Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

EPAS1 (Endothelial PAS Domain Protein 1)

Written2013-12Sofie Mohlin, Arash Hamidian, Daniel Bexell, Sven Pœhlman, Caroline Wigerup
Lund University, Center for Translational Cancer Research, Department of Laboratory Medicine, Medicon Village, Building 404, C3, SE-223 81 Lund, Sweden

(Note : for Links provided by Atlas : click)


Other aliasECYT4
LocusID (NCBI) 2034
Atlas_Id 44088
Location 2p21  [Link to chromosome band 2p21]
Location_base_pair Starts at and ends at bp from pter
Local_order RPL26P15 - RPL36AP14 - uncharacterized LOC101926974 - EPAS1 - uncharacterized LOC101805491 - TMEM247 - ATP6V1E2.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CYR61 (1p22.3) / EPAS1 (2p21)EPAS1 (2p21) / AFF3 (2q11.2)EPAS1 (2p21) / EPAS1 (2p21)
EPAS1 (2p21) / HNRNPA2B1 (7p15.2)EPAS1 (2p21) / PLP1 (Xq22.2)EPAS1 (2p21) / SLC43A2 (17p13.3)
EPAS1 (2p21) / SMARCD3 (7q36.1)EPAS1 (2p21) / TCF7L1 (2p11.2)FAM46A (6q14.1) / EPAS1 (2p21)
HLA-H (6p22.1) / EPAS1 (2p21)PAPPA (9q33.1) / EPAS1 (2p21)TCF7L1 (2p11.2) / EPAS1 (2p21)


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.


  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.


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.


