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PTGS2 (prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase))

Identity

Other namesCOX2 (Cyclooxygenase 2)
COX-2
PGG/HS
PGHS-2
PHS-2
hCox-2
HGNC (Hugo) PTGS2
LocusID (NCBI) 5743
Location 1q31.1
Location_base_pair Starts at 186640944 and ends at 186649559 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description 8633 bases, 10 Exons.
Transcription One transcript (chr1:184907546-184916179). COX2 promoter is regulated via the interplay between two opposite beta isoforms of the CCAAT/enhancer binding protein and the p300 coactivator.

Protein

Description COX2 is an enzyme that belongs to the prostaglandin G/H synthase family. It consists of 604 amino acids and has a molecular weight of 68996Da.
COX2 possesses two catalytic activities and respective active sites:
  • a cyclooxygenase (COX) that converts arachidonic acid to a prostaglandin endoperoxide, prostaglandin G2 (PGG2), and
  • a peroxidase (POX) that reduces PGG2 to PGH2.
    COX2 functions as homodimer although each subunit has both a POX and a COX active site.
    Each subunit binds one heme B (iron-protoporphyrin IX) group.
  • Expression Wide expression in alimentary system (esophagus, pharynx), male reproductive system (prostate, seminal vesicles, ejaculatory duct), female reproductive system (cervix, uterus), hematopoietic system (bone marrow, monocytes).
    Localisation Intracellular, cytoplasm, microsome, microsomal membrane.
    Function Enzyme that functions both as a dioxygenase and as a peroxidase. COX-2 catalyzes the transformation of arachidonic acid to prostaglandin H2, which is the rate-limiting step in the formation of prostaglandins (PGs) and thromboxane A2 (TXA2). COX-2 is a potent mediator of inflammation and is implicated in prostanoid signaling in activity dependent plasticity. It is an inducible enzyme that plays an important role in several pathophysiological processes, including inflammation, angiogenesis, and tumorigenesis.

    Mutations

    Note Five heterozygous mutations (1 missense/nonsense, 1 splicing, 3 regulatory) have been identified. Two were associated with diabetes mellitus type 2, one with bladder cancer risk, one with increased risk of colorectal cancer and one with decreased risk of colorectal cancer.

    Implicated in

    Entity Colorectal Cancers
    Disease COX2 is involved in regulation of apoptosis, proliferation and invasiveness of colorectal tumor cells and promotes angiogenesis in several animal colon cancer models. It is also implicated in several premalignant lesions including adenomatous polyps. COX2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor, EP2.
      
    Entity Gastric Cancer
    Disease Expression of COX2 is elevated in gastric adenocarcinomas, which correlates with several clinicopathological parameters, including depth of invasion and lymph node metastasis.
      
    Entity Non small cell lung cancer
    Disease Non-small-cell lung cancer (NSCLC), especially adenocarcinomas, overexpress COX2, which contributes to the progression of malignancy by several mechanisms.
      
    Entity Cholangiocarcinoma
    Disease COX2 has been implicated in cholangiocarcinogenesis. Selective COX-2 inhibitors have been shown to inhibit cholangiocarcinoma cell growth in vitro and in animal models.
      
    Entity Uterine Carcinosarcoma
    Disease COX2 is overexpressed in one-third of uterine carcinosarcomas. COX-2 expression is a strong indicator of unfavorable prognosis.
      
    Entity Head and Neck squamous cell cancer
    Disease COX2 is overexpressed in a variety of premalignant and malignant conditions, including oral leukoplakia and squamous cell carcinoma of the head and neck.
      
    Entity Ovarian cancer
    Disease COX-2 is increased in epithelial ovarian cancer and PGE2-synthesis and signalling are important for malignant transformation and progression.
      
