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EPAS1 (Endothelial PAS Domain Protein 1)

Identity

Other namesECYT4
HIF2A
HLF
MOP2
PASD2
bHLHe73
HGNC (Hugo) EPAS1
LocusID (NCBI) 2034
Location 2p21
Location_base_pair Starts at 46524541 and ends at 46613842 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order RPL26P15 - RPL36AP14 - uncharacterized LOC101926974 - EPAS1 - uncharacterized LOC101805491 - TMEM247 - ATP6V1E2.

DNA/RNA

Description Genomic size: Starts at 46524541 and ends at 46613842.
Transcription Transcript length: The gene is comprised of 16 exons, constituting one main transcript of 5184 base pairs.
Pseudogene None described.

Protein

 
  Representation of the EPAS1/HIF2A protein with its specific domains specified. Critical hydroxylation sites are indicated.
Description The HIF-2α protein is 870 amino acids long and consists of a basic-helix-loop-helix domain, two PER-ARNT-SIM domains (A and B), an oxygen-dependent degradation domain (ODDD) and two transcriptional-activation domains (N-TAD and C-TAD). Two proline residues (P405 in ODDD and P531 in N-TAD) and an asparaginyl residue (N847 in C-TAD) are subjected to hydroxylation during physiologic oxygen tensions, regulating the stability and activity of the HIF-2α protein. Phosphorylation of HIF-2α at T844 has been reported as necessary for its transcriptional activation function (Gradin et al., 2002).
Expression In adult human tissue, HIF-2α protein is mainly expressed in cells experiencing low oxygen levels, and the HIF-2α mRNA has been shown to be predominantly expressed in highly vascularized tissues (Tian et al., 1997). During human embryonic and fetal development, HIF-2α is transiently but specifically expressed in cells of the developing sympathetic nervous system (SNS) (Nilsson et al., 2005; Mohlin et al., 2013). In embryonic and adult mouse tissue, the expression of HIF-2α mRNA is more or less restricted to endothelial cells (Tian et al., 1997; Jain et al., 1998). In a zebrafish model, the HIF-2α transcript is expressed early in brain tissue and blood vessels, and later on HIF-2α replaces HIF-1α transcription in the notochord (Rojas et al., 2007).
Localisation HIF-2α is part of a transcriptional complex and is hence localized mainly in the nucleus upon hypoxic induction. However, HIF-2α protein can also be detected in the cytoplasm, at hypoxic conditions and foremost at more physiological oxygen conditions, as demonstrated in cultured cells in vitro and in tumor specimens in vivo (Holmquist-Mengelbier et al., 2006). These findings were recently strengthened by the demonstration of a role for HIF-2α as part of an oxygen-regulated translation initiation complex and presence of HIF-2α in the cellular polysome fraction (Uniacke et al., 2012).
Function At lower oxygen tensions, the hydroxylation of HIF-2α by prolyl hydroxylases (PHDs) and Factor Inhibiting HIF (FIH) is prevented, and the HIF-2α subunit relocates to the nucleus where it forms a transcriptional complex together with its binding partner ARNT (also known as HIF-1β) and co-factors such as p300 and CBP. By binding to hypoxia response elements (HREs) in the promoter of target genes, the HIF complex initiates transcription of numerous genes involved in a variety of tumorigenic cellular processes, including angiogenesis, invasion and metastasis, growth, dedifferentiation, and apoptosis (Semenza, 2003). As mentioned under the Localization section, HIF-2α has also been demonstrated to be part of a hypoxia-regulated translation initiation complex. Hypoxia induces HIF-2α to form a complex together with RNA-binding protein RBM4 and cap-binding eIF4E2, and this complex is then recruited to a wide variety of mRNAs, promoting active translation at polysomes (Uniacke et al., 2012). In a recent report, HIF-2α was further shown to protect human hematopoietic stem/progenitor cells from endoplasmic reticulum (ER) stress-induced apoptosis and to enhance the long-term repopulating ability of these cells (Rouault-Pierre et al., 2013).
Homology HIF-2α is part of the basic helix-loop-helix-PAS family of proteins and is structurally related to the HIF-1α and HIF-3α subunits. While HIF-3α is believed to negatively regulate the other two alpha subunits (Makino et al., 2001; Maynard et al., 2007), HIF-1α and HIF-2α share both sequence similarity and target genes. However, despite 48% primary amino acid sequence homology between HIF-1α and HIF-2α (Tian et al., 1997), it is becoming increasingly evident that these two proteins also function at distinct sites and during differential cellular conditions.