Genetic evidence for a tumor suppressor role of HIF-2alpha.
Acker T, Diez-Juan A, Aragones J, Tjwa M, Brusselmans K, Moons L, Fukumura D, Moreno-Murciano MP, Herbert JM, Burger A, Riedel J, Elvert G, Flamme I, Maxwell PH, Collen D, Dewerchin M, Jain RK, Plate KH, Carmeliet P.
Cancer Cell. 2005 Aug;8(2):131-41.
PMID 16098466
Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders.
Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y, Knight J, Li C, Li JC, Liang Y, McCormack M, Montgomery HE, Pan H, Robbins PA, Shianna KV, Tam SC, Tsering N, Veeramah KR, Wang W, Wangdui P, Weale ME, Xu Y, Xu Z, Yang L, Zaman MJ, Zeng C, Zhang L, Zhang X, Zhaxi P, Zheng YT.
Proc Natl Acad Sci U S A. 2010 Jun 22;107(25):11459-64. doi: 10.1073/pnas.1002443107. Epub 2010 Jun 7.
PMID 20534544
The androgen receptor is significantly associated with vascular endothelial growth factor and hypoxia sensing via hypoxia-inducible factors HIF-1a, HIF-2a, and the prolyl hydroxylases in human prostate cancer.
Boddy JL, Fox SB, Han C, Campo L, Turley H, Kanga S, Malone PR, Harris AL.
Clin Cancer Res. 2005 Nov 1;11(21):7658-63.
PMID 16278385
Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway.
Carroll VA, Ashcroft M.
Cancer Res. 2006 Jun 15;66(12):6264-70.
PMID 16778202
Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis.
Comino-Mendez I, de Cubas AA, Bernal C, Alvarez-Escola C, Sanchez-Malo C, Ramirez-Tortosa CL, Pedrinaci S, Rapizzi E, Ercolino T, Bernini G, Bacca A, Leton R, Pita G, Alonso MR, Leandro-Garcia LJ, Gomez-Grana A, Inglada-Perez L, Mancikova V, Rodriguez-Antona C, Mannelli M, Robledo M, Cascon A.
Hum Mol Genet. 2013 Jun 1;22(11):2169-76. doi: 10.1093/hmg/ddt069. Epub 2013 Feb 14.
PMID 23418310
Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice.
Compernolle V, Brusselmans K, Acker T, Hoet P, Tjwa M, Beck H, Plaisance S, Dor Y, Keshet E, Lupu F, Nemery B, Dewerchin M, Van Veldhoven P, Plate K, Moons L, Collen D, Carmeliet P.
Nat Med. 2002 Jul;8(7):702-10. Epub 2002 Jun 10.
PMID 12053176
Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia.
Fang HY, Hughes R, Murdoch C, Coffelt SB, Biswas SK, Harris AL, Johnson RS, Imityaz HZ, Simon MC, Fredlund E, Greten FR, Rius J, Lewis CE.
Blood. 2009 Jul 23;114(4):844-59. doi: 10.1182/blood-2008-12-195941. Epub 2009 May 19.
PMID 19454749
HIF2 alpha reduces growth rate but promotes angiogenesis in a mouse model of neuroblastoma.
Favier J, Lapointe S, Maliba R, Sirois MG.
BMC Cancer. 2007 Jul 26;7:139.
PMID 17655754
Autosomal dominant erythrocytosis and pulmonary arterial hypertension associated with an activating HIF2 alpha mutation.
Gale DP, Harten SK, Reid CD, Tuddenham EG, Maxwell PH.
Blood. 2008 Aug 1;112(3):919-21. doi: 10.1182/blood-2008-04-153718.
PMID 18650473
Hypoxia-inducible factor-2 alpha (HIF-2 alpha) induces angiogenesis in breast carcinomas.
Giatromanolaki A, Sivridis E, Fiska A, Koukourakis MI.
Appl Immunohistochem Mol Morphol. 2006 Mar;14(1):78-82.
PMID 16540735
Mutations of the VHL tumour suppressor gene in renal carcinoma.
Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, Latif F, Liu S, Chen F, Duh FM, et al.
Nat Genet. 1994 May;7(1):85-90.
PMID 7915601
The transcriptional activation function of the HIF-like factor requires phosphorylation at a conserved threonine.
Gradin K, Takasaki C, Fujii-Kuriyama Y, Sogawa K.
J Biol Chem. 2002 Jun 28;277(26):23508-14. Epub 2002 Apr 30.
PMID 11983697
Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer.
Helczynska K, Larsson AM, Holmquist Mengelbier L, Bridges E, Fredlund E, Borgquist S, Landberg G, Pahlman S, Jirstrom K.
