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Homo sapiens
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Homo sapiens
Mus musculus
Mus musculus
Homo sapiens
Mus musculus
Transcription Factor Encyclopedia  BETA
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No annotation is available in this section for this article. The content below is taken from a related TF, EPAS1 (Homo sapiens).

EPAS1 is a hypoxia-responsive transcription factor of the basic Helix-Loop-Helix/Per-Arnt-Sim homology (bHLH/PAS) family[1]. It is commonly referred to in the literature as the Hypoxia Inducible Factor-2α (HIF-2α), but is also known as HIF-1α-like Factor (HLF)[2] or HIF-Related Factor (HRF)[3]. HIF-2α dimerises with constitutive bHLH/PAS partner ARNT (also known as HIF-1β) to form the Hypoxia Inducible Factor (HIF-2), which binds directly to DNA and enhances transcription of target genes.

HIF-2α has two known mammalian paralogs: the more extensively studied HIF-1α, and the less well understood HIF-3α. Both HIF-1α and -2α undergo similar post-translational regulation at the level of protein stability and transactivation in response to changes in oxygen concentration (Figure 1), and bind DNA with similar specificity. Together, HIF-1α and -2α are the major mediators of the transcriptional response to physiological hypoxia.

In normoxic conditions, HIF-2α is rapidly degraded following ubiquitination by the von Hippel Lindau protein, part of an E3 ubiquitin ligase complex (pVHL)[4][5]. Recognition by pVHL is facilitated by two sites of prolyl hydroxylation within the central HIF-α Oxygen Dependent Degradation domain (ODDD) by one of the three HIF Prolyl-4 Hydroxylases (PHD1, PHD2, PHD3)[6][7], with PHD1 and PHD3 having a preference for regulating HIF-2α[8]. In addition, interaction with coactivators such as CBP and p300 is inhibited in normoxia. This is caused by a single asparaginyl hydroxylation within the C-terminal Transactivation Domain of HIF-2α by the oxygen-dependent asparaginyl hydroxylase Factor Inhibiting HIF (FIH-1)[9][10]. As these hydroxylation reactions require O2[11], in hypoxic (or oxygen-limiting) conditions hydroxylation is reduced, , enabling HIF-2α to avoid ubiquitylation and degradation, and bind efficiently to coactivators, resulting in robust target gene induction. The HIF-α proteins can also be activated independent of hypoxia by growth hormones and other cellular signals[12].

Although HIF-2α has an overlapping cellular role with HIF-1α, it is not redundant. Mouse HIF-2α knockout models exhibit developmental phenotypes including disrupted catecholamine release [13], vascular remodelling[14], haematopoiesis[15], response to oxidative stress [16], iron absorption [17] and lipid metabolism [18], while substitution of the HIF-1α gene for HIF-2α in mice results in a more severe phenotype than HIF-1α loss alone[19]. Furthermore, dysregulation of HIF-2α has been implicated in cancer, and can be more oncogenic than HIF-1α dysregulation;[20]. However, the specific physiological roles for HIF-2α are not well understood, with minimal knowledge of specific target genes and their physiological regulation. Both factors have distinct expression patterns, with HIF-2α displaying a more discrete expression pattern with high levels in the placenta, heart, lung and endothelial cells compared with the ubiquitous HIF-1α [1][2][3].

Drosophila melanogaster has one gene, Sima, which displays homology to both mammalian HIF-1α and HIF-2α genes[21]. It encodes a protein which has similar hypoxia-regulated function to the mammalian HIF-α proteins.

  1. Tian H et al. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev., 11(1):72-82. (PMID 9000051)
  2. Ema M et al. 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., 94(9):4273-8. (PMID 9113979)
  3. Flamme I et al. 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., 63(1):51-60. (PMID 9178256)
  4. Maxwell PH et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature, 399(6733):271-5. (PMID 10353251)
  5. Cockman ME et al. Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J. Biol. Chem., 275(33):25733-41. (PMID 10823831)
  6. Jaakkola P et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science, 292(5516):468-72. (PMID 11292861)
  7. Hirsilä M et al. Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J. Biol. Chem., 278(33):30772-80. (PMID 12788921)
  8. Appelhoff RJ et al. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J. Biol. Chem., 279(37):38458-65. (PMID 15247232)
  9. Lando D et al. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science, 295(5556):858-61. (PMID 11823643)
  10. Lando D et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev., 16(12):1466-71. (PMID 12080085)
  11. McNeill LA et al. The use of dioxygen by HIF prolyl hydroxylase (PHD1). Bioorg. Med. Chem. Lett., 12(12):1547-50. (PMID 12039559)
  1. Bilton RL and Booker GW. The subtle side to hypoxia inducible factor (HIFalpha) regulation. Eur. J. Biochem., 270(5):791-8. (PMID 12603312)
  2. Tian H et al. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev., 12(21):3320-4. (PMID 9808618)
  3. Peng J et al. The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling. Proc. Natl. Acad. Sci. U.S.A., 97(15):8386-91. (PMID 10880563)
  4. Scortegagna M et al. The HIF family member EPAS1/HIF-2alpha is required for normal hematopoiesis in mice. Blood, 102(5):1634-40. (PMID 12750163)
  5. Scortegagna M et al. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice. Nat. Genet., 35(4):331-40. (PMID 14608355)
  6. Mastrogiannaki M et al. HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J. Clin. Invest., 119(5):1159-66. (PMID 19352007)
  7. Rankin EB et al. Hypoxia-inducible factor 2 regulates hepatic lipid metabolism. Mol. Cell. Biol., 29(16):4527-38. (PMID 19528226)
  8. Covello KL et al. HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev., 20(5):557-70. (PMID 16510872)
  9. Covello KL et al. Targeted replacement of hypoxia-inducible factor-1alpha by a hypoxia-inducible factor-2alpha knock-in allele promotes tumor growth. Cancer Res., 65(6):2277-86. (PMID 15781641)
  10. Gorr TA et al. Regulation of Drosophila hypoxia-inducible factor (HIF) activity in SL2 cells: identification of a hypoxia-induced variant isoform of the HIFalpha homolog gene similar. J. Biol. Chem., 279(34):36048-58. (PMID 15169765)
No annotation is available in this section for this article. The content below is taken from a related TF, EPAS1 (Homo sapiens).
FIGURE 1 Normoxic and Hypoxic Regulation of HIF-α Subunits
Depiction of the regulation of HIF-α subunits by oxygen levels. Normoxia results in hydroxylation of HIF-α, allowing for ubiquitination by pVHL and proteasomal degradation, while preventing interaction with CBP/p300 coactivators. Hypoxic conditions prevent hydroxylase activity, allowing HIF-α to be stabilised and to bind coactivators at enhancers.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.