Genomes and Genes
Gene Symbol: EPAS1
Description: endothelial PAS domain protein 1
Alias: ECYT4, HIF2A, HLF, MOP2, PASD2, bHLHe73, endothelial PAS domain-containing protein 1, EPAS-1, HIF-1-alpha-like factor, HIF-1alpha-like factor, HIF-2-alpha, HIF2-alpha, PAS domain-containing protein 2, basic-helix-loop-helix-PAS protein MOP2, class E basic helix-loop-helix protein 73, hypoxia-inducible factor 2 alpha, member of PAS protein 2
- Scheuermann T, Tomchick D, Machius M, Guo Y, Bruick R, Gardner K. Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor. Proc Natl Acad Sci U S A. 2009;106:450-5 pubmed publisher..Given the essential role of PAS domains in forming active HIF heterodimers, these results suggest a presently uncharacterized ligand-mediated mechanism for regulating HIF2 activity in endogenous and clinical settings. ..
- Pietras A, Hansford L, Johnsson A, Bridges E, Sjölund J, Gisselsson D, et al. HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells. Proc Natl Acad Sci U S A. 2009;106:16805-10 pubmed publisher..Because low differentiation is associated with poor outcome and angiogenesis is crucial for tumor growth, HIF-2alpha is an attractive target for neuroblastoma therapy. ..
- Koivunen P, Hirsilä M, Kivirikko K, Myllyharju J. The length of peptide substrates has a marked effect on hydroxylation by the hypoxia-inducible factor prolyl 4-hydroxylases. J Biol Chem. 2006;281:28712-20 pubmed..Even this value is high compared with tissue O(2) levels, indicating that HIF-P4Hs are effective oxygen sensors. ..
- Erbel P, Card P, Karakuzu O, Bruick R, Gardner K. Structural basis for PAS domain heterodimerization in the basic helix--loop--helix-PAS transcription factor hypoxia-inducible factor. Proc Natl Acad Sci U S A. 2003;100:15504-9 pubmed
- Lando D, Peet D, Whelan D, Gorman J, Whitelaw M. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science. 2002;295:858-61 pubmed..Full induction of HIF-1alpha and -2alpha, therefore, relies on the abrogation of both Pro and Asn hydroxylation, which during normoxia occur at the degradation and COOH-terminal transactivation domains, respectively. ..
- Koizume S, Ito S, Miyagi E, Hirahara F, Nakamura Y, Sakuma Y, et al. HIF2?-Sp1 interaction mediates a deacetylation-dependent FVII-gene activation under hypoxic conditions in ovarian cancer cells. Nucleic Acids Res. 2012;40:5389-401 pubmed publisher..These results suggest the presence of a stress-responsive transcription mediated by the HIF2?/Sp1/HDAC4 network and explain how CCC shed their procoagulant activity under hypoxia. ..
- Martini M, Teofili L, Cenci T, Giona F, Torti L, Rea M, et al. A novel heterozygous HIF2AM535I mutation reinforces the role of oxygen sensing pathway disturbances in the pathogenesis of familial erythrocytosis. Haematologica. 2008;93:1068-71 pubmed publisherb>HIF2A transcription factor plays a central role in the regulation of the hypoxia responding pathway in mammalian cells, by modulating erythropoiesis and angiogenesis...
- Cockman M, Masson N, Mole D, Jaakkola P, Chang G, Clifford S, et al. Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem. 2000;275:25733-41 pubmed
- Petrella B, Brinckerhoff C. PTEN suppression of YY1 induces HIF-2 activity in von-Hippel-Lindau-null renal-cell carcinoma. Cancer Biol Ther. 2009;8:1389-401 pubmed
- Petrella B, Brinckerhoff C. Tumor cell invasion of von Hippel Lindau renal cell carcinoma cells is mediated by membrane type-1 matrix metalloproteinase. Mol Cancer. 2006;5:66 pubmed..As such, MT1-MMP may represent a novel target for anti-invasion therapy for this disease. ..