    Entity Pancreatic cancer
    Disease Mounting evidence suggests that COX2 is implicated in pancreatic cancer.
    Immunohistochemical, RT-PCR, and Western blotting studies have shown that COX2, is upregulated in human pancreatic cancer cell lines as well as human pancreatic cancer tissues compared with normal ductal cells and normal pancreas specimens. COX2 inhibitors significantly inhibit pancreatic cancer growth both in vitro and in vivo while simultaneously induce apoptosis.
      
    Entity Other Malignant Diseases
    Disease Similar to above tumors, COX2 is implicated in carcinogenesis of multiple tumors including transitional cell bladder cancer, prostate cancer, uterine cancer, cervical cancer, angiosarcoma, hepatocellular cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, thyroid cancer, Wilms tumor.
      
    Entity Primary Dysmenorrhea
    Disease In vivo studies have demonstrated that selective COX-2 inhibitors are effective in treatment of primary dysmenorrhea in women.
      
    Entity Inflammatory Conditions
    Disease COX2 occupies an important in several inflammatory diseases such as osteoarthritis and rheumatoid arthritis.
      
    Entity Neurolomuscular Disorders
    Disease COX2 is implicated in encephalitis, cerebral infarction, polyneuropathy and muscular dystrophies.
      
    Entity Cardiovascular toxicity and thromboembolic Discorders
    Note Selective inhibition of COX2 (without concomitant inhibition of COX1) is associated with significant cardiovascular risk and thromboembolic phenomena.
      
    Entity Retinopathy
    Disease COX2 plays an important role in ischemic proliferative retinopathy, as in the case of diabetic retinopathy.
      

    Other Solid tumors implicated (Data extracted from papers in the Atlas)