Mutations

Germinal Functional mutations in human EPAS1 are associated with variations in hemoglobin and red blood cell concentration (Percy et al., 2008b; Beall et al., 2010; Yi et al., 2010). Percy et al. described a gain of function mutation in a family with high hemoglobin concentrations and erythrocytosis (Percy et al., 2008b). Similar mutations, all associated with small amino acid substitutions leading to protein stabilization, have been reported in other clinical cases (Gale et al., 2008; Martini et al., 2008; Percy et al., 2008a; van Wijk et al., 2010). In contrast, EPAS1 mutations associated with a loss of function and low hemoglobin concentrations have been described in healthy individuals living at high altitudes. Extensive analysis of genome-wide sequence variations and exome sequencing in Tibetans have shown that EPAS1 is a key gene mutated in Tibetan populations (Beall et al., 2010; Simonson et al., 2010; Yi et al., 2010; Peng et al., 2011). The functional consequence of EPAS1 SNPs associated with low hemoglobin concentrations is described as adaptation to low oxygen without elevated red blood cell production, thereby avoiding high blood viscosity creating cardiovascular risks.
Somatic Several studies have recently identified the first mutations in any of the HIF alpha subunits in cancer. Somatic gain-of-function mutations in exon 12 of the EPAS1 gene in two patients with paraganglioma and associated erythrocytosis results in an amino acid substitution in proximity to the PHD hydroxylation site and increased protein half-life and HIF-2α activity (Zhuang et al., 2012). Additional mutations in EPAS1 have also been identified in patients with paraganglioma and pheochromocytoma without associated erythrocytosis (Comino-Mendez et al., 2013), and in patients with somatostatinoma and paraganglioma (Yang et al., 2013).

Implicated in

Entity Renal clear cell carcinoma
Note The predominant loss of von Hippel Lindau in clear cell renal cell carcinoma (ccRCC), results in defective targeting of HIF-α proteins for degradation at normoxia (Gnarra et al., 1994). Therefore, both HIF-1α and HIF-2α accumulate irrespective of oxygen levels in VHL-defective cells and are abundantly expressed in cells of ccRCC origin (Krieg et al., 2000). For unknown reasons, the expression of HIF-2α is more prominent than that of HIF-1α in RCC cell lines and tumors and HIF-1α expression is often lost in RCC cell lines (Maxwell et al., 1999; Krieg et al., 2000). Regulation of HIF target genes in RCC cell lines are more dependent on HIF-2α than on HIF-1α and silencing of HIF-2α in VHL-deficient cells suppress tumor growth, suggesting an important role for HIF-2α in renal carcinoma (Kondo et al., 2003; Carroll et al., 2006).
  
Entity Paraganglioma/pheochromocytoma
Note Paraganglioma and pheochromocytoma derive from the chromaffin cell lineage of the sympathetic nervous system, and notably, genes involved in the hypoxic response (e.g. VHL and SDH genes) are frequently mutated in these tumors (Neumann et al., 2002). Recently, somatic mutations in the EPAS1 gene itself were discovered in two paraganglioma patients, describing the first cases of EPAS1 mutations in any cancer type (Zhuang et al., 2012). These gain-of-function mutations lead to increased protein half-life and HIF-2α activity, in turn resulting in up-regulation of HIF-2α downstream target genes, presumably explaining the clinical presentation in these patients. In a follow-up study, two additional EPAS1 mutations were discovered in patients presenting with polycythemia and somatostatinoma or paraganglioma (Yang et al., 2013). These novel mutations lead to disruption of the ODD domain-PHD2 interaction and thereby result in less ubiquitination and higher activity of the HIF-2α protein. In another study, 7 out of 41 examined patients with pheochromocytoma or paraganglioma presented with somatic EPAS1 mutations, and interestingly, three of these cases were also accompanied by an exclusive gain of chromosome 2p (Comino-Mendez et al., 2013).
  