- Cleven A, van Engeland M, Wouters B, De Bruine A. Stromal expression of hypoxia regulated proteins is an adverse prognostic factor in colorectal carcinomas. Cell Oncol. 2007;29:229-40 pubmed..This study suggests that tumor hypoxia may influence tumor-associated stromal cells in a way that ultimately contributes to patient prognosis. ..
- Shinojima T, Oya M, Takayanagi A, Mizuno R, Shimizu N, Murai M. Renal cancer cells lacking hypoxia inducible factor (HIF)-1alpha expression maintain vascular endothelial growth factor expression through HIF-2alpha. Carcinogenesis. 2007;28:529-36 pubmed..HIF-1alpha may therefore represent an important target molecule for RCC therapy; however, HIF-2alpha should be targeted in HIF-1alpha defective renal cancer cells. ..
- Warnecke C, Weidemann A, Volke M, Schietke R, Wu X, Knaup K, et al. The specific contribution of hypoxia-inducible factor-2alpha to hypoxic gene expression in vitro is limited and modulated by cell type-specific and exogenous factors. Exp Cell Res. 2008;314:2016-27 pubmed publisher..Thus, HIF-2alpha effects are modulated by a number of intrinsic and extrinsic factors which may be most relevant in tumour cells. ..
- Gordan J, Bertout J, Hu C, Diehl J, Simon M. HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell. 2007;11:335-47 pubmed..Enhanced c-Myc activity likely contributes to HIF-2alpha-mediated neoplastic progression following loss of the VHL tumor suppressor and influences the behavior of hypoxic tumor cells. ..
- Uchida T, Rossignol F, Matthay M, Mounier R, Couette S, Clottes E, et al. Prolonged hypoxia differentially regulates hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression in lung epithelial cells: implication of natural antisense HIF-1alpha. J Biol Chem. 2004;279:14871-8 pubmed..This trans-regulation between HIF-1alpha and HIF-2alpha during hypoxia likely conveys target gene specificity. ..
- Elvert G, Kappel A, Heidenreich R, Englmeier U, Lanz S, Acker T, et al. Cooperative interaction of hypoxia-inducible factor-2alpha (HIF-2alpha ) and Ets-1 in the transcriptional activation of vascular endothelial growth factor receptor-2 (Flk-1). J Biol Chem. 2003;278:7520-30 pubmed
- Zhuang Z, Yang C, Lorenzo F, Merino M, Fojo T, Kebebew E, et al. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med. 2012;367:922-30 pubmed publisher..Here we report two novel somatic gain-of-function mutations in the gene encoding hypoxia-inducible factor 2Î± (HIF2A) in two patients, one presenting with paraganglioma and the other with paraganglioma and somatostatinoma, both of ..
- Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii Kuriyama Y. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci U S A. 1997;94:4273-8 pubmed..The HIF1alpha-like factor (HLF) encoded by the isolated cDNA bound the hypoxia-response element (HRE) found in enhancers of genes for ..
- Thoms B, Dudek K, Lafont J, Murphy C. Hypoxia promotes the production and inhibits the destruction of human articular cartilage. Arthritis Rheum. 2013;65:1302-12 pubmed publisher..This is all the more important since it is upstream regulators such as this that need to be directly targeted for therapeutic benefit. HIF-specific hydroxylase PHD-2 may represent a relevant target for cartilage repair. ..
- Peng Y, Yang Z, Zhang H, Cui C, Qi X, Luo X, et al. Genetic variations in Tibetan populations and high-altitude adaptation at the Himalayas. Mol Biol Evol. 2011;28:1075-81 pubmed publisher..combination with the reported data, we identified strong signals of selective sweep in two hypoxia-related genes, EPAS1 and EGLN1...
- Helczynska K, Larsson A, Holmquist Mengelbier L, Bridges E, Fredlund E, Borgquist S, et al. Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer. Cancer Res. 2008;68:9212-20 pubmed publisher..At prolonged hypoxia, HIF-2alpha remained accumulated, whereas HIF-1alpha protein levels decreased, in agreement with the oxygen level and time-dependent induction of HIFs recently reported in neuroblastoma. ..