    Solid Tumors AmeloblastomID5945 MedulloblastomaID5065 rhab5004

    External links

    Nomenclature
    HGNC (Hugo)PTGS2   9605
    Cards
    AtlasPTGS2ID509ch1q31
    Entrez_Gene (NCBI)PTGS2  5743  prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)
    GeneCards (Weizmann)PTGS2
    Ensembl (Hinxton)ENSG00000073756 [Gene_View]  chr1:186640944-186649559 [Contig_View]  PTGS2 [Vega]
    ICGC DataPortalENSG00000073756
    AceView (NCBI)PTGS2
    Genatlas (Paris)PTGS2
    WikiGenes5743
    SOURCE (Princeton)NM_000963
    Genomic and cartography
    GoldenPath (UCSC)PTGS2  -  1q31.1   chr1:186640944-186649559 -  1q25.2-q25.3   [Description]    (hg19-Feb_2009)
    EnsemblPTGS2 - 1q25.2-q25.3 [CytoView]
    Mapping of homologs : NCBIPTGS2 [Mapview]
    OMIM600262   
    Gene and transcription
    Genbank (Entrez)AJ634912 AK292167 AY151286 AY462100 BC013734
    RefSeq transcript (Entrez)NM_000963
    RefSeq genomic (Entrez)AC_000133 NC_000001 NC_018912 NG_028206 NT_004487 NW_001838533 NW_004929293
    Consensus coding sequences : CCDS (NCBI)PTGS2
    Cluster EST : UnigeneHs.196384 [ NCBI ]
    CGAP (NCI)Hs.196384
    Alternative Splicing : Fast-db (Paris)GSHG0002812
    Alternative Splicing GalleryENSG00000073756
    Gene ExpressionPTGS2 [ NCBI-GEO ]     PTGS2 [ SEEK ]   PTGS2 [ MEM ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP35354 (Uniprot)
    NextProtP35354  [Medical]
    With graphics : InterProP35354
    Splice isoforms : SwissVarP35354 (Swissvar)
    Catalytic activity : Enzyme1.14.99.1 [ Enzyme-Expasy ]   1.14.99.11.14.99.1 [ IntEnz-EBI ]   1.14.99.1 [ BRENDA ]   1.14.99.1 [ KEGG ]   
    Domaine pattern : Prosite (Expaxy)EGF_3 (PS50026)    PEROXIDASE_3 (PS50292)   
    Domains : Interpro (EBI)EG-like_dom    Haem_peroxidase    Haem_peroxidase_animal    Haem_peroxidase_animal_subgr   
    Related proteins : CluSTrP35354
    Domain families : Pfam (Sanger)An_peroxidase (PF03098)   
    Domain families : Pfam (NCBI)pfam03098   
    Domain families : Smart (EMBL)EGF (SM00181)  
    DMDM Disease mutations5743
    Blocks (Seattle)P35354
    PDB (SRS)1V0X   
    PDB (PDBSum)1V0X   
    PDB (IMB)1V0X   
    PDB (RSDB)1V0X   
    Human Protein AtlasENSG00000073756
    Peptide AtlasP35354
    HPRD02599
    IPIIPI00018109   IPI00816025   
    Protein Interaction databases
    DIP (DOE-UCLA)P35354
    IntAct (EBI)P35354
    FunCoupENSG00000073756
    BioGRIDPTGS2
    InParanoidP35354
    Interologous Interaction database P35354
    IntegromeDBPTGS2
    STRING (EMBL)PTGS2
    Ontologies - Pathways
    Ontology : AmiGOprostaglandin biosynthetic process  prostaglandin biosynthetic process  angiogenesis  peroxidase activity  prostaglandin-endoperoxide synthase activity  nucleus  cytoplasm  cytoplasm  endoplasmic reticulum membrane  prostaglandin metabolic process  cellular component movement  inflammatory response  response to oxidative stress  embryo implantation  learning  memory  regulation of blood pressure  negative regulation of cell proliferation  lipid binding  response to fructose  response to manganese ion  response to lithium ion  positive regulation vascular endothelial growth factor production  sensory perception of pain  arachidonic acid metabolic process  cyclooxygenase pathway  cyclooxygenase pathway  lipoxygenase pathway  enzyme binding  heme binding  bone mineralization  ovulation  positive regulation of prostaglandin biosynthetic process  positive regulation of fever generation  positive regulation of synaptic plasticity  negative regulation of synaptic transmission, dopaminergic  response to estradiol  response to lipopolysaccharide  response to vitamin D  response to tumor necrosis factor  cellular response to UV  maintenance of blood-brain barrier  positive regulation of NF-kappaB import into nucleus  response to drug  anagen  protein homodimerization activity  neuron projection  positive regulation of apoptotic process  protein complex  small molecule metabolic process  positive regulation of nitric oxide biosynthetic process  negative regulation of cell cycle  positive regulation of vasoconstriction  negative regulation of smooth muscle contraction  positive regulation of smooth muscle contraction  decidualization  metal ion binding  positive regulation of smooth muscle cell proliferation  arachidonate 15-lipoxygenase activity  regulation of inflammatory response  brown fat cell differentiation  response to glucocorticoid  negative regulation of calcium ion transport  positive regulation of synaptic transmission, glutamatergic  oxidation-reduction process  response to fatty acid  cellular response to mechanical stimulus  cellular response to ATP  cellular response to hypoxia  positive regulation of transforming growth factor beta production  positive regulation of cell migration involved in sprouting angiogenesis  positive regulation of fibroblast growth factor production  positive regulation of brown fat cell differentiation  positive regulation of platelet-derived growth factor production  
