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PTGIS (prostaglandin I2 (prostacyclin) synthase)

Written2009-05Inês Cebola, Miguel A Peinado
Institute of Predictive, Personalized Medicine of Cancer (IMPPC), Badalona, Barcelona, Spain

(Note : for Links provided by Atlas : click)

Identity

Alias_namesprostaglandin I2 (prostacyclin) synthase
Alias_symbol (synonym)PGIS
CYP8A1
Other aliasCYP8
EC 5.3.99.4
MGC126858
MGC126860
PTGI
HGNC (Hugo) PTGIS
LocusID (NCBI) 5740
Atlas_Id 44219
Location 20q13.13  [Link to chromosome band 20q13]
Location_base_pair Starts at 49503874 and ends at 49568170 bp from pter ( according to hg19-Feb_2009)  [Mapping PTGIS.png]
 
  Map of 20q13 chromosomal region.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
PMEPA1 (20q13.31) / PTGIS (20q13.13)RIMS2 (8q22.3) / PTGIS (20q13.13)

DNA/RNA

 
  Schematic diagram of PTGIS genomic region.
Description 64297 bases (chr20:47553818-47618114); 10 exons; telomere to centromere orientation.
Transcription Two alternative splicing products; 5624bp (coding, 1578bp ORF) and 313bp (non-coding). A 1.5kb upstream sequence presents CG-rich and pyrimidine-rich regions and contains consensus sequences for the recognition sites of Sp-1, AP-2, INF-gamma responsive element, GATA, NF-kB, glucocorticoid responsive element and a CACCC box.
It has been demonstrated that PTGIS transcription is regulated via Sp1 binding, which may affected by polymorphisms in the promoter region. The CG-rich region presents significant promoter activity.

Protein

Description PTGIS is a protein from the cytochrome P450 superfamily that consists of 500 amino acids and has a molecular weight of 57kDa. Is a single-pass membrane protein with a single transmembrane domain (1-20) and presents a heme-binding site at position 441. No post-translational modifications have been described for this protein.
 
  PTGIS protein structure: secondary structure composition and features of interest.
Expression Abundant in heart, lung, skeletal muscle, ovary and prostate. PTGIS is found underexpressed in most colorectal carcinomas and in several lung carcinomas and hypertensive subjects.
Localisation At cellular level can be found in the endoplasmatic reticulum membrane and in microsomes as a peripheral membrane protein.
Function Catalyses the isomerization of prostaglandin H2 to prostacyclin (prostaglandin I2), a potent vasodilator and inhibitor of platelet aggregation.
Homology Pan troglodytes - Prostaglandin I2 (prostacyclin) Synthase.
Canis lupus familiaris - Prostaglandin I2 (prostacyclin) Synthase.
Bos taurus - Prostaglandin I2 (prostacyclin) Synthase.
Mus musculus - Prostaglandin I2 (prostacyclin) Synthase.
Rattus norvegicus - Prostaglandin I2 (prostacyclin) Synthase.
Danio rerio - Prostaglandin I2 (prostacyclin) Synthase like.

Mutations

Note One splicing mutation has been associated with essential hypertension.

Implicated in

Note
  
Entity Colorectal cancer
Note PTGIS promoter is silenced by through promoter hypermethylation in a large subset of colorectal carcinomas (also observed in colorectal adenomas and in several colorectal cancer cell lines). The PTGIS silencing is an early event on tumor progression and age and sex-independent. A PTGIS promoter VNTR polymorphism has been associated with the risk of colorectal polyps, being the risk increased when both alleles present less than 6 repeats.
  
  
Entity Non-small cell lung cancer
Disease PTGIS promoter is hypermethylated in lung cancer cell lines. The VNTR polymophism has also been associated with gene silencing in lung cancer cells.
  
  
Entity Breast cancer
Disease The combination of the SNPs PTGIS(11)rs477627, PTGIS(21)rs476496 and PTGIS(20)rs1066894, located in the 5' region and first intron, confers reduced susceptibility to breast cancer.
  