- Partch C, Gardner K. Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B. Proc Natl Acad Sci U S A. 2011;108:7739-44 pubmed publisher..Finally, mutations on ARNT PAS-B modulate coactivator selectivity and target gene induction by HIF in vivo, demonstrating a bifunctional role for transcriptional regulation by PAS domains within bHLH-PAS transcription factors. ..
- Florczyk U, Czauderna S, Stachurska A, Tertil M, Nowak W, Kozakowska M, et al. Opposite effects of HIF-1? and HIF-2? on the regulation of IL-8 expression in endothelial cells. Free Radic Biol Med. 2011;51:1882-92 pubmed publisher..However, despite stabilization of both isoforms in hypoxia the effect of HIF-1 is predominant, and downregulation of IL-8 expression in hypoxia is caused by attenuation of Nrf2 and c-Myc. ..
- Hogenesch J, Chan W, Jackiw V, Brown R, Gu Y, Pray Grant M, et al. Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway. J Biol Chem. 1997;272:8581-93 pubmed..studies, yeast two-hybrid analysis, and transient transfection experiments demonstrated that MOP1 and MOP2 dimerize with ARNT and that these complexes are transcriptionally active at defined DNA enhancer sequences in vivo...
- Sanchez M, Galy B, Muckenthaler M, Hentze M. Iron-regulatory proteins limit hypoxia-inducible factor-2alpha expression in iron deficiency. Nat Struct Mol Biol. 2007;14:420-6 pubmed..element (IRE) in the 5' untranslated region of the messenger RNA encoding endothelial PAS domain protein-1, EPAS1 (also called hypoxia-inducible factor-2alpha, HIF2alpha)...
- Tian H, McKnight S, Russell D. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 1997;11:72-82 pubmedHere we describe the cloning and characterization of a PAS domain transcription factor termed endothelial PAS-1 (EPAS1)...
- Zimmer M, Doucette D, Siddiqui N, Iliopoulos O. Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL-/- tumors. Mol Cancer Res. 2004;2:89-95 pubmed..These data suggest that deregulation of hypoxia-inducible genes in VHL-/- cells can be attributed mainly to deregulation of HIF and validate HIF as a therapeutic anticancer drug target. ..
- Bracken C, Fedele A, Linke S, Balrak W, Lisy K, Whitelaw M, et al. Cell-specific regulation of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha stabilization and transactivation in a graded oxygen environment. J Biol Chem. 2006;281:22575-85 pubmed..Interestingly, the initial stabilization of HIF-alpha prior to transactivation up-regulation predicted from in vitro derived hydroxylation data is only true for a subset of cells. ..
- Hu C, Wang L, Chodosh L, Keith B, Simon M. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol. 2003;23:9361-74 pubmed..Importantly, HIF-1alpha (and not HIF-2alpha) stimulates glycolytic gene expression in both types of cells, clearly showing for the first time that HIF-1alpha and HIF-2alpha have unique targets. ..
- Corn P, McDonald E, Herman J, El Deiry W. Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel-Lindau protein. Nat Genet. 2003;35:229-37 pubmed..Thus, the ability of pVHL to degrade Hif1 alpha depends in part on its interaction with TBP-1 and suggests a new mechanism for Hif1 alpha stabilization in some pVHL-deficient tumors. ..
- Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292:464-8 pubmed..Because proline hydroxylation requires molecular oxygen and Fe(2+), this protein modification may play a key role in mammalian oxygen sensing. ..
- van Hagen M, Overmeer R, Abolvardi S, Vertegaal A. RNF4 and VHL regulate the proteasomal degradation of SUMO-conjugated Hypoxia-Inducible Factor-2alpha. Nucleic Acids Res. 2010;38:1922-31 pubmed publisher..The ubiquitin E3 ligases von Hippel-Lindau and RNF4 control the levels of sumoylated HIF-2alpha, indicating that sumoylated HIF-2alpha is degraded via SUMO-targeted ubiquitin ligases. ..