    Ontology : EGO-EBIprostaglandin biosynthetic process  prostaglandin biosynthetic process  angiogenesis  peroxidase activity  prostaglandin-endoperoxide synthase activity  nucleus  cytoplasm  cytoplasm  endoplasmic reticulum membrane  prostaglandin metabolic process  cellular component movement  inflammatory response  response to oxidative stress  embryo implantation  learning  memory  regulation of blood pressure  negative regulation of cell proliferation  lipid binding  response to fructose  response to manganese ion  response to lithium ion  positive regulation vascular endothelial growth factor production  sensory perception of pain  arachidonic acid metabolic process  cyclooxygenase pathway  cyclooxygenase pathway  lipoxygenase pathway  enzyme binding  heme binding  bone mineralization  ovulation  positive regulation of prostaglandin biosynthetic process  positive regulation of fever generation  positive regulation of synaptic plasticity  negative regulation of synaptic transmission, dopaminergic  response to estradiol  response to lipopolysaccharide  response to vitamin D  response to tumor necrosis factor  cellular response to UV  maintenance of blood-brain barrier  positive regulation of NF-kappaB import into nucleus  response to drug  anagen  protein homodimerization activity  neuron projection  positive regulation of apoptotic process  protein complex  small molecule metabolic process  positive regulation of nitric oxide biosynthetic process  negative regulation of cell cycle  positive regulation of vasoconstriction  negative regulation of smooth muscle contraction  positive regulation of smooth muscle contraction  decidualization  metal ion binding  positive regulation of smooth muscle cell proliferation  arachidonate 15-lipoxygenase activity  regulation of inflammatory response  brown fat cell differentiation  response to glucocorticoid  negative regulation of calcium ion transport  positive regulation of synaptic transmission, glutamatergic  oxidation-reduction process  response to fatty acid  cellular response to mechanical stimulus  cellular response to ATP  cellular response to hypoxia  positive regulation of transforming growth factor beta production  positive regulation of cell migration involved in sprouting angiogenesis  positive regulation of fibroblast growth factor production  positive regulation of brown fat cell differentiation  positive regulation of platelet-derived growth factor production  
    Pathways : BIOCARTAMechanism of Acetaminophen Activity and Toxicity [Genes]    Mechanism of Gene Regulation by Peroxisome Proliferators via PPARa(alpha) [Genes]    Eicosanoid Metabolism [Genes]   
    Pathways : KEGGArachidonic acid metabolism    NF-kappa B signaling pathway    VEGF signaling pathway    TNF signaling pathway    Retrograde endocannabinoid signaling    Serotonergic synapse    Ovarian steroidogenesis    Leishmaniasis    Pathways in cancer    Chemical carcinogenesis    MicroRNAs in cancer    Small cell lung cancer   
    REACTOMEP35354 [protein]
    REACTOME PathwaysREACT_111217 Metabolism [pathway]
    Protein Interaction DatabasePTGS2
    Wikipedia pathwaysPTGS2
    Gene fusion - rearrangments
    Polymorphisms : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)PTGS2
    SNP (GeneSNP Utah)PTGS2
    SNP : HGBasePTGS2
    Genetic variants : HAPMAPPTGS2
    1000_GenomesPTGS2 
    ICGC programENSG00000073756 
    CONAN: Copy Number AnalysisPTGS2 
    Somatic Mutations in Cancer : COSMICPTGS2 
    LOVD (Leiden Open Variation Database)Whole genome datasets
    LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
    LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
    Mutations and Diseases : HGMDPTGS2
    OMIM600262   
    MedgenPTGS2
    GENETestsPTGS2
    Disease Genetic AssociationPTGS2
    Huge Navigator PTGS2 [HugePedia]  PTGS2 [HugeCancerGEM]
    Genomic VariantsPTGS2  PTGS2 [DGVbeta]
    Exome VariantPTGS2
    dbVarPTGS2
    ClinVarPTGS2
    snp3D : Map Gene to Disease5743
    General knowledge
    Homologs : HomoloGenePTGS2
    Homology/Alignments : Family Browser (UCSC)PTGS2
    Phylogenetic Trees/Animal Genes : TreeFamPTGS2
    Chemical/Protein Interactions : CTD5743
    Chemical/Pharm GKB GenePA293
    Clinical trialPTGS2
    Cancer Resource (Charite)ENSG00000073756
    Other databases
    Probes
    Litterature
    PubMed499 Pubmed reference(s) in Entrez
    CoreMinePTGS2
    iHOPPTGS2