Entity Neuroblastoma
Note In the childhood tumor neuroblastoma, HIF-2α positive tumor cells have been identified in a perivascular niche, suggesting a non-hypoxic driven expression (Pietras et al., 2008). The HIF-2α positive cells display an immature tumor stem cell-like phenotype and their presence in neuroblastoma specimens correlate to poor overall survival (Holmquist-Mengelbier et al., 2006; Noguera et al., 2009). In neuroblastoma cell lines, HIF-2α is expressed at hypoxic conditions (1% oxygen) and at near end-capillary physiological oxygen levels (5% oxygen) (Jogi et al., 2002; Holmquist-Mengelbier et al., 2006). At prolonged hypoxic conditions, HIF-2α is continuously expressed in contrast to its homologue HIF-1α. In addition, overexpression of HIF-2α in a mouse neuroblastoma cell line promoted in vivo tumor angiogenesis, while mutant HIF-2α cells formed tumors that were highly necrotic (Favier et al., 2007).
  
Entity Glioma
Note Knockdown of HIF-2α expression can reduce vascularization but accelerate tumor growth of human glioblastoma cells pointing to a role for HIF-2α as a tumor suppressor in glioblastoma (Acker et al., 2005). In contrast, recent work has focused on HIF-2α as a putative glioblastoma cancer stem cell (CSC) marker. Specifically, HIF-2α protein expression co-localizes with CD133 in a fraction of tumor cells (McCord et al., 2009) and with cancer stem cell markers in glioma specimens (Li et al., 2009). Glioblastoma putative CSCs respond to hypoxia by induction of HIF2-α (Li et al., 2009; Seidel et al., 2010), and inhibiting HIF2-α in glioblastoma CSCs decreases self-renewal, proliferation and survival in vitro and tumor-initiating capacity in vivo (Li et al., 2009). In addition, elevated HIF2A mRNA levels are associated with poor prognosis in glioma patients (Li et al., 2009).
  
Entity Breast cancer
Note HIF-2α is expressed and associates with high vascular density, high c-erbB-2 expression and extensive nodal metastasis in breast cancer (Giatromanolaki et al., 2006). In a slightly larger study, HIF-2α was associated with ABCG2 expression, histology grade and Ki67 expression in invasive ductal carcinoma (Xiang et al., 2012). Importantly, in two separate breast cancer cohorts, HIF-2α correlate to reduced recurrence-free survival, breast-cancer specific survival and presence of distal metastasis (Helczynska et al., 2008).
  
Entity Acute myeloid leukemia
Note Knockdown of HIF-2α in CD34+ acute myeloid leukemia (AML) cells reduce engraftment ability in irradiated mice (Rouault-Pierre et al., 2013). The HIF-2α deficient cells are more susceptible to apoptosis as a result of increased ROS and ER-induced stress indicating that HIF-2α is important for AML cell survival.
  
Entity Other tumor types
Note Expression of the HIF-2α protein has also been reported in other solid tumor types including colorectal cancer (Yoshimura et al., 2004), prostate cancer (Boddy et al., 2005), non-small cell lung cancer (Giatromanolaki et al., 2001), squamous cell head-and-neck cancer (Koukourakis et al., 2002), nodular malignant melanoma (Giatromanolaki et al., 2003) and endometrial adenocarcinoma (Sivridis et al., 2002).
  
Entity Inflammation
Note Sites of inflammation are often hypoxic due to vascular damage and large infiltration of cells. In order to operate under this condition, cells of the innate immunity adapt by expressing the HIF proteins (Fang et al., 2009; Imtiyaz and Simon, 2010). HIF-2α has been directly coupled to the regulation of proinflammatory cytokine expression in activated macrophages (Fang et al., 2009; Imtiyaz et al., 2010). Furthermore, HIF-2α has been detected in bone marrow-derived macropahges (BMDMs) and tumor associated macrophages (TAMs) of various human cancers (Talks et al., 2000). Importantly, HIF-2α is essential for TAM migration into tumor lesions (Imtiyaz et al., 2010), which in turn will promote progression and metastasis of tumor cells (Pollard, 2004).
Disease Erythrocytosis, see section on germinal mutations.
  