Cancer Res. 2008 Nov 15;68(22):9212-20. doi: 10.1158/0008-5472.CAN-08-1135.
PMID 19010893
Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype.
Holmquist-Mengelbier L1, Fredlund E, Lofstedt T, Noguera R, Navarro S, Nilsson H, Pietras A, Vallon-Christersson J, Borg A, Gradin K, Poellinger L, Pahlman S.
Cancer Cell. 2006 Nov;10(5):413-23.
PMID 17097563
Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation.
Imtiyaz HZ, Williams EP, Hickey MM, Patel SA, Durham AC, Yuan LJ, Hammond R, Gimotty PA, Keith B, Simon MC.
J Clin Invest. 2010 Aug;120(8):2699-714. doi: 10.1172/JCI39506. Epub 2010 Jul 19.
PMID 20644254
Expression of ARNT, ARNT2, HIF1 alpha, HIF2 alpha and Ah receptor mRNAs in the developing mouse.
Jain S, Maltepe E, Lu MM, Simon C, Bradfield CA.
Mech Dev. 1998 Apr;73(1):117-23.
PMID 9545558
Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype.
Jogi A, Ora I, Nilsson H, Lindeheim A, Makino Y, Poellinger L, Axelson H, Pahlman S.
Proc Natl Acad Sci U S A. 2002 May 14;99(10):7021-6.
PMID 12011461
Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth.
Kondo K, Kim WY, Lechpammer M, Kaelin WG Jr.
PLoS Biol. 2003 Dec;1(3):E83. Epub 2003 Dec 22.
PMID 14691554
Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer.
Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos C, Turley H, Talks K, Gatter KC, Harris AL.
Int J Radiat Oncol Biol Phys. 2002 Aug 1;53(5):1192-202.
PMID 12128120
Up-regulation of hypoxia-inducible factors HIF-1alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function.
Krieg M, Haas R, Brauch H, Acker T, Flamme I, Plate KH.
Oncogene. 2000 Nov 16;19(48):5435-43.
PMID 11114720
Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells.
Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, Shi Q, Cao Y, Lathia J, McLendon RE, Hjelmeland AB, Rich JN.
Cancer Cell. 2009 Jun 2;15(6):501-13. doi: 10.1016/j.ccr.2009.03.018.
PMID 19477429
Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression.
Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, Cao Y, Berkenstam A, Poellinger L.
Nature. 2001 Nov 29;414(6863):550-4.
PMID 11734856
A novel heterozygous HIF2AM535I mutation reinforces the role of oxygen sensing pathway disturbances in the pathogenesis of familial erythrocytosis.
Martini M, Teofili L, Cenci T, Giona F, Torti L, Rea M, Foa R, Leone G, Larocca LM.
Haematologica. 2008 Jul;93(7):1068-71. doi: 10.3324/haematol.13210. Epub 2008 May 27.
PMID 18508787
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.
Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ.
Nature. 1999 May 20;399(6733):271-5.
PMID 10353251
Dominant-negative HIF-3 alpha 4 suppresses VHL-null renal cell carcinoma progression.
Maynard MA, Evans AJ, Shi W, Kim WY, Liu FF, Ohh M.
Cell Cycle. 2007 Nov 15;6(22):2810-6. Epub 2007 Aug 29.
PMID 17998805
Physiologic oxygen concentration enhances the stem-like properties of CD133+ human glioblastoma cells in vitro.
McCord AM, Jamal M, Shankavaram UT, Lang FF, Camphausen K, Tofilon PJ.
Mol Cancer Res. 2009 Apr;7(4):489-97. doi: 10.1158/1541-7786.MCR-08-0360.
PMID 19372578
HIF2A and IGF2 expression correlates in human neuroblastoma cells and normal immature sympathetic neuroblasts.
Mohlin S, Hamidian A, Pahlman S.
Neoplasia. 2013 Mar;15(3):328-34.
PMID 23479510
Germ-line mutations in nonsyndromic pheochromocytoma.
Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peczkowska M, Szmigielski C, Eng C; Freiburg-Warsaw-Columbus Pheochromocytoma Study Group.
N Engl J Med. 2002 May 9;346(19):1459-66.