- Block K, Gorin Y, New D, Eid A, Chelmicki T, Reed A, et al. The NADPH oxidase subunit p22phox inhibits the function of the tumor suppressor protein tuberin. Am J Pathol. 2010;176:2447-55 pubmed publisher..Our data provide the first evidence that p22(phox)-based Nox oxidases maintain HIF-2alpha protein expression through inactivation of tuberin and downstream activation of ribosomal protein S6 kinase 1/4E-BP1 pathway. ..
- Majmundar A, Wong W, Simon M. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. 2010;40:294-309 pubmed publisher..These transcription factors function in normal tissue homeostasis and impinge on critical aspects of disease progression and recovery. Insights from basic HIF biology are being translated into pharmaceuticals targeting the HIF pathway. ..
- Kondo K, Kim W, Lechpammer M, Kaelin W. Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol. 2003;1:E83 pubmed..These results establish that tumor suppression by pVHL is linked to regulation of HIF target genes. ..
- Holmquist Mengelbier L, Fredlund E, Löfstedt T, Noguera R, Navarro S, Nilsson H, et al. Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer Cell. 2006;10:413-23 pubmed..Our results demonstrate the relevance of HIF-2alpha in neuroblastoma progression and have general tumor biological implications. ..
- Yang C, Sun M, Matro J, Huynh T, Rahimpour S, Prchal J, et al. Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas. Blood. 2013;121:2563-6 pubmed publisher..Here, we report 2 additional unique HIF2A mutations, which disrupt the hydroxylation domain recognized by prolyl hydroxylase domain-2 containing protein, ..
- Chen R, Xu M, Hogg R, Li J, Little B, Gerard R, et al. The acetylase/deacetylase couple CREB-binding protein/Sirtuin 1 controls hypoxia-inducible factor 2 signaling. J Biol Chem. 2012;287:30800-11 pubmed publisher..Maximal CBP/HIF-2 signaling requires intact CBP acetyltransferase activity in both Hep3B cells as well as in mice. ..
- Aprelikova O, Chandramouli G, Wood M, Vasselli J, Riss J, Maranchie J, et al. Regulation of HIF prolyl hydroxylases by hypoxia-inducible factors. J Cell Biochem. 2004;92:491-501 pubmed..These data further advance our understanding of the differential role of HIF factors and putative feedback loop in HIF regulation. ..
- Koizume S, Yokota N, Miyagi E, Hirahara F, Tsuchiya E, Miyagi Y. Heterogeneity in binding and gene-expression regulation by HIF-2alpha. Biochem Biophys Res Commun. 2008;371:251-5 pubmed publisher..These results demonstrate that, unlike HIF-1alpha, HIF-2alpha differentially binds and regulates transcription under hypoxia. ..
- Percy M. Familial erythrocytosis arising from a gain-of-function mutation in the HIF2A gene of the oxygen sensing pathway. Ulster Med J. 2008;77:86-8 pubmed..Continued study of idiopathic cases of erythrocytosis with raised serum Epo will reveal whether HIF-2 alpha will be a major cause of erythrocytosis on par with VHL. ..
- Percy M, Zhao Q, Flores A, Harrison C, Lappin T, Maxwell P, et al. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci U S A. 2006;103:654-9 pubmed..Our findings indicate that PHD2 is critical for normal regulation of HIF in humans. ..
- Imamura T, Kikuchi H, Herraiz M, Park D, Mizukami Y, Mino Kenduson M, et al. HIF-1alpha and HIF-2alpha have divergent roles in colon cancer. Int J Cancer. 2009;124:763-71 pubmed publisher..In particular, HIF-1alpha promoted the growth of SW480 colon cancer cells but HIF-2alpha appeared to restrain growth. Consequently, therapeutic approaches that target HIF may need to consider these isoform-specific properties. ..
- Percy M, Beer P, Campbell G, Dekker A, Green A, Oscier D, et al. Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis. Blood. 2008;111:5400-2 pubmed publisher..This raises the possibility of HIF2A mutations being associated with other cases of erythrocytosis...
