Genomes and Genes
Gene Symbol: Epas1
Description: endothelial PAS domain protein 1
Alias: HIF-2alpha, HIF2A, HLF, HRF, MOP2, bHLHe73, endothelial PAS domain-containing protein 1, EPAS-1, HIF-1-alpha-like factor, HIF-2-alpha, HIF-related factor, HIF1 alpha-like factor, HIF1alpha-like factor, HIF2-alpha, HLF (HIF1alpha-like factor), Hif like protein, hypoxia inducible transcription factor 2alpha, hypoxia-inducible factor 2-alpha, mHLF
- Weidemann A, Krohne T, Aguilar E, Kurihara T, Takeda N, Dorrell M, et al. Astrocyte hypoxic response is essential for pathological but not developmental angiogenesis of the retina. Glia. 2010;58:1177-85 pubmed publisher..Thus, we demonstrate that astrocytes in the retina have highly divergent roles during developmental, physiological angiogenesis, and ischemia-driven, pathological neovascularization. ..
- Bhatt A, Amin S, Chess P, Watkins R, Maniscalco W. Expression of vascular endothelial growth factor and Flk-1 in developing and glucocorticoid-treated mouse lung. Pediatr Res. 2000;47:606-13 pubmed..b>HLF (hypoxia-inducible factor-like factor) is a transcription factor that increases VEGF gene transcription...
- Flamme I, Frohlich T, von Reutern M, Kappel A, Damert A, Risau W. HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1 alpha and developmentally expressed in blood vessels. Mech Dev. 1997;63:51-60 pubmed..In the present study we describe mRNA cloning and mRNA expression pattern of mouse HIF-related factor (HRF), a novel close relative of HIF-1 alpha which is expressed most prominently in brain capillary endothelial cells ..
- Kapitsinou P, Liu Q, Unger T, Rha J, Davidoff O, Keith B, et al. Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia. Blood. 2010;116:3039-48 pubmed publisher..Furthermore, we provide evidence that hepatocyte-derived Hif-2 is involved in the regulation of iron metabolism genes, supporting a role for HIF-2 in the coordination of EPO synthesis with iron homeostasis. ..
- Hu C, Sataur A, Wang L, Chen H, Simon M. The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1alpha and HIF-2alpha. Mol Biol Cell. 2007;18:4528-42 pubmed..These results demonstrate that the HIF-alpha TADs, particularly the N-TADs, confer HIF target gene specificity, by interacting with additional transcriptional cofactors. ..
- Peng J, Zhang L, Drysdale L, Fong G. The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling. Proc Natl Acad Sci U S A. 2000;97:8386-91 pubmed..Our results suggest that EPAS-1 plays an important role at postvasculogenesis stages and is required for the remodeling of the primary vascular network into a mature hierarchy pattern. ..
- Tian H, Hammer R, Matsumoto A, Russell D, McKnight S. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev. 1998;12:3320-4 pubmedMice lacking the hypoxia-inducible transcription factor EPAS1 die at mid-gestation. Despite normal morphological development of the circulatory system, EPAS1-deficient mice display pronounced bradycardia...
- Yeo E, Cho Y, Kim M, Park J. Contribution of HIF-1alpha or HIF-2alpha to erythropoietin expression: in vivo evidence based on chromatin immunoprecipitation. Ann Hematol. 2008;87:11-7 pubmed..Thus, HIF-1alpha and HIF-2alpha appear to contribute to EPO expression tissue specifically. ..
- Imtiyaz H, Williams E, Hickey M, Patel S, Durham A, Yuan L, et al. Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest. 2010;120:2699-714 pubmed publisher..Collectively, our data identify HIF-2alpha as an important regulator of innate immunity, suggesting it may be a useful therapeutic target for treating inflammatory disorders and cancer. ..
- Yang S, Kim J, Ryu J, Oh H, Chun C, Kim B, et al. Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction. Nat Med. 2010;16:687-93 pubmed publisher..Here, we show that hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) is a catabolic transcription factor in the osteoarthritic process...
- Compernolle V, Brusselmans K, Acker T, Hoet P, Tjwa M, Beck H, et al. Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med. 2002;8:702-10 pubmed..The pneumotrophic effect of VEGF may have therapeutic potential for lung maturation in preterm infants. ..
