Checksum: C4D6D5B320666A77
  • Sequence:
    • MGRYRIRVAT GAWLFSGSYN RVQLWLVGTR GEAELELQLR PARGEEEEFD HDVAEDLGLL 
QFVRLRKHHW LVDDAWFCDR ITVQGPGACA EVAFPCYRWV QGEDILSLPE GTARLPGDNA 
LDMFQKHREK ELKDRQQIYC WATWKEGLPL TIAADRKDDL PPNMRFHEEK RLDFEWTLKA 
GALEMALKRV YTLLSSWNCL EDFDQIFWGQ KSALAEKVRQ CWQDDELFSY QFLNGANPML 
LRRSTSLPSR LVLPSGMEEL QAQLEKELQN GSLFEADFIL LDGIPANVIR GEKQYLAAPL 
VMLKMEPNGK LQPMVIQIQP PNPSSPTPTL FLPSDPPLAW LLAKSWVRNS DFQLHEIQYH 
LLNTHLVAEV IAVATMRCLP GLHPIFKFLI PHIRYTMEIN TRARTQLISD GGIFDKAVST 
GGGGHVQLLR RAAAQLTYCS LCPPDDLADR GLLGLPGALY AHDALRLWEI IARYVEGIVH 
LFYQRDDIVK GDPELQAWCR EITEVGLCQA QDRGFPVSFQ SQSQLCHFLT MCVFTCTAQH 
AAINQGQLDW YAWVPNAPCT MRMPPPTTKE DVTMATVMGS LPDVRQACLQ MAISWHLSRR 
QPDMVPLGHH KEKYFSGPKP KAVLNQFRTD LEKLEKEITA RNEQLDWPYE YLKPSCIENS 
VTI