PMID 12000816
HIF-2alpha expression in human fetal paraganglia and neuroblastoma: relation to sympathetic differentiation, glucose deficiency, and hypoxia.
Nilsson H, Jogi A, Beckman S, Harris AL, Poellinger L, Pahlman S.
Exp Cell Res. 2005 Feb 15;303(2):447-56.
PMID 15652356
HIF-1alpha and HIF-2alpha are differentially regulated in vivo in neuroblastoma: high HIF-1alpha correlates negatively to advanced clinical stage and tumor vascularization.
Noguera R, Fredlund E, Piqueras M, Pietras A, Beckman S, Navarro S, Pahlman S.
Clin Cancer Res. 2009 Dec 1;15(23):7130-6. doi: 10.1158/1078-0432.CCR-09-0223. Epub 2009 Nov 10.
PMID 19903792
The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling.
Peng J, Zhang L, Drysdale L, Fong GH.
Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8386-91.
PMID 10880563
Genetic variations in Tibetan populations and high-altitude adaptation at the Himalayas.
Peng Y, Yang Z, Zhang H, Cui C, Qi X, Luo X, Tao X, Wu T, Ouzhuluobu, Basang, Ciwangsangbu, Danzengduojie, Chen H, Shi H, Su B.
Mol Biol Evol. 2011 Feb;28(2):1075-81. doi: 10.1093/molbev/msq290. Epub 2010 Oct 28.
PMID 21030426
Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis.
Percy MJ, Beer PA, Campbell G, Dekker AW, Green AR, Oscier D, Rainey MG, van Wijk R, Wood M, Lappin TR, McMullin MF, Lee FS.
Blood. 2008a Jun 1;111(11):5400-2. doi: 10.1182/blood-2008-02-137703. Epub 2008 Mar 31.
PMID 18378852
A gain-of-function mutation in the HIF2A gene in familial erythrocytosis.
Percy MJ, Furlow PW, Lucas GS, Li X, Lappin TR, McMullin MF, Lee FS.
N Engl J Med. 2008b Jan 10;358(2):162-8. doi: 10.1056/NEJMoa073123.
PMID 18184961
High levels of HIF-2alpha highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche.
Pietras A, Gisselsson D, Ora I, Noguera R, Beckman S, Navarro S, Pahlman S.
J Pathol. 2008 Mar;214(4):482-8. doi: 10.1002/path.2304.
PMID 18189331
Tumour-educated macrophages promote tumour progression and metastasis.
Pollard JW.
Nat Rev Cancer. 2004 Jan;4(1):71-8. (REVIEW)
PMID 14708027
Cloning of hif-1alpha and hif-2alpha and mRNA expression pattern during development in zebrafish.
Rojas DA, Perez-Munizaga DA, Centanin L, Antonelli M, Wappner P, Allende ML, Reyes AE.
Gene Expr Patterns. 2007 Jan;7(3):339-45. Epub 2006 Aug 15.
PMID 16997637
HIF-2α protects human hematopoietic stem/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress.
Rouault-Pierre K, Lopez-Onieva L, Foster K, Anjos-Afonso F, Lamrissi-Garcia I, Serrano-Sanchez M, Mitter R, Ivanovic Z, de Verneuil H, Gribben J, Taussig D, Rezvani HR, Mazurier F, Bonnet D.
Cell Stem Cell. 2013 Nov 7;13(5):549-63. doi: 10.1016/j.stem.2013.08.011. Epub 2013 Oct 3.
PMID 24095676
The HIF family member EPAS1/HIF-2alpha is required for normal hematopoiesis in mice.
Scortegagna M, Morris MA, Oktay Y, Bennett M, Garcia JA.
Blood. 2003b Sep 1;102(5):1634-40. Epub 2003 May 15.
PMID 12750163
A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha.
Seidel S, Garvalov BK, Wirta V, von Stechow L, Schanzer A, Meletis K, Wolter M, Sommerlad D, Henze AT, Nister M, Reifenberger G, Lundeberg J, Frisen J, Acker T.
Brain. 2010 Apr;133(Pt 4):983-95. doi: 10.1093/brain/awq042.
PMID 20375133
Targeting HIF-1 for cancer therapy.
Semenza GL.
Nat Rev Cancer. 2003 Oct;3(10):721-32. (REVIEW)
PMID 13130303
Genetic evidence for high-altitude adaptation in Tibet.
Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon DJ, Bai Z, Lorenzo FR, Xing J, Jorde LB, Prchal JT, Ge R.
Science. 2010 Jul 2;329(5987):72-5. doi: 10.1126/science.1189406. Epub 2010 May 13.