- Scortegagna M, Ding K, Zhang Q, Oktay Y, Bennett M, Bennett M, et al. HIF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner. Blood. 2005;105:3133-40 pubmed..We previously reported that mice lacking wild-type HIF-2alpha, encoded by the EPAS1 gene, exhibit pancytopenia. In this study, we have characterized the etiology of this hematopoietic phenotype...
- Wagner K, Hellberg A, Balenger S, Depping R, Dodd O J, Johns R, et al. Hypoxia-induced mitogenic factor has antiapoptotic action and is upregulated in the developing lung: coexpression with hypoxia-inducible factor-2alpha. Am J Respir Cell Mol Biol. 2004;31:276-82 pubmed..These results indicate a role for HIMF in lung development, possibly under the control of HIF-2, and suggest that HIMF regulates apoptosis and may participate in lung alveolarization and maturation. ..
- Scortegagna M, Ding K, Oktay Y, Gaur A, Thurmond F, Yan L, et al. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice. Nat Genet. 2003;35:331-40 pubmed..We report that mice lacking the HIF family member HIF-2alpha (encoded by Epas1) have a syndrome of multiple-organ pathology, biochemical abnormalities and altered gene expression patterns...
- Weidemann A, Kerdiles Y, Knaup K, Rafie C, Boutin A, Stockmann C, et al. The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice. J Clin Invest. 2009;119:3373-83 pubmed publisher..Thus, we have demonstrated that the glial component of the CNS is an essential component of hypoxia-induced erythropoiesis. ..
- Scortegagna M, Morris M, Oktay Y, Bennett M, Garcia J. The HIF family member EPAS1/HIF-2alpha is required for normal hematopoiesis in mice. Blood. 2003;102:1634-40 pubmed..After generating adult mice that globally lack endothelial PAS domain protein 1 (EPAS1, also known as HIF-2alpha/HRF/HLF/MOP3), the second member of the HIF family, characterization of the ..
- Ryu J, Shin Y, Huh Y, Yang S, Chun C, Chun J. Hypoxia-inducible factor-2? regulates Fas-mediated chondrocyte apoptosis during osteoarthritic cartilage destruction. Cell Death Differ. 2012;19:440-50 pubmed publisher..Recently, we demonstrated that hypoxia-inducible factor (HIF)-2?, encoded by Epas1, causes OA cartilage destruction by regulating the expression of various matrix-degrading enzymes...
- Rankin E, Rha J, Unger T, Wu C, Shutt H, Johnson R, et al. Hypoxia-inducible factor-2 regulates vascular tumorigenesis in mice. Oncogene. 2008;27:5354-8 pubmed publisher..These findings suggest that HIF-2 is the dominant HIF in the pathogenesis of VHL-associated vascular tumors and that pharmacologic targeting of HIF-2 may be an effective strategy for their treatment. ..
- Yamashita T, Ohneda O, Nagano M, Iemitsu M, Makino Y, Tanaka H, et al. Abnormal heart development and lung remodeling in mice lacking the hypoxia-inducible factor-related basic helix-loop-helix PAS protein NEPAS. Mol Cell Biol. 2008;28:1285-97 pubmed
- Lando D, Peet D, Gorman J, Whelan D, Whitelaw M, Bruick R. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 2002;16:1466-71 pubmed..Together with the recently discovered prolyl hydroxylases that regulate HIF stability, this class of oxygen-dependent enzymes comprises critical regulatory components of the hypoxic response pathway. ..
- Cowden Dahl K, Fryer B, Mack F, Compernolle V, Maltepe E, Adelman D, et al. Hypoxia-inducible factors 1alpha and 2alpha regulate trophoblast differentiation. Mol Cell Biol. 2005;25:10479-91 pubmed..This novel genetic approach provides new insights into the role of O2 tension in the development of life-threatening pregnancy-related diseases such as preeclampsia. ..
- Rankin E, Rha J, Selak M, Unger T, Keith B, Liu Q, et al. Hypoxia-inducible factor 2 regulates hepatic lipid metabolism. Mol Cell Biol. 2009;29:4527-38 pubmed publisher..These findings demonstrate that HIF-2 functions as an important regulator of hepatic lipid metabolism and identify HIF-2 as a potential target for the treatment of fatty liver disease. ..