  
Entity Essential hypertension
Disease A splicing mutation (T->C at the +2 position of the donor site of the intron 9) alters the reading frame and results in the production of a truncated protein with the heme-binding region deleted. The subjects found with this mutation presented lower levels of prostacyclin and hypertension.
The polymorphism C1117A has been significantly associated with hypertension, being the allele C associated with higher risk the condition, although it does not change the aminoacid sequence.
A polymorphism in the 5' region with a variable number of repeats of a 9-bp sequence (CCGCCAGCC) is associated with hypertension. The alleles less repeats possess less Sp1 sites and present lower promoter activity, being related with higher pulse pressure in women and higher systolic blood pressure in older individuals.
  
  
Entity Cerebral infarction
Disease Association between cerebral infarction and the PTGIS promoter VNTR alleles with less repeats.
  
  
Entity Myocardial infarction
Disease A synonymous SNP at codon 373 (Arg373Arg) in exon 8 has been associated with risk of myocardial infarction in the japanese population.
  

Bibliography

Common polymorphisms in the prostaglandin pathway genes and their association with breast cancer susceptibility and survival.
Abraham JE, Harrington P, Driver KE, Tyrer J, Easton DF, Dunning AM, Pharoah PD.
Clin Cancer Res. 2009 Mar 15;15(6):2181-91. Epub 2009 Mar 10.
PMID 19276290
 
The DNA sequence and comparative analysis of human chromosome 20.
Deloukas P, Matthews LH, Ashurst J, Burton J, Gilbert JG, Jones M, Stavrides G, Almeida JP, Babbage AK, Bagguley CL, Bailey J, Barlow KF, Bates KN, Beard LM, Beare DM, Beasley OP, Bird CP, Blakey SE, Bridgeman AM, Brown AJ, Buck D, Burrill W, Butler AP, Carder C, Carter NP, Chapman JC, Clamp M, Clark G, Clark LN, Clark SY, Clee CM, Clegg S, Cobley VE, Collier RE, Connor R, Corby NR, Coulson A, Coville GJ, Deadman R, Dhami P, Dunn M, Ellington AG, Frankland JA, Fraser A, French L, Garner P, Grafham DV, Griffiths C, Griffiths MN, Gwilliam R, Hall RE, Hammond S, Harley JL, Heath PD, Ho S, Holden JL, Howden PJ, Huckle E, Hunt AR, Hunt SE, Jekosch K, Johnson CM, Johnson D, Kay MP, Kimberley AM, King A, Knights A, Laird GK, Lawlor S, Lehvaslaiho MH, Leversha M, Lloyd C, Lloyd DM, Lovell JD, Marsh VL, Martin SL, McConnachie LJ, McLay K, McMurray AA, Milne S, Mistry D, Moore MJ, Mullikin JC, Nickerson T, Oliver K, Parker A, Patel R, Pearce TA, Peck AI, Phillimore BJ, Prathalingam SR, Plumb RW, Ramsay H, Rice CM, Ross MT, Scott CE, Sehra HK, Shownkeen R, Sims S, Skuce CD, Smith ML, Soderlund C, Steward CA, Sulston JE, Swann M, Sycamore N, Taylor R, Tee L, Thomas DW, Thorpe A, Tracey A, Tromans AC, Vaudin M, Wall M, Wallis JM, Whitehead SL, Whittaker P, Willey DL, Williams L, Williams SA, Wilming L, Wray PW, Hubbard T, Durbin RM, Bentley DR, Beck S, Rogers J.
Nature. 2001 Dec 20-27;414(6866):865-71.
PMID 11780052
 
Hypermethylation of the prostacyclin synthase (PTGIS) promoter is a frequent event in colorectal cancer and associated with aneuploidy.
Frigola J, Munoz M, Clark SJ, Moreno V, Capella G, Peinado MA.
Oncogene. 2005 Nov 10;24(49):7320-6.
PMID 16007128
 