- Appelhoff R, Tian Y, Raval R, Turley H, Harris A, Pugh C, et al. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem. 2004;279:38458-65 pubmed
- Takeda N, Maemura K, Imai Y, Harada T, Kawanami D, Nojiri T, et al. Endothelial PAS domain protein 1 gene promotes angiogenesis through the transactivation of both vascular endothelial growth factor and its receptor, Flt-1. Circ Res. 2004;95:146-53 pubmedEndothelial PAS domain protein 1 (EPAS1) is a basic-helix-loop-helix/PAS domain transcription factor that is expressed preferentially in vascular endothelial cells...
- Mowat F, Luhmann U, Smith A, Lange C, Duran Y, Harten S, et al. HIF-1alpha and HIF-2alpha are differentially activated in distinct cell populations in retinal ischaemia. PLoS ONE. 2010;5:e11103 pubmed publisher..Our findings suggest that HIF-2alpha activation plays a key role in regulating the response of MÃ¼ller glia to hypoxia. ..
- Maxwell P, Wiesener M, Chang G, Clifford S, Vaux E, Cockman M, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399:271-5 pubmed..Thus, constitutive HIF-1 activation may underlie the angiogenic phenotype of VHL-associated tumours. The pVHL/HIF-1 interaction provides a new focus for understanding cellular oxygen sensing. ..
- Bracken C, Whitelaw M, Peet D. Activity of hypoxia-inducible factor 2alpha is regulated by association with the NF-kappaB essential modulator. J Biol Chem. 2005;280:14240-51 pubmed
- Rasheed S, Harris A, Tekkis P, Turley H, Silver A, McDonald P, et al. Hypoxia-inducible factor-1alpha and -2alpha are expressed in most rectal cancers but only hypoxia-inducible factor-1alpha is associated with prognosis. Br J Cancer. 2009;100:1666-73 pubmed publisher..Our results indicate that HIF-1alpha, but not HIF-2alpha, might be used as a marker of prognosis, in addition to methods currently used, to enhance patient management. ..
- Dioum E, Chen R, Alexander M, Zhang Q, Hogg R, Gerard R, et al. Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1. Science. 2009;324:1289-93 pubmed publisher..Thus, Sirt1 promotes HIF-2 signaling during hypoxia and likely other environmental stresses. ..
- Henderson J, Withford Cave J, Duffy D, Cole S, Sawyer N, Gulbin J, et al. The EPAS1 gene influences the aerobic-anaerobic contribution in elite endurance athletes. Hum Genet. 2005;118:416-23 pubmedb>EPAS1 is a gene involved in complex oxygen sensing. It is expressed in microvascular endothelial cells, lung epithelial cells, cardiac myocytes and the brain...
- Bertout J, Majmundar A, Gordan J, Lam J, Ditsworth D, Keith B, et al. HIF2alpha inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. Proc Natl Acad Sci U S A. 2009;106:14391-6 pubmed publisher..These results correlate with altered p53 phosphorylation and target gene expression in untreated human tumor samples and show that HIF2alpha likely contributes to tumor cell survival including during radiation therapy. ..
- Tuckerman J, Zhao Y, Hewitson K, Tian Y, Pugh C, Ratcliffe P, et al. Determination and comparison of specific activity of the HIF-prolyl hydroxylases. FEBS Lett. 2004;576:145-50 pubmed
- Yi X, Liang Y, Huerta Sanchez E, Jin X, Cuo Z, Pool J, et al. Sequencing of 50 human exomes reveals adaptation to high altitude. Science. 2010;329:75-8 pubmed publisher..The strongest signal of natural selection came from endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1), a transcription factor involved in response to hypoxia...
- Morris M, Hughes D, Tian Y, Ricketts C, Lau K, Gentle D, et al. Mutation analysis of hypoxia-inducible factors HIF1A and HIF2A in renal cell carcinoma. Anticancer Res. 2009;29:4337-43 pubmed