- Morita M, Ohneda O, Yamashita T, Takahashi S, Suzuki N, Nakajima O, et al. HLF/HIF-2alpha is a key factor in retinopathy of prematurity in association with erythropoietin. EMBO J. 2003;22:1134-46 pubmedAn HLF (HIF-1alpha-like factor)/HIF-2alpha-knockout mouse is embryonic lethal, preventing investigation of HLF function in adult mice...
- Huang Y, Kempen M, Munck A, Swagemakers S, Driegen S, Mahavadi P, et al. Hypoxia-inducible factor 2? plays a critical role in the formation of alveoli and surfactant. Am J Respir Cell Mol Biol. 2012;46:224-32 pubmed publisher..We conclude that Hif2? is a key regulator in alveolar maturation and the production of phospholipids by Type II cells. ..
- Hill P, Shukla D, Tran M, Aragones J, Cook H, Carmeliet P, et al. Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury. J Am Soc Nephrol. 2008;19:39-46 pubmed publisher..To determine whether HIF may protect the kidney from ischemia-reperfusion injury, we subjected hif1a(+/-) and hif2a(+/-) mice to renal ischemia-reperfusion injury...
- Hu C, Iyer S, Sataur A, Covello K, Chodosh L, Simon M. Differential regulation of the transcriptional activities of hypoxia-inducible factor 1 alpha (HIF-1alpha) and HIF-2alpha in stem cells. Mol Cell Biol. 2006;26:3514-26 pubmed..HIF-2alpha repression may explain why patients with mutations in the VHL tumor suppressor gene display cancerous lesions in specific tissue types. ..
- Yan Q, Bartz S, Mao M, Li L, Kaelin W. The hypoxia-inducible factor 2alpha N-terminal and C-terminal transactivation domains cooperate to promote renal tumorigenesis in vivo. Mol Cell Biol. 2007;27:2092-102 pubmed
- Dioum E, Clarke S, Ding K, Repa J, Garcia J. HIF-2alpha-haploinsufficient mice have blunted retinal neovascularization due to impaired expression of a proangiogenic gene battery. Invest Ophthalmol Vis Sci. 2008;49:2714-20 pubmed publisher..Retinal samples were obtained from HIF-2alpha-haploinsufficient (Epas1+/-) and wild-type (Epas1+/+) neonatal mice subjected to an oxygen-induced retinopathy (OIR) protocol...
- Bridges J, Lin S, Ikegami M, Shannon J. Conditional hypoxia inducible factor-1? induction in embryonic pulmonary epithelium impairs maturation and augments lymphangiogenesis. Dev Biol. 2012;362:24-41 pubmed publisherHypoxia inducible factor (HIF) 1a, EPAS1 and NEPAS are expressed in the embryonic mouse lung and each isoform exhibits distinct spatiotemporal expression patterns throughout morphogenesis...
- Hickey M, Lam J, Bezman N, Rathmell W, Simon M. von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis. J Clin Invest. 2007;117:3879-89 pubmed..This mouse model is a faithful recapitulation of this VHL-associated syndrome and represents a useful tool for studying polycythemias and investigating potential therapeutics. ..
- Gruber M, Hu C, Johnson R, Brown E, Keith B, Simon M. Acute postnatal ablation of Hif-2alpha results in anemia. Proc Natl Acad Sci U S A. 2007;104:2301-6 pubmed
- Brusselmans K, Compernolle V, Tjwa M, Wiesener M, Maxwell P, Collen D, et al. Heterozygous deficiency of hypoxia-inducible factor-2alpha protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. J Clin Invest. 2003;111:1519-27 pubmed
- Kim J, Evans C, Weidemann A, Takeda N, Lee Y, Stockmann C, et al. Loss of fibroblast HIF-1Î± accelerates tumorigenesis. Cancer Res. 2012;72:3187-95 pubmed publisher..Together, our findings indicate that the fibroblast HIF-1Î± response is a critical component of tumor vascularization. ..
- 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. ..
- Doedens A, Phan A, Stradner M, Fujimoto J, Nguyen J, Yang E, et al. Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat Immunol. 2013;14:1173-82 pubmed publisher..We found that HIFs and oxygen influenced the expression of pivotal transcription, effector and costimulatory-inhibitory molecules of CTLs, which was relevant to strategies that promote the clearance of viruses and tumors. ..