    Bibliography

    Cyclooxygenase-2: a novel molecular target for the prevention and treatment of head and neck cancer.
    Lin DT, Subbaramaiah K, Shah JP, Dannenberg AJ, Boyle JO
    Head & neck. 2002 ; 24 (8) : 792-799.
    PMID 12203806
     
    Dynamic regulation of cyclooxygenase-2 promoter activity by isoforms of CCAAT/enhancer-binding proteins.
    Zhu Y, Saunders MA, Yeh H, Deng WG, Wu KK
    The Journal of biological chemistry. 2002 ; 277 (9) : 6923-6928.
    PMID 11741938
     
    Cyclooxygenase-2 and gastric carcinogenesis.
    Saukkonen K, Rintahaka J, Sivula A, Buskens CJ, Van Rees BP, Rio MC, Haglund C, Van Lanschot JJ, Offerhaus GJ, Ristimaki A
    APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. 2003 ; 111 (10) : 915-925.
    PMID 14616542
     
    Cyclooxygenase-2 inhibitors in lung cancer.
    Ramalingam S, Belani CP
    Clinical lung cancer. 2004 ; 5 (4) : 245-253.
    PMID 14967078
     
    Cyclooxygenases in cancer: progress and perspective.
    Zha S, Yegnasubramanian V, Nelson WG, Isaacs WB, De Marzo AM
    Cancer letters. 2004 ; 215 (1) : 1-20.
    PMID 15374627
     
    The cardiovascular toxicity of selective and nonselective cyclooxygenase inhibitors: comparisons, contrasts, and aspirin confounding.
    Konstantinopoulos PA, Lehmann DF
    Journal of clinical pharmacology. 2005 ; 45 (7) : 742-750.
    PMID 15951464
     
    COX-2, c-KIT and HER-2/neu expression in uterine carcinosarcomas: prognostic factors or potential markers for targeted therapies?
    Raspollini MR, Susini T, Amunni G, Paglierani M, Taddei A, Marchionni M, Scarselli G, Taddei GL
    Gynecologic oncology. 2005 ; 96 (1) : 159-167.
    PMID 15589595
     
    Cyclooxygenase-2 and prostaglandin signaling in cholangiocarcinoma.
    Wu T
    Biochimica et biophysica acta. 2005 ; 1755 (2) : 135-150.
    PMID 15921858
     
    Ovarian epithelial cancer: a role for PGE2-synthesis and signalling in malignant transformation and progression.
    Rask K, Zhu Y, Wang W, Hedin L, Sundfeldt K
    Molecular cancer. 2006 ; 5 : page 62.
    PMID 17107625
     
    NF-kappaB/PPAR gamma and/or AP-1/PPAR gamma 'on/off' switches and induction of CBP in colon adenocarcinomas: correlation with COX-2 expression.
    Konstantinopoulos PA, Vandoros GP, Sotiropoulou-Bonikou G, Kominea A, Papavassiliou AG
    International journal of colorectal disease. 2007 ; 22 (1) : 57-68.
    PMID 16506021
     
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    Contributor(s)

    Written05-2007Panagiotis A Konstantinopoulos, Michalis V Karamouzis, Athanasios G Papavassiliou
    Department of Biological Chemistry, Medical School, University of Athens, GR-11527 Goudi-Athens, Greece (AGP).

    Citation

    This paper should be referenced as such :
    Konstantinopoulos PA, Karamouzis MV, Papavassiliou AG
    PTGS2 (prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase));
    Atlas Genet Cytogenet Oncol Haematol. May 2007
    Free online version   Free pdf version   [Bibliographic record ]
    URL : http://AtlasGeneticsOncology.org/Genes/PTGS2ID509ch1q31.html

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Mon Oct 13 13:36:51 CEST 2014

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