Isolation and molecular cloning of prostacyclin synthase from bovine endothelial cells.
Hara S, Miyata A, Yokoyama C, Inoue H, Brugger R, Lottspeich F, Ullrich V, Tanabe T.
J Biol Chem. 1994 Aug 5;269(31):19897-903.
PMID 8051072
 
Human prostacyclin synthase gene and hypertension : the Suita Study.
Iwai N, Katsuya T, Ishikawa K, Mannami T, Ogata J, Higaki J, Ogihara T, Tanabe T, Baba S.
Circulation. 1999 Nov 30;100(22):2231-6.
PMID 10577996
 
Molecular cloning and expression of human prostacyclin synthase.
Miyata A, Hara S, Yokoyama C, Inoue H, Ullrich V, Tanabe T.
Biochem Biophys Res Commun. 1994 May 16;200(3):1728-34.
PMID 8185632
 
Splicing mutation of the prostacyclin synthase gene in a family associated with hypertension.
Nakayama T, Soma M, Watanabe Y, Hasimu B, Sato M, Aoi N, Kosuge K, Kanmatsuse K, Kokubun S, Marrow JD, Oates JA.
Biochem Biophys Res Commun. 2002 Oct 11;297(5):1135-9.
PMID 12372404
 
Prostacyclin in human non-small cell lung cancers.
Nana-Sinkam P, Golpon H, Keith RL, Oyer RJ, Sotto-Santiago S, Moore MD, Franklin W, Nemenoff RA, Geraci MW.
Chest. 2004 May;125(5 Suppl):141S.
PMID 15136467
 
Prostacyclin signaling in the kidney: implications for health and disease.
Nasrallah R, Hebert RL.
Am J Physiol Renal Physiol. 2005 Aug;289(2):F235-46. (REVIEW)
PMID 16006589
 
Molecular mechanisms responsible for the antiinflammatory and protective effect of HDL on the endothelium.
Norata GD, Catapano AL.
Vasc Health Risk Manag. 2005;1(2):119-29. (REVIEW)
PMID 17315398
 
Prostacyclin synthase and arachidonate 5-lipoxygenase polymorphisms and risk of colorectal polyps.
Poole EM, Bigler J, Whitton J, Sibert JG, Potter JD, Ulrich CM.
Cancer Epidemiol Biomarkers Prev. 2006 Mar;15(3):502-8.
PMID 16537708
 
Identification of copy number gain and overexpressed genes on chromosome arm 20q by an integrative genomic approach in cervical cancer: potential role in progression.
Scotto L, Narayan G, Nandula SV, Arias-Pulido H, Subramaniyam S, Schneider A, Kaufmann AM, Wright JD, Pothuri B, Mansukhani M, Murty VV.
Genes Chromosomes Cancer. 2008 Sep;47(9):755-65.
PMID 18506748
 
Genetic and epigenetic regulation of the human prostacyclin synthase promoter in lung cancer cell lines.
Stearman RS, Grady MC, Nana-Sinkam P, Varella-Garcia M, Geraci MW.
Mol Cancer Res. 2007 Mar;5(3):295-308.
PMID 17374734
 
Organization of the gene encoding human prostacyclin synthase.
Wang LH, Chen L.
Biochem Biophys Res Commun. 1996 Sep 24;226(3):631-7.
PMID 8831668
 
Human gene encoding prostacyclin synthase (PTGIS): genomic organization, chromosomal localization, and promoter activity.
Yokoyama C, Yabuki T, Inoue H, Tone Y, Hara S, Hatae T, Nagata M, Takahashi EI, Tanabe T.
Genomics. 1996 Sep 1;36(2):296-304.
PMID 8812456
 

Citation

This paper should be referenced as such :
Cebola, I ; Peinado, MA
PTGIS (prostaglandin I2 (prostacyclin) synthase)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(4):416-420.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PTGISID44219ch20q13.html