- Aragones J, Schneider M, van Geyte K, Fraisl P, Dresselaers T, Mazzone M, et al. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet. 2008;40:170-80 pubmed publisher..These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress. ..
- Branco Price C, Zhang N, Schnelle M, Evans C, Katschinski D, Liao D, et al. Endothelial cell HIF-1Î± and HIF-2Î± differentially regulate metastatic success. Cancer Cell. 2012;21:52-65 pubmed publisher..These opposing roles for the two HIF factors indicate that both they and endothelial cells regulate metastasis as malignancy progresses. ..
- Yamashita T, Ohneda K, Nagano M, Miyoshi C, Kaneko N, Miwa Y, et al. Hypoxia-inducible transcription factor-2alpha in endothelial cells regulates tumor neovascularization through activation of ephrin A1. J Biol Chem. 2008;283:18926-36 pubmed publisher..We conclude that in ECs, HIF-2alpha plays an essential role in vascular remodeling during tumor vascularization through activation of at least ephrin A1. ..
- Cowden Dahl K, Robertson S, Weaver V, Simon M. Hypoxia-inducible factor regulates alphavbeta3 integrin cell surface expression. Mol Biol Cell. 2005;16:1901-12 pubmed..Together, these data suggest that HIF and O(2) tension influence placental invasion and tumor migration by increasing cell surface expression of alphavbeta3 integrin. ..
- 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. ..
- 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
- 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 ..
- Kurihara T, Kubota Y, Ozawa Y, Takubo K, Noda K, Simon M, et al. von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina. Development. 2010;137:1563-71 pubmed publisher..Our results suggest that not only macrophages but also tissue oxygen-sensing mechanisms regulate the transition from the fetal to the adult circulatory system in the retina. ..
- 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. ..
- Taylor M, Qu A, Anderson E, Matsubara T, Martin A, Gonzalez F, et al. Hypoxia-inducible factor-2? mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice. Gastroenterology. 2011;140:2044-55 pubmed publisher..Therapies that target FPN might be developed for patients with iron-related disorders. ..
- Torii S, Goto Y, Ishizawa T, Hoshi H, Goryo K, Yasumoto K, et al. Pro-apoptotic activity of inhibitory PAS domain protein (IPAS), a negative regulator of HIF-1, through binding to pro-survival Bcl-2 family proteins. Cell Death Differ. 2011;18:1711-25 pubmed publisher..IPAS contributed to dysfunction of Bcl-x(L) by inhibiting the interaction of Bcl-x(L) with Bax. These results demonstrate that IPAS functions as a dual function protein involved in transcription repression and apoptosis. ..
- Covello K, Kehler J, Yu H, Gordan J, Arsham A, Hu C, et al. HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev. 2006;20:557-70 pubmed
- Skuli N, Majmundar A, Krock B, Mesquita R, Mathew L, Quinn Z, et al. Endothelial HIF-2? regulates murine pathological angiogenesis and revascularization processes. J Clin Invest. 2012;122:1427-43 pubmed publisher..Using mice in which Hif2a was specifically deleted in ECs, we demonstrate here that HIF-2? expression is required for angiogenic responses ..
- Anderson S, Nizzi C, Chang Y, Deck K, Schmidt P, Galy B, et al. The IRP1-HIF-2? axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption. Cell Metab. 2013;17:282-90 pubmed publisher..These results uncover separable physiological roles of each IRP and identify IRP1 as a therapeutic target for manipulating HIF-2? action in hematologic, oncologic, and other disorders...
- Hackenbeck T, Knaup K, Schietke R, Schödel J, Willam C, Wu X, et al. HIF-1 or HIF-2 induction is sufficient to achieve cell cycle arrest in NIH3T3 mouse fibroblasts independent from hypoxia. Cell Cycle. 2009;8:1386-95 pubmed..Importantly, recent approaches to stabilize HIFalpha in normoxia could have deleterious effects on proliferating tissues. ..
- 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)...
- Kurihara T, Westenskow P, Bravo S, Aguilar E, Friedlander M. Targeted deletion of Vegfa in adult mice induces vision loss. J Clin Invest. 2012;122:4213-7 pubmed publisher..Targeting factors upstream of VEGF, such as HIFs, may be therapeutically advantageous compared with more potent and selective VEGF antagonists, which may have more off-target inhibitory trophic effects. ..