PMID 20466884
Association of hypoxia-inducible factors 1alpha and 2alpha with activated angiogenic pathways and prognosis in patients with endometrial carcinoma.
Sivridis E, Giatromanolaki A, Gatter KC, Harris AL, Koukourakis MI; Tumor and Angiogenesis Research Group.
Cancer. 2002 Sep 1;95(5):1055-63.
PMID 12209691
The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages.
Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL.
Am J Pathol. 2000 Aug;157(2):411-21.
PMID 10934146
Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells.
Tian H, McKnight SL, Russell DW.
Genes Dev. 1997 Jan 1;11(1):72-82.
PMID 9000051
An oxygen-regulated switch in the protein synthesis machinery.
Uniacke J, Holterman CE, Lachance G, Franovic A, Jacob MD, Fabian MR, Payette J, Holcik M, Pause A, Lee S.
Nature. 2012 May 6;486(7401):126-9. doi: 10.1038/nature11055.
PMID 22678294
Hypoxia-inducible factor-2a is associated with ABCG2 expression, histology-grade and Ki67 expression in breast invasive ductal carcinoma.
Xiang L1, Liu ZH, Huan Q, Su P, Du GJ, Wang Y, Gao P, Zhou GY.
Diagn Pathol. 2012 Mar 27;7:32. doi: 10.1186/1746-1596-7-32.
PMID 22452996
Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas.
Yang C, Sun MG, Matro J, Huynh TT, Rahimpour S, Prchal JT, Lechan R, Lonser R, Pacak K, Zhuang Z.
Blood. 2013 Mar 28;121(13):2563-6. doi: 10.1182/blood-2012-10-460972. Epub 2013 Jan 29.
PMID 23361906
Sequencing of 50 human exomes reveals adaptation to high altitude.
Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZX, Pool JE, Xu X, Jiang H, Vinckenbosch N, Korneliussen TS, Zheng H, Liu T, He W, Li K, Luo R, Nie X, Wu H, Zhao M, Cao H, Zou J, Shan Y, Li S, Yang Q, Asan, Ni P, Tian G, Xu J, Liu X, Jiang T, Wu R, Zhou G, Tang M, Qin J, Wang T, Feng S, Li G, Huasang, Luosang J, Wang W, Chen F, Wang Y, Zheng X, Li Z, Bianba Z, Yang G, Wang X, Tang S, Gao G, Chen Y, Luo Z, Gusang L, Cao Z, Zhang Q, Ouyang W, Ren X, Liang H, Zheng H, Huang Y, Li J, Bolund L, Kristiansen K, Li Y, Zhang Y, Zhang X, Li R, Li S, Yang H, Nielsen R, Wang J, Wang J.
Science. 2010 Jul 2;329(5987):75-8. doi: 10.1126/science.1190371.
PMID 20595611
Prognostic impact of hypoxia-inducible factors 1alpha and 2alpha in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression.
Yoshimura H, Dhar DK, Kohno H, Kubota H, Fujii T, Ueda S, Kinugasa S, Tachibana M, Nagasue N.
Clin Cancer Res. 2004 Dec 15;10(24):8554-60.
PMID 15623639
Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia.
Zhuang Z, Yang C, Lorenzo F, Merino M, Fojo T, Kebebew E, Popovic V, Stratakis CA, Prchal JT, Pacak K.
N Engl J Med. 2012 Sep 6;367(10):922-30. doi: 10.1056/NEJMoa1205119.
PMID 22931260
Erythrocytosis associated with a novel missense mutation in the HIF2A gene.
van Wijk R, Sutherland S, Van Wesel AC, Huizinga EG, Percy MJ, Bierings M, Lee FS.
Haematologica. 2010 May;95(5):829-32. doi: 10.3324/haematol.2009.017582. Epub 2009 Dec 8.
PMID 20007141


This paper should be referenced as such :
Mohlin, S ; Hamidian, A ; Bexell, D ; Phlman, S ; Wigerup, C
EPAS1 (Endothelial PAS Domain Protein 1)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(8):550-555.
Free journal version : [ pdf ]   [ DOI ]
On line version :

External links

Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)2034
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
canSAR (ICR) (select the gene name)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Thu Oct 18 17:35:16 CEST 2018

Home   Genes   Leukemias   Solid Tumors   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us