External links

Nomenclature
HGNC (Hugo)PTGIS   9603
Cards
AtlasPTGISID44219ch20q13
Entrez_Gene (NCBI)PTGIS  5740  prostaglandin I2 synthase
AliasesCYP8; CYP8A1; PGIS; PTGI
GeneCards (Weizmann)PTGIS
Ensembl hg19 (Hinxton)ENSG00000124212 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000124212 [Gene_View]  chr20:49503874-49568170 [Contig_View]  PTGIS [Vega]
ICGC DataPortalENSG00000124212
TCGA cBioPortalPTGIS
AceView (NCBI)PTGIS
Genatlas (Paris)PTGIS
WikiGenes5740
SOURCE (Princeton)PTGIS
Genetics Home Reference (NIH)PTGIS
Genomic and cartography
GoldenPath hg38 (UCSC)PTGIS  -     chr20:49503874-49568170 -  20q13.13   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PTGIS  -     20q13.13   [Description]    (hg19-Feb_2009)
EnsemblPTGIS - 20q13.13 [CytoView hg19]  PTGIS - 20q13.13 [CytoView hg38]
Mapping of homologs : NCBIPTGIS [Mapview hg19]  PTGIS [Mapview hg38]
OMIM145500   601699   
Gene and transcription
Genbank (Entrez)AF297048 AF297049 AF297050 AF297051 AF297052
RefSeq transcript (Entrez)NM_000961
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)PTGIS
Cluster EST : UnigeneHs.302085 [ NCBI ]
CGAP (NCI)Hs.302085
Alternative Splicing GalleryENSG00000124212
Gene ExpressionPTGIS [ NCBI-GEO ]   PTGIS [ EBI - ARRAY_EXPRESS ]   PTGIS [ SEEK ]   PTGIS [ MEM ]
Gene Expression Viewer (FireBrowse)PTGIS [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5740
GTEX Portal (Tissue expression)PTGIS
Human Protein AtlasENSG00000124212-PTGIS [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ16647   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ16647  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ16647
Splice isoforms : SwissVarQ16647
PhosPhoSitePlusQ16647
Domains : Interpro (EBI)Cyt_P450    Cyt_P450_CYP7A1-type    Cyt_P450_E_grp-IV    PTGIS   
Domain families : Pfam (Sanger)p450 (PF00067)   
Domain families : Pfam (NCBI)pfam00067   
Conserved Domain (NCBI)PTGIS
DMDM Disease mutations5740
Blocks (Seattle)PTGIS
PDB (SRS)2IAG    3B6H   
PDB (PDBSum)2IAG    3B6H   
PDB (IMB)2IAG    3B6H   
PDB (RSDB)2IAG    3B6H   
Structural Biology KnowledgeBase2IAG    3B6H   
SCOP (Structural Classification of Proteins)2IAG    3B6H   
CATH (Classification of proteins structures)2IAG    3B6H   
SuperfamilyQ16647
Human Protein Atlas [tissue]ENSG00000124212-PTGIS [tissue]
Peptide AtlasQ16647
HPRD09046
IPIIPI00003411   
Protein Interaction databases
DIP (DOE-UCLA)Q16647
IntAct (EBI)Q16647
FunCoupENSG00000124212
BioGRIDPTGIS
STRING (EMBL)PTGIS
ZODIACPTGIS
Ontologies - Pathways
QuickGOQ16647
Ontology : AmiGOprostaglandin biosynthetic process  monooxygenase activity  iron ion binding  protein binding  extracellular space  nucleus  endoplasmic reticulum  endoplasmic reticulum membrane  caveola  icosanoid metabolic process  embryo implantation  prostaglandin-I synthase activity  prostaglandin-I synthase activity  integral component of membrane  oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen  cyclooxygenase pathway  heme binding  negative regulation of NF-kappaB transcription factor activity  NAD biosynthesis via nicotinamide riboside salvage pathway  positive regulation of peroxisome proliferator activated receptor signaling pathway  negative regulation of nitric oxide biosynthetic process  positive regulation of angiogenesis  decidualization  negative regulation of inflammatory response  oxidation-reduction process  cellular response to interleukin-1  cellular response to interleukin-6  cellular response to hypoxia  apoptotic signaling pathway  positive regulation of execution phase of apoptosis  
