PTGIS (prostaglandin I2 (prostacyclin) synthase)

2009-05-01   Inês Cebola , Miguel A Peinado 

Institute of Predictive, Personalized Medicine of Cancer (IMPPC), Badalona, Barcelona, Spain

Identity

HGNC
LOCATION
20q13.13
IMAGE
Atlas Image
LEGEND
Map of 20q13 chromosomal region.
LOCUSID
ALIAS
CYP8,CYP8A1,PGIS,PTGI
FUSION GENES

DNA/RNA

Atlas Image
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.

Proteins

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.
Atlas Image
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

Entity name
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 name
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 name
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 name
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 name
Cerebral infarction
Disease
Association between cerebral infarction and the PTGIS promoter VNTR alleles with less repeats.
Entity name
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

Pubmed IDLast YearTitleAuthors
192762902009Common polymorphisms in the prostaglandin pathway genes and their association with breast cancer susceptibility and survival.Abraham JE et al
117800522001The DNA sequence and comparative analysis of human chromosome 20.Deloukas P et al
160071282005Hypermethylation of the prostacyclin synthase (PTGIS) promoter is a frequent event in colorectal cancer and associated with aneuploidy.Frigola J et al
80510721994Isolation and molecular cloning of prostacyclin synthase from bovine endothelial cells.Hara S et al
105779961999Human prostacyclin synthase gene and hypertension : the Suita Study.Iwai N et al
81856321994Molecular cloning and expression of human prostacyclin synthase.Miyata A et al
123724042002Splicing mutation of the prostacyclin synthase gene in a family associated with hypertension.Nakayama T et al
151364672004Prostacyclin in human non-small cell lung cancers.Nana-Sinkam P et al
160065892005Prostacyclin signaling in the kidney: implications for health and disease.Nasrallah R et al
173153982005Molecular mechanisms responsible for the antiinflammatory and protective effect of HDL on the endothelium.Norata GD et al
165377082006Prostacyclin synthase and arachidonate 5-lipoxygenase polymorphisms and risk of colorectal polyps.Poole EM et al
185067482008Identification 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 et al
173747342007Genetic and epigenetic regulation of the human prostacyclin synthase promoter in lung cancer cell lines.Stearman RS et al
88316681996Organization of the gene encoding human prostacyclin synthase.Wang LH et al
88124561996Human gene encoding prostacyclin synthase (PTGIS): genomic organization, chromosomal localization, and promoter activity.Yokoyama C et al

Other Information

Locus ID:

NCBI: 5740
MIM: 601699
HGNC: 9603
Ensembl: ENSG00000124212

Variants:

dbSNP: 5740
ClinVar: 5740
TCGA: ENSG00000124212
COSMIC: PTGIS

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000124212ENST00000244043Q16647

Expression (GTEx)

0
50
100
150
200
250
300

Pathways

PathwaySourceExternal ID
Arachidonic acid metabolismKEGGko00590
Arachidonic acid metabolismKEGGhsa00590
Metabolic pathwaysKEGGhsa01100
MetabolismREACTOMER-HSA-1430728
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Bile acid and bile salt metabolismREACTOMER-HSA-194068
Synthesis of bile acids and bile saltsREACTOMER-HSA-192105
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterolREACTOMER-HSA-193368
Synthesis of bile acids and bile salts via 24-hydroxycholesterolREACTOMER-HSA-193775
Synthesis of bile acids and bile salts via 27-hydroxycholesterolREACTOMER-HSA-193807
Arachidonic acid metabolismREACTOMER-HSA-2142753
Synthesis of Prostaglandins (PG) and Thromboxanes (TX)REACTOMER-HSA-2162123
Metabolism of vitamins and cofactorsREACTOMER-HSA-196854
Metabolism of water-soluble vitamins and cofactorsREACTOMER-HSA-196849
Nicotinate metabolismREACTOMER-HSA-196807
Nicotinamide salvagingREACTOMER-HSA-197264
Biological oxidationsREACTOMER-HSA-211859
Phase 1 - Functionalization of compoundsREACTOMER-HSA-211945
Cytochrome P450 - arranged by substrate typeREACTOMER-HSA-211897
Endogenous sterolsREACTOMER-HSA-211976
Sterols are 12-hydroxylated by CYP8B1REACTOMER-HSA-211994
EicosanoidsREACTOMER-HSA-211979

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA166155905rs5629VariantVipGeneassociated17070428, 12040339
PA443670Cerebral InfarctionDiseaseVipGeneassociated
PA444552HypertensionDiseaseVipGeneassociated
PA445019Myocardial InfarctionDiseaseVipGeneassociated

References

Pubmed IDYearTitleCitations
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
192762902009Common polymorphisms in the prostaglandin pathway genes and their association with breast cancer susceptibility and survival.23
197891902009A gene-based risk score for lung cancer susceptibility in smokers and ex-smokers.23
204530002010A Large-scale genetic association study of esophageal adenocarcinoma risk.23
190467482009Variation in eicosanoid genes, non-fatal myocardial infarction and ischemic stroke.22
190467482009Variation in eicosanoid genes, non-fatal myocardial infarction and ischemic stroke.22
191245062009Common genetic variation in candidate genes and susceptibility to subtypes of breast cancer.22
191475282009Haplotype analysis of the CYP8A1 gene associated with myocardial infarction.22
191475282009Haplotype analysis of the CYP8A1 gene associated with myocardial infarction.22
203463602010Genetic risk factors for hepatopulmonary syndrome in patients with advanced liver disease.21

Citation

Inês Cebola ; Miguel A Peinado

PTGIS (prostaglandin I2 (prostacyclin) synthase)

Atlas Genet Cytogenet Oncol Haematol. 2009-05-01

Online version: http://atlasgeneticsoncology.org/gene/44219/ptgis