Entity Development
Note The four available HIF2A knockout mice display substantial differences in phenotype, presumably due to strain background. The first knockout mouse was created on a 129/SvJ background, and resulted in embryonic lethality due to circulatory failure during midgestation (Tian et al., 1997). Two of the following knockout studies demonstrated a role for HIF-2α in vascular development. HIF2A deficient embryos from an ICR/129Sv background die in utero and display severe post-vasculogenic defects (Peng et al., 2000), while HIF2A deficient mice on 129/Sv x Swiss background display lowered VEGF levels (Compernolle et al., 2002). The latter mice are embryonically lethal due to respiratory distress syndrome and cardiac failure (Compernolle et al., 2002). HIF-2α is also important in normal hematopoiesis, as demonstrated by creating adult HIF2A knockout mice by crossing of heterozygous 129S6/SvEvTac EPAS1 and heterozygous C57BL/6J EPAS1 knockout mice (Scortegagna et al., 2003b). These adult HIF2A deficient mice suffer from cardiac hypertrophy, hepatomegaly, oxidative stress and pancytopenia (Scortegagna et al., 2003a). In summary, HIF2A knockout studies demonstrate important roles for HIF-2α in catecholamine synthesis, reactive oxygen species (ROS) homeostasis and vascular remodeling during development.
  

External links

Nomenclature
HGNC (Hugo)EPAS1   3374
Cards
AtlasEPAS1ID44088ch2p21
Entrez_Gene (NCBI)EPAS1  2034  endothelial PAS domain protein 1
GeneCards (Weizmann)EPAS1
Ensembl (Hinxton)ENSG00000116016 [Gene_View]  chr2:46524541-46613842 [Contig_View]  EPAS1 [Vega]
ICGC DataPortalENSG00000116016
cBioPortalEPAS1
AceView (NCBI)EPAS1
Genatlas (Paris)EPAS1
WikiGenes2034
SOURCE (Princeton)NM_001430
Genomic and cartography
GoldenPath (UCSC)EPAS1  -  2p21   chr2:46524541-46613842 +  2p21-p16   [Description]    (hg19-Feb_2009)
EnsemblEPAS1 - 2p21-p16 [CytoView]
Mapping of homologs : NCBIEPAS1 [Mapview]
OMIM603349   611783   
Gene and transcription
Genbank (Entrez)AF052094 AK123845 BC015869 BC051338 BM671511
RefSeq transcript (Entrez)NM_001430
RefSeq genomic (Entrez)AC_000134 NC_000002 NC_018913 NG_016000 NT_022184 NW_001838769 NW_004929300
Consensus coding sequences : CCDS (NCBI)EPAS1
Cluster EST : UnigeneHs.468410 [ NCBI ]
CGAP (NCI)Hs.468410
Alternative Splicing : Fast-db (Paris)GSHG0016433
Alternative Splicing GalleryENSG00000116016
Gene ExpressionEPAS1 [ NCBI-GEO ]     EPAS1 [ SEEK ]   EPAS1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ99814 (Uniprot)
NextProtQ99814  [Medical]
With graphics : InterProQ99814
Splice isoforms : SwissVarQ99814 (Swissvar)
Domaine pattern : Prosite (Expaxy)BHLH (PS50888)    PAS (PS50112)   
Domains : Interpro (EBI)bHLH_dom [organisation]   HIF-1_TAD_C [organisation]   HIF_alpha_subunit [organisation]   Nuc_translocat [organisation]   PAC [organisation]   PAS [organisation]   PAS_fold [organisation]  
Related proteins : CluSTrQ99814
Domain families : Pfam (Sanger)HIF-1 (PF11413)    HIF-1a_CTAD (PF08778)    PAS (PF00989)   
Domain families : Pfam (NCBI)pfam11413    pfam08778    pfam00989   
Domain families : Smart (EMBL)HLH (SM00353)  PAC (SM00086)  PAS (SM00091)  
DMDM Disease mutations2034
Blocks (Seattle)Q99814
PDB (SRS)1P97    2A24    3F1N    3F1O    3F1P    3H7W    3H82    4GHI    4GS9   
PDB (PDBSum)1P97    2A24    3F1N    3F1O    3F1P    3H7W    3H82    4GHI    4GS9   
PDB (IMB)1P97    2A24    3F1N    3F1O    3F1P    3H7W    3H82    4GHI    4GS9   
PDB (RSDB)1P97    2A24    3F1N    3F1O    3F1P    3H7W    3H82    4GHI    4GS9   
Human Protein AtlasENSG00000116016 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ99814
HPRD06787
IPIIPI00294084   IPI00917611   
Protein Interaction databases
DIP (DOE-UCLA)Q99814
IntAct (EBI)Q99814
FunCoupENSG00000116016
BioGRIDEPAS1
InParanoidQ99814
Interologous Interaction database Q99814
IntegromeDBEPAS1
STRING (EMBL)EPAS1
Ontologies - Pathways