Ontology : EGO-EBIprostaglandin biosynthetic process  monooxygenase activity  iron ion binding  protein binding  extracellular space  nucleus  endoplasmic reticulum  endoplasmic reticulum membrane  caveola  icosanoid metabolic process  embryo implantation  prostaglandin-I synthase activity  prostaglandin-I synthase activity  integral component of membrane  oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen  cyclooxygenase pathway  heme binding  negative regulation of NF-kappaB transcription factor activity  NAD biosynthesis via nicotinamide riboside salvage pathway  positive regulation of peroxisome proliferator activated receptor signaling pathway  negative regulation of nitric oxide biosynthetic process  positive regulation of angiogenesis  decidualization  negative regulation of inflammatory response  oxidation-reduction process  cellular response to interleukin-1  cellular response to interleukin-6  cellular response to hypoxia  apoptotic signaling pathway  positive regulation of execution phase of apoptosis  
Pathways : BIOCARTAEicosanoid Metabolism [Genes]   
Pathways : KEGGArachidonic acid metabolism   
REACTOMEQ16647 [protein]
REACTOME PathwaysR-HSA-2162123 [pathway]   
NDEx NetworkPTGIS
Atlas of Cancer Signalling NetworkPTGIS
Wikipedia pathwaysPTGIS
Orthology - Evolution
OrthoDB5740
GeneTree (enSembl)ENSG00000124212
Phylogenetic Trees/Animal Genes : TreeFamPTGIS
HOVERGENQ16647
HOGENOMQ16647
Homologs : HomoloGenePTGIS
Homology/Alignments : Family Browser (UCSC)PTGIS
Gene fusions - Rearrangements
Fusion : MitelmanPMEPA1/PTGIS [20q13.31/20q13.13]  [t(20;20)(q13;q13)]  
Fusion : MitelmanRIMS2/PTGIS [8q22.3/20q13.13]  [t(8;20)(q22;q13)]  
Fusion: TCGA_MDACCPMEPA1 20q13.31 PTGIS 20q13.13 BRCA
Fusion: TCGA_MDACCRIMS2 8q22.3 PTGIS 20q13.13 BRCA
Tumor Fusion PortalPTGIS
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPTGIS [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PTGIS
dbVarPTGIS
ClinVarPTGIS
1000_GenomesPTGIS 
Exome Variant ServerPTGIS
ExAC (Exome Aggregation Consortium)ENSG00000124212
GNOMAD BrowserENSG00000124212
Genetic variants : HAPMAP5740
Genomic Variants (DGV)PTGIS [DGVbeta]
DECIPHERPTGIS [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPTGIS 
Mutations
ICGC Data PortalPTGIS 
TCGA Data PortalPTGIS 
Broad Tumor PortalPTGIS
OASIS PortalPTGIS [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPTGIS  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPTGIS
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
BioMutasearch PTGIS
DgiDB (Drug Gene Interaction Database)PTGIS
DoCM (Curated mutations)PTGIS (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PTGIS (select a term)
intoGenPTGIS
NCG5 (London)PTGIS
Cancer3DPTGIS(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM145500    601699   
Orphanet
DisGeNETPTGIS
MedgenPTGIS
Genetic Testing Registry PTGIS
NextProtQ16647 [Medical]
TSGene5740
GENETestsPTGIS
Target ValidationPTGIS
Huge Navigator PTGIS [HugePedia]
snp3D : Map Gene to Disease5740
BioCentury BCIQPTGIS
ClinGenPTGIS
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5740
Chemical/Pharm GKB GenePA292
Clinical trialPTGIS
Miscellaneous
canSAR (ICR)PTGIS (select the gene name)
Probes
Litterature
PubMed82 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePTGIS
EVEXPTGIS
GoPubMedPTGIS
iHOPPTGIS
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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