Ontology : AmiGORNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription  angiogenesis  response to hypoxia  embryonic placenta development  blood vessel remodeling  regulation of heart rate  DNA binding  signal transducer activity  protein binding  nucleoplasm  transcription factor complex  transcription factor complex  cytosol  transcription from RNA polymerase II promoter  mitochondrion organization  signal transduction  visual perception  transcription factor binding  erythrocyte differentiation  lung development  histone acetyltransferase binding  norepinephrine metabolic process  surfactant homeostasis  sequence-specific DNA binding  regulation of transcription from RNA polymerase II promoter in response to oxidative stress  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  protein heterodimerization activity  cell maturation  myoblast fate commitment  regulation of transcription from RNA polymerase II promoter in response to hypoxia  cellular response to hypoxia  cellular response to hypoxia  
Ontology : EGO-EBIRNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription  angiogenesis  response to hypoxia  embryonic placenta development  blood vessel remodeling  regulation of heart rate  DNA binding  signal transducer activity  protein binding  nucleoplasm  transcription factor complex  transcription factor complex  cytosol  transcription from RNA polymerase II promoter  mitochondrion organization  signal transduction  visual perception  transcription factor binding  erythrocyte differentiation  lung development  histone acetyltransferase binding  norepinephrine metabolic process  surfactant homeostasis  sequence-specific DNA binding  regulation of transcription from RNA polymerase II promoter in response to oxidative stress  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  protein heterodimerization activity  cell maturation  myoblast fate commitment  regulation of transcription from RNA polymerase II promoter in response to hypoxia  cellular response to hypoxia  cellular response to hypoxia  
Pathways : KEGGPathways in cancer    Renal cell carcinoma   
Protein Interaction DatabaseEPAS1
Wikipedia pathwaysEPAS1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)EPAS1
snp3D : Map Gene to Disease2034
SNP (GeneSNP Utah)EPAS1
SNP : HGBaseEPAS1
Genetic variants : HAPMAPEPAS1
Exome VariantEPAS1
1000_GenomesEPAS1 
ICGC programENSG00000116016 
Somatic Mutations in Cancer : COSMICEPAS1 
CONAN: Copy Number AnalysisEPAS1 
Mutations and Diseases : HGMDEPAS1
Genomic VariantsEPAS1  EPAS1 [DGVbeta]
dbVarEPAS1
ClinVarEPAS1
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM603349    611783   
MedgenEPAS1
GENETestsEPAS1
Disease Genetic AssociationEPAS1
Huge Navigator EPAS1 [HugePedia]  EPAS1 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneEPAS1
Homology/Alignments : Family Browser (UCSC)EPAS1
Phylogenetic Trees/Animal Genes : TreeFamEPAS1
Chemical/Protein Interactions : CTD2034
Chemical/Pharm GKB GenePA27809
Clinical trialEPAS1
Cancer Resource (Charite)ENSG00000116016
Other databases
Probes
Litterature
PubMed286 Pubmed reference(s) in Entrez
CoreMineEPAS1
iHOPEPAS1
OncoSearchEPAS1

Bibliography

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PMID 7915601
 
Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells.
Tian H, McKnight SL, Russell DW.
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Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression.
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Nature. 2001 Nov 29;414(6863):550-4.
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Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice.
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Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype.
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Germ-line mutations in nonsyndromic pheochromocytoma.
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Hypoxia-inducible factors 1alpha and 2alpha are related to vascular endothelial growth factor expression and a poorer prognosis in nodular malignant melanomas of the skin.
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Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice.
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Written12-2013Sofie Mohlin, Arash Hamidian, Daniel Bexell, Sven Påhlman, Caroline Wigerup
Lund University, Center for Translational Cancer Research, Department of Laboratory Medicine, Medicon Village, Building 404, C3, SE-223 81 Lund, Sweden

Citation

This paper should be referenced as such :
Mohlin S, Hamidian A, Bexell D, Påhlman S, Wigerup C
EPAS1 (Endothelial PAS Domain Protein 1);
Atlas Genet Cytogenet Oncol Haematol. December 2013
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/EPAS1ID44088ch